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976617b188abf08f9cffadf2ef54c1fc1a5f62e2	nice	Non-rigid stabilisation techniques for the treatment of low back pain	Non-rigid stabilisation techniques for the treatment of low back pain # Guidance This document replaces previous guidance on non-rigid stabilisation procedures for the treatment of low back pain (interventional procedure guidance 183). Current evidence on the efficacy of non-rigid stabilisation techniques for the treatment of low back pain shows that these procedures are efficacious for a proportion of patients with intractable back pain. There are no major safety concerns. Therefore these procedures may be used provided that normal arrangements are in place for clinical governance, consent and audit. Patient selection should be carried out by specialist spinal surgeons who are able to offer patients a range of surgical treatment options.# The procedure # Indications and current treatments Chronic low back pain commonly may result from minor abnormalities of spinal movement as a result of degenerative change affecting intervertebral discs and/or spinal facet joints. Conservative treatments include advice and education, posture and exercise training, manual therapies, analgesics, non-steroidal anti-inflammatory drugs and acupuncture. For patients with severe, life-limiting chronic low back pain that is refractory to conservative interventions, surgery may be appropriate, such as spinal fusion procedures or insertion of prosthetic intervertebral discs. # Outline of the procedure Non-rigid (flexible, dynamic) lumbar spine stabilisation involves insertion of implants aiming to support and partially restrict spinal segment movement, and minimise abnormal loading in adjacent segments. With the patient under general or epidural anaesthesia, a posterior approach via a midline incision or minimal access techniques is used. Adjacent vertebrae across one or more segments are linked by a non-rigid connector system (usually pedicle screws and an artificial ligament or flexible rod) to restrict painful intervertebral movements. Adjunct laminectomy and/or discectomy may be done where appropriate. Various devices can be used for this procedure. Sections 2.3 and 2.4 describe efficacy and safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview. # Efficacy A non-randomised comparative study of 218 patients treated by posterior lumbar interbody fusion (n = 78), posterolateral fusion (n = 75) or Graf ligamentoplasty (n = 65) reported that additional surgery for adjacent-level segment disease was reported in 6 patients, 5 patients and 1 patient respectively at 37- to 45-month follow-up (no significant difference reported between groups). A non-randomised comparative study of 45 patients (18 non-rigid stabilisation vs 27 fusion) reported that additional surgery was required for adjacent-level disc lesion, disc herniation or spinal stenosis in 1 patient in the non-rigid stabilisation group and 5 patients in the fusion group at mean follow-ups of 71 and 75 months respectively (significance not stated). A case series of 101 patients reported that 15% (15/101) of patients required a total of 18 further procedures by 1-year follow-up, of which 10 were revision surgery (including decompression, extension of segmental fixation or removal of a synovial facet cyst) for increased back pain, radiculopathy or increased instability. The non-randomised comparative study of 45 patients (18 non-rigid stabilisation vs 27 fusion) reported adjacent-segment disc deterioration at the L2–L3 level confirmed by X-ray in 7% and 36% of patients at mean follow-ups of 71 months and 75 months respectively (p < 0.05). A non-randomised comparative study of 26 patients treated by dynamic stabilisation (n = 11) or rigid stabilisation (n = 15) reported changes from baseline in mean lumbar spine range of motion of 14.4° to 18.3° and 23.6° to 12.7° respectively at 6-week follow-up (p = 0.05, p = 0.02 respectively). A non-randomised comparative study of 103 patients treated by non-rigid stabilisation (n = 46) or rigid stabilisation (n = 57) reported reductions in pre-operative back pain (measured on a visual analogue scale from 0 to 10; higher score indicates greater pain) from 7.3 to 1.4 and from 7.4 to 2.1 respectively (mean follow-ups of 9.3 and 10.6 months respectively) (p = not significant). The non-randomised comparative study of 103 patients reported improvement in disability (measured on the Oswestry Disability Index scale 0–100%; higher scores indicate greater disability) from 35.2 pre-operatively to 12.1 at a mean follow-up of 9.3 months in the non-rigid stabilisation group and from 37.8 pre-operatively to 13.6 at a mean follow-up of 10.6 months in the rigid stabilisation group (significance not stated). The case series of 101 patients reported a significant decrease in mean leg pain (measured on a VAS from 0 to 100) from 80.3 at baseline to 25.6 at 1-year follow-up (p < 0.01). The Specialist Advisers listed key efficacy outcomes as relief of pain, ODI, return to work, patient satisfaction and quality of life, and low rates of adjacent segment disease and revision. # Safety Dural tears were reported in 12% (12/101) of patients in a case series. Eleven of the tears were repaired intraoperatively, of which 1 continued to leak and required subsequent surgical closure. The non-randomised comparative study of 103 patients (46 non-rigid stabilisation vs 57 rigid stabilisation) reported screw fracture in 1 patient in the non-rigid stabilisation group at 3 months. The case series of 101 patients reported 1 patient in whom the vertebral pedicle fractured during screw insertion. The pedicle screw was not placed and a hemilaminectomy was done. The case series of 83 patients reported 2 patients with screw misplacement (1 patient required revisional surgery) and 7 cases of screw loosening (confirmed by X-ray). The Specialist Advisers considered theoretical adverse events to include paralysis, vessel or visceral injury, increase in lordosis, nerve root entrapment, screw malpositioning leading to sciatica or nerve damage, weakness and numbness, screw breakage leading to construct failure, and infection.# Further information For related NICE guidance see our website. # Information for patients NICE has produced information on this procedure for patients and carers ('Understanding NICE guidance'). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.# About this guidance NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland. This guidance was developed using the NICE interventional procedure guidance process. It updates and replaces NICE interventional procedure guidance 183. We have produced a summary of this guidance for patients and carers. Information about the evidence it is based on is also available. Changes since publication January 2012: minor maintenance. Your responsibility This guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer. Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties. Copyright © National Institute for Health and Clinical Excellence 2010. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE. Contact NICE National Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT www.nice.org.uk nice@nice.org.uk	{'Guidance': 'This document replaces previous guidance on non-rigid stabilisation procedures for the treatment of low back pain (interventional procedure guidance 183).\n\n\n\nCurrent evidence on the efficacy of non-rigid stabilisation techniques for the treatment of low back pain shows that these procedures are efficacious for a proportion of patients with intractable back pain. There are no major safety concerns. Therefore these procedures may be used provided that normal arrangements are in place for clinical governance, consent and audit.\n\nPatient selection should be carried out by specialist spinal surgeons who are able to offer patients a range of surgical treatment options.', 'The procedure': '# Indications and current treatments\n\nChronic low back pain commonly may result from minor abnormalities of spinal movement as a result of degenerative change affecting intervertebral discs and/or spinal facet joints.\n\nConservative treatments include advice and education, posture and exercise training, manual therapies, analgesics, non-steroidal anti-inflammatory drugs and acupuncture. For patients with severe, life-limiting chronic low back pain that is refractory to conservative interventions, surgery may be appropriate, such as spinal fusion procedures or insertion of prosthetic intervertebral discs.\n\n# Outline of the procedure\n\nNon-rigid (flexible, dynamic) lumbar spine stabilisation involves insertion of implants aiming to support and partially restrict spinal segment movement, and minimise abnormal loading in adjacent segments.\n\nWith the patient under general or epidural anaesthesia, a posterior approach via a midline incision or minimal access techniques is used. Adjacent vertebrae across one or more segments are linked by a non-rigid connector system (usually pedicle screws and an artificial ligament or flexible rod) to restrict painful intervertebral movements.\n\nAdjunct laminectomy and/or discectomy may be done where appropriate.\n\nVarious devices can be used for this procedure.\n\nSections 2.3 and 2.4 describe efficacy and safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview.\n\n# Efficacy\n\nA non-randomised comparative study of 218 patients treated by posterior lumbar interbody fusion (n = 78), posterolateral fusion (n = 75) or Graf ligamentoplasty (n = 65) reported that additional surgery for adjacent-level segment disease was reported in 6 patients, 5 patients and 1 patient respectively at 37- to 45-month follow-up (no significant difference reported between groups).\n\nA non-randomised comparative study of 45 patients (18 non-rigid stabilisation vs 27 fusion) reported that additional surgery was required for adjacent-level disc lesion, disc herniation or spinal stenosis in 1 patient in the non-rigid stabilisation group and 5 patients in the fusion group at mean follow-ups of 71 and 75 months respectively (significance not stated).\n\nA case series of 101 patients reported that 15% (15/101) of patients required a total of 18 further procedures by 1-year follow-up, of which 10 were revision surgery (including decompression, extension of segmental fixation or removal of a synovial facet cyst) for increased back pain, radiculopathy or increased instability.\n\nThe non-randomised comparative study of 45 patients (18 non-rigid stabilisation vs 27 fusion) reported adjacent-segment disc deterioration at the L2–L3 level confirmed by X-ray in 7% and 36% of patients at mean follow-ups of 71 months and 75 months respectively (p < 0.05).\n\nA non-randomised comparative study of 26 patients treated by dynamic stabilisation (n = 11) or rigid stabilisation (n = 15) reported changes from baseline in mean lumbar spine range of motion of 14.4° to 18.3° and 23.6° to 12.7° respectively at 6-week follow-up (p = 0.05, p = 0.02 respectively).\n\nA non-randomised comparative study of 103 patients treated by non-rigid stabilisation (n = 46) or rigid stabilisation (n = 57) reported reductions in pre-operative back pain (measured on a visual analogue scale [VAS] from 0 to 10; higher score indicates greater pain) from 7.3 to 1.4 and from 7.4 to 2.1 respectively (mean follow-ups of 9.3 and 10.6 months respectively) (p = not significant).\n\nThe non-randomised comparative study of 103 patients reported improvement in disability (measured on the Oswestry Disability Index [ODI] scale 0–100%; higher scores indicate greater disability) from 35.2 pre-operatively to 12.1 at a mean follow-up of 9.3 months in the non-rigid stabilisation group and from 37.8 pre-operatively to 13.6 at a mean follow-up of 10.6 months in the rigid stabilisation group (significance not stated).\n\nThe case series of 101 patients reported a significant decrease in mean leg pain (measured on a VAS from 0 to 100) from 80.3 at baseline to 25.6 at 1-year follow-up (p < 0.01).\n\nThe Specialist Advisers listed key efficacy outcomes as relief of pain, ODI, return to work, patient satisfaction and quality of life, and low rates of adjacent segment disease and revision.\n\n# Safety\n\nDural tears were reported in 12% (12/101) of patients in a case series. Eleven of the tears were repaired intraoperatively, of which 1 continued to leak and required subsequent surgical closure.\n\nThe non-randomised comparative study of 103 patients (46 non-rigid stabilisation vs 57 rigid stabilisation) reported screw fracture in 1 patient in the non-rigid stabilisation group at 3 months.\n\nThe case series of 101 patients reported 1 patient in whom the vertebral pedicle fractured during screw insertion. The pedicle screw was not placed and a hemilaminectomy was done.\n\nThe case series of 83 patients reported 2 patients with screw misplacement (1 patient required revisional surgery) and 7 cases of screw loosening (confirmed by X-ray).\n\nThe Specialist Advisers considered theoretical adverse events to include paralysis, vessel or visceral injury, increase in lordosis, nerve root entrapment, screw malpositioning leading to sciatica or nerve damage, weakness and numbness, screw breakage leading to construct failure, and infection.', 'Further information': "For related NICE guidance see our website.\n\n# Information for patients\n\nNICE has produced information on this procedure for patients and carers ('Understanding NICE guidance'). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.", 'About this guidance': 'NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland.\n\nThis guidance was developed using the NICE interventional procedure guidance process.\n\nIt updates and replaces NICE interventional procedure guidance 183.\n\nWe have produced a summary of this guidance for patients and carers. Information about the evidence it is based on is also available.\n\nChanges since publication\n\nJanuary 2012: minor maintenance.\n\nYour responsibility\n\nThis guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.\n\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.\n\nCopyright\n\n© National Institute for Health and Clinical Excellence 2010. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.\n\nContact NICE\n\nNational Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT\n\nwww.nice.org.uk\n \n nice@nice.org.uk\n 0845 033 7780'}	https://www.nice.org.uk/guidance/ipg366
5ef6ae0f5d6531f69e306fefd6d0201c9221a7c2	nice	Uterine artery embolisation for fibroids	Uterine artery embolisation for fibroids # Guidance This document replaces previous guidance on uterine artery embolisation for the treatment of fibroids (interventional procedure guidance 94). Current evidence on uterine artery embolisation (UAE) for fibroids shows that the procedure is efficacious for symptom relief in the short and medium term for a substantial proportion of patients. There are no major safety concerns. Therefore this procedure may be used provided that normal arrangements are in place for clinical governance and audit. During the consent process patients should be informed, in particular, that symptom relief may not be achieved in some women, that symptoms may return and that further procedures may therefore be required. Patients contemplating pregnancy should be informed that the effects of the procedure on fertility and on pregnancy are uncertain. Patient selection should be carried out by a multidisciplinary team, including a gynaecologist and an interventional radiologist. NICE encourages further research into the effects of UAE compared with other procedures to treat fibroids, particularly for women wishing to maintain or improve their fertility.# The procedure # Indications and current treatments Uterine fibroids, also known as uterine leiomyomas or uterine myomas, are benign tumours of smooth muscle cells and fibrous tissue that develop within the wall of the uterus. They are classified by their location relative to the layers of the uterus (subserous, intramural or submucous) and can be single or multiple. Uterine fibroids are one of the most common gynaecological problems among women in the UK. They may be asymptomatic or may cause symptoms such as abnormal uterine bleeding, urinary incontinence, a feeling of pelvic pressure, or pain. They may also be associated with reproductive problems such as infertility and miscarriage. Asymptomatic fibroids require no treatment. Treatments for symptomatic fibroids include hysterectomy and myomectomy. # Outline of the procedure The aim of UAE for fibroids is to offer a less invasive alternative to hysterectomy or myomectomy with preservation of the uterus, and a faster recovery time. Uterine artery embolisation is sometimes used before a planned myomectomy. With the patient under conscious sedation and local anaesthesia, a catheter is inserted into the femoral artery (bilateral catheters are sometimes used). Fluoroscopic guidance is used to manipulate the catheter into the uterine artery. Small embolisation particles are injected through the catheter into the arteries supplying the fibroids, with the aim of causing thrombosis and consequent fibroid infarction. Various embolisation agents can be used for this procedure. Sections 2.3 and 2.4 describe efficacy and safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview. # Efficacy A register of 1387 patients reported that 84% and 83% of patients had an improvement in their symptoms after UAE at 6 and 24 months respectively. The register of 1387 patients reported an improvement in mean health-related quality of life scores (on a scale from 0 to 100) from 44.1 at baseline to 79.5 after UAE at a maximum 3-year follow-up (p < 0.001). In a register of 2112 patients, the mean symptom score (on a scale from 0 to 100) improved from 58.6 at baseline to 16.5 among 1218 patients at 3-year follow-up (p < 0.001). A randomised controlled trial (RCT) of 157 patients treated by UAE or surgery (hysterectomy or myomectomy) reported symptom improvement in both groups, but this improvement was significantly greater among patients treated by surgery than by UAE (p = 0.004 at 1 month, p = 0.03 at 12 months). The register of 1387 patients reported a mean uterine volume reduction of 40% (n = 666) and a mean reduction in fibroid diameter of 2.2 cm (n = 847). The register of 2112 patients reported a re-intervention rate of 15% during a 3-year follow-up (10% hysterectomy, 3% myomectomy and 2% repeat UAE). An RCT of 177 patients treated by UAE or hysterectomy reported that 28% (23/81) of UAE-treated patients had required hysterectomy at 5-year follow-up. An RCT of 121 women treated by UAE or myomectomy reported that 50% (13/26) of women who tried to conceive after UAE became pregnant compared with 78% (31/40) of women after myomectomy at a mean follow-up of 25 months (p < 0.05). The rate of spontaneous abortion or missed miscarriage was 64% in the UAE group and 23% in the myomectomy group (p < 0.05). The Specialist Advisers listed key efficacy outcomes as symptom improvement, quality of life and the need for further treatment. # Safety Uterine infection was reported in 2% (28/1387) of patients in one of the registers (there were significantly fewer infective complications after discharge in patients who received prophylactic antibiotics compared with those who did not; figures not provided). Septic shock and multiple organ failure leading to death 25 days after UAE occurred in 1 patient in a case series of 21 patients, reported in a systematic review of 36 papers. Septicaemia and emergency myomectomy or hysterectomy were reported in 3% (17/649) of UAE-treated patients in a non-randomised comparative study of 1108 patients. Arterial dissection or perforation were reported in 2 patients, groin bleeding or pseudoaneurysm were reported in 2 patients, and femoral artery occlusion was reported in 1 patient from the register of 1387 patients (events reported prior to discharge from hospital; clinical sequelae not described). One case of bowel perforation treated by laparotomy was reported in the register of 1387 patients. A severe vasovagal event requiring atropine was reported in 1 out of 106 UAE-treated patients in the RCT of 157 patients. The Specialist Advisers listed adverse events reported in the literature as uterine infarction, bladder and vulval damage, ovarian damage, post embolisation syndrome, pain, vaginal discharge and premature menopause.# Further information For related NICE guidance see our website. # Information for patients NICE has produced information on this procedure for patients and carers ('Understanding NICE guidance'). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.# About this guidance NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland. This guidance was developed using the NICE interventional procedure guidance process. It updates and replaces NICE interventional procedure guidance 94. We have produced a summary of this guidance for patients and carers. Information about the evidence it is based on is also available. Changes since publication January 2012: minor maintenance. Your responsibility This guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer. Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties. Copyright © National Institute for Health and Clinical Excellence 2010. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE. Contact NICE National Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT www.nice.org.uk nice@nice.org.uk	{'Guidance': 'This document replaces previous guidance on uterine artery embolisation for the treatment of fibroids (interventional procedure guidance 94).\n\n\n\nCurrent evidence on uterine artery embolisation (UAE) for fibroids shows that the procedure is efficacious for symptom relief in the short and medium term for a substantial proportion of patients. There are no major safety concerns. Therefore this procedure may be used provided that normal arrangements are in place for clinical governance and audit.\n\nDuring the consent process patients should be informed, in particular, that symptom relief may not be achieved in some women, that symptoms may return and that further procedures may therefore be required. Patients contemplating pregnancy should be informed that the effects of the procedure on fertility and on pregnancy are uncertain.\n\nPatient selection should be carried out by a multidisciplinary team, including a gynaecologist and an interventional radiologist.\n\nNICE encourages further research into the effects of UAE compared with other procedures to treat fibroids, particularly for women wishing to maintain or improve their fertility.', 'The procedure': '# Indications and current treatments\n\nUterine fibroids, also known as uterine leiomyomas or uterine myomas, are benign tumours of smooth muscle cells and fibrous tissue that develop within the wall of the uterus. They are classified by their location relative to the layers of the uterus (subserous, intramural or submucous) and can be single or multiple.\n\nUterine fibroids are one of the most common gynaecological problems among women in the UK. They may be asymptomatic or may cause symptoms such as abnormal uterine bleeding, urinary incontinence, a feeling of pelvic pressure, or pain. They may also be associated with reproductive problems such as infertility and miscarriage.\n\nAsymptomatic fibroids require no treatment. Treatments for symptomatic fibroids include hysterectomy and myomectomy.\n\n# Outline of the procedure\n\nThe aim of UAE for fibroids is to offer a less invasive alternative to hysterectomy or myomectomy with preservation of the uterus, and a faster recovery time. Uterine artery embolisation is sometimes used before a planned myomectomy.\n\nWith the patient under conscious sedation and local anaesthesia, a catheter is inserted into the femoral artery (bilateral catheters are sometimes used). Fluoroscopic guidance is used to manipulate the catheter into the uterine artery. Small embolisation particles are injected through the catheter into the arteries supplying the fibroids, with the aim of causing thrombosis and consequent fibroid infarction.\n\nVarious embolisation agents can be used for this procedure.\n\nSections 2.3 and 2.4 describe efficacy and safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview.\n\n# Efficacy\n\nA register of 1387 patients reported that 84% and 83% of patients had an improvement in their symptoms after UAE at 6 and 24 months respectively. The register of 1387 patients reported an improvement in mean health-related quality of life scores (on a scale from 0 to 100) from 44.1 at baseline to 79.5 after UAE at a maximum 3-year follow-up (p < 0.001).\n\nIn a register of 2112 patients, the mean symptom score (on a scale from 0 to 100) improved from 58.6 at baseline to 16.5 among 1218 patients at 3-year follow-up (p < 0.001).\n\nA randomised controlled trial (RCT) of 157 patients treated by UAE or surgery (hysterectomy or myomectomy) reported symptom improvement in both groups, but this improvement was significantly greater among patients treated by surgery than by UAE (p = 0.004 at 1 month, p = 0.03 at 12 months).\n\nThe register of 1387 patients reported a mean uterine volume reduction of 40% (n = 666) and a mean reduction in fibroid diameter of 2.2 cm (n = 847).\n\nThe register of 2112 patients reported a re-intervention rate of 15% during a 3-year follow-up (10% hysterectomy, 3% myomectomy and 2% repeat UAE).\n\nAn RCT of 177 patients treated by UAE or hysterectomy reported that 28% (23/81) of UAE-treated patients had required hysterectomy at 5-year follow-up.\n\nAn RCT of 121 women treated by UAE or myomectomy reported that 50% (13/26) of women who tried to conceive after UAE became pregnant compared with 78% (31/40) of women after myomectomy at a mean follow-up of 25 months (p < 0.05). The rate of spontaneous abortion or missed miscarriage was 64% in the UAE group and 23% in the myomectomy group (p < 0.05).\n\nThe Specialist Advisers listed key efficacy outcomes as symptom improvement, quality of life and the need for further treatment.\n\n# Safety\n\nUterine infection was reported in 2% (28/1387) of patients in one of the registers (there were significantly fewer infective complications after discharge in patients who received prophylactic antibiotics compared with those who did not; figures not provided). Septic shock and multiple organ failure leading to death 25 days after UAE occurred in 1 patient in a case series of 21 patients, reported in a systematic review of 36 papers. Septicaemia and emergency myomectomy or hysterectomy were reported in 3% (17/649) of UAE-treated patients in a non-randomised comparative study of 1108 patients.\n\nArterial dissection or perforation were reported in 2 patients, groin bleeding or pseudoaneurysm were reported in 2 patients, and femoral artery occlusion was reported in 1 patient from the register of 1387 patients (events reported prior to discharge from hospital; clinical sequelae not described).\n\nOne case of bowel perforation treated by laparotomy was reported in the register of 1387 patients.\n\nA severe vasovagal event requiring atropine was reported in 1 out of 106 UAE-treated patients in the RCT of 157 patients.\n\nThe Specialist Advisers listed adverse events reported in the literature as uterine infarction, bladder and vulval damage, ovarian damage, post embolisation syndrome, pain, vaginal discharge and premature menopause.', 'Further information': "For related NICE guidance see our website.\n\n# Information for patients\n\nNICE has produced information on this procedure for patients and carers ('Understanding NICE guidance'). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.", 'About this guidance': 'NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland.\n\nThis guidance was developed using the NICE interventional procedure guidance process.\n\nIt updates and replaces NICE interventional procedure guidance 94.\n\nWe have produced a summary of this guidance for patients and carers. Information about the evidence it is based on is also available.\n\nChanges since publication\n\nJanuary 2012: minor maintenance.\n\nYour responsibility\n\nThis guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.\n\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.\n\nCopyright\n\n© National Institute for Health and Clinical Excellence 2010. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.\n\nContact NICE\n\nNational Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT\n\nwww.nice.org.uk\n \n nice@nice.org.uk\n 0845 033 7780'}	https://www.nice.org.uk/guidance/ipg367
51835fd523b64d46a68dadbd340f4849fdbd83c8	nice	Interspinous distraction procedures for lumbar spinal stenosis causing neurogenic claudication	Interspinous distraction procedures for lumbar spinal stenosis causing neurogenic claudication # Guidance This document replaces previous guidance on interspinous distraction procedures for lumbar spinal stenosis causing neurogenic claudication (interventional procedure guidance 165). Current evidence on interspinous distraction procedures for lumbar spinal stenosis causing neurogenic claudication shows that these procedures are efficacious for carefully selected patients in the short and medium term, although failure may occur and further surgery may be needed. There are no major safety concerns. Therefore these procedures may be used provided that normal arrangements are in place for clinical governance, consent and audit. Patient selection should be carried out by specialist spinal surgeons who are able to offer patients a range of surgical treatment options.# The procedure # Indications and current treatments Lumbar spinal stenosis is most often caused by degenerative disease of the lumbar vertebrae and their associated joints. Neurogenic claudication can then result from compression of spinal nerves by inward buckling of the ligamentum flavum. The principal symptom is leg pain when standing or walking, which is relieved by sitting or by flexing the spine. Conservative treatments include non-steroidal anti-inflammatory drugs and rest. For patients with refractory symptoms, surgery may be performed to decompress the spinal nerve roots (laminectomy or ligamentectomy). Spinal fusion may also be performed. # Outline of the procedure Interspinous distraction procedures involve placing an implant between the spinous processes of the affected vertebrae (usually L4/5) with the aim of limiting extension and so preventing or reducing leg pain when standing or walking. These procedures are normally carried out with the patient under local anaesthesia and conscious sedation, but general anaesthesia may be used. The patient is positioned with their spine flexed: operative level(s) are usually confirmed by fluoroscopy. The vertebral spinous processes and their interspinous ligament are exposed through a midline incision. An implant of appropriate size is positioned through the supraspinous ligament, which helps to hold the implant in place between the flexed spinous processes of adjacent vertebrae. More than one spacer may be inserted for multiple-level disease. Various devices are available for these procedures. Sections 2.3 and 2.4 describe efficacy and safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview. # Efficacy A randomised controlled trial (RCT) of 191 patients treated by interspinous distraction (n = 100) or conservatively (n = 91) reported improvements in symptom severity (measured using the Zurich Claudication Questionnaire) of 45% and 7% respectively at 2-year follow-up (p < 0.001). A non-randomised controlled study of 61 patients treated by interspinous distraction (n = 30, mean follow-up 40.4 months) or posterior lateral interbody fusion (n = 31, mean follow-up 38.4 months) reported a significant improvement in visual analogue scores (0–10 scale) for low back pain (from 4.7 to 2.4 and from 5.5 to 3.3 respectively) and for leg pain (from 6.9 to 2.4 and from 6.5 to 2.6 respectively; p < 0.001 from baseline to follow-up for all scores but no significant difference between groups). The non-randomised study of 61 patients reported a significant decrease in the Oswestry Disability Index (0–100 scale, 100 being greatest disability) for patients treated by interspinous distraction and those treated by interbody fusion, from 23% to 11% and from 21% to 11% respectively; p < 0.001; no significant difference between groups (mean follow-up 40.4 months and 38.4 months respectively). The RCT of 191 patients reported that subsequent laminectomy because of unresolved stenosis was required in 6% (6/100) of patients who had interspinous distraction and 26% (24/91) of patients in the control group (time of conversion not stated). The RCT of 191 patients showed significantly better Short Form-36 scores for physical function, health-related physical limitations, bodily pain, energy levels, social functioning and mental health for patients treated by interspinous distraction compared with those who had conservative treatment at 2-year follow-up. The Specialist Advisers listed key efficacy outcomes as relief of claudication pain in the leg and functional improvement. # Safety The RCT of 191 patients reported 1 case of implant malpositioning (not otherwise described) and 1 of implant migration after a fall, requiring removal without sequelae. An RCT of 75 patients reported that 1 of the 42 patients treated by interspinous distraction had implant malpositioning, detected on 6‑month radiographic examination (not otherwise described). A case series of 69 patients (92 implantations) reported 4 cases of device dislocation (3 patients) at 4-day, 6-day and 2-week follow-up. The same study reported device malpositioning in 1 patient at 6-week follow-up. All 4 patients had revision surgery. The non-randomised study of 61 patients reported device fracture in 1 of the 30 patients treated by interspinous distraction (time of occurrence and further details not stated). A case series of 69 patients reported spinous process fracture in 1 patient intraoperatively and 3 patients postoperatively (at 1 week, 4 months and 6 months). The postoperative fractures were treated by revision surgery. One was caused by trauma. An unpublished abstract of 69 patients treated by interspinous distraction reported that 27% (18/66) of patients required removal of the spacer and revision surgery (timing of events not stated). A case series of 175 patients reported that 5% (8/175) of patients required removal of the device because the effect of the procedure was unsatisfactory. The Specialist Advisers considered anecdotal adverse events to include infection and movement of the implant after placement.# Further information # Information for patients NICE has produced information on this procedure for patients and carers ('Understanding NICE guidance'). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.# About this guidance NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland. This guidance was developed using the NICE interventional procedure guidance process. It updates and replaces NICE interventional procedure guidance 165. We have produced a summary of this guidance for patients and carers. Information about the evidence it is based on is also available. Changes since publication January 2012: minor maintenance. Your responsibility This guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer. Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties. Copyright © National Institute for Health and Clinical Excellence 2010. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE. Contact NICE National Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT www.nice.org.uk nice@nice.org.uk	{'Guidance': 'This document replaces previous guidance on interspinous distraction procedures for lumbar spinal stenosis causing neurogenic claudication (interventional procedure guidance 165).\n\n\n\nCurrent evidence on interspinous distraction procedures for lumbar spinal stenosis causing neurogenic claudication shows that these procedures are efficacious for carefully selected patients in the short and medium term, although failure may occur and further surgery may be needed. There are no major safety concerns. Therefore these procedures may be used provided that normal arrangements are in place for clinical governance, consent and audit.\n\nPatient selection should be carried out by specialist spinal surgeons who are able to offer patients a range of surgical treatment options.', 'The procedure': '# Indications and current treatments\n\nLumbar spinal stenosis is most often caused by degenerative disease of the lumbar vertebrae and their associated joints. Neurogenic claudication can then result from compression of spinal nerves by inward buckling of the ligamentum flavum. The principal symptom is leg pain when standing or walking, which is relieved by sitting or by flexing the spine.\n\nConservative treatments include non-steroidal anti-inflammatory drugs and rest. For patients with refractory symptoms, surgery may be performed to decompress the spinal nerve roots (laminectomy or ligamentectomy). Spinal fusion may also be performed.\n\n# Outline of the procedure\n\nInterspinous distraction procedures involve placing an implant between the spinous processes of the affected vertebrae (usually L4/5) with the aim of limiting extension and so preventing or reducing leg pain when standing or walking.\n\nThese procedures are normally carried out with the patient under local anaesthesia and conscious sedation, but general anaesthesia may be used. The patient is positioned with their spine flexed: operative level(s) are usually confirmed by fluoroscopy. The vertebral spinous processes and their interspinous ligament are exposed through a midline incision. An implant of appropriate size is positioned through the supraspinous ligament, which helps to hold the implant in place between the flexed spinous processes of adjacent vertebrae. More than one spacer may be inserted for multiple-level disease.\n\nVarious devices are available for these procedures.\n\nSections 2.3 and 2.4 describe efficacy and safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview.\n\n# Efficacy\n\nA randomised controlled trial (RCT) of 191 patients treated by interspinous distraction (n = 100) or conservatively (n = 91) reported improvements in symptom severity (measured using the Zurich Claudication Questionnaire) of 45% and 7% respectively at 2-year follow-up (p < 0.001).\n\nA non-randomised controlled study of 61 patients treated by interspinous distraction (n = 30, mean follow-up 40.4 months) or posterior lateral interbody fusion (n = 31, mean follow-up 38.4 months) reported a significant improvement in visual analogue scores (0–10 scale) for low back pain (from 4.7 to 2.4 and from 5.5 to 3.3 respectively) and for leg pain (from 6.9 to 2.4 and from 6.5 to 2.6 respectively; p\xa0<\xa00.001 from baseline to follow-up for all scores but no significant difference between groups).\n\nThe non-randomised study of 61 patients reported a significant decrease in the Oswestry Disability Index (0–100 scale, 100 being greatest disability) for patients treated by interspinous distraction and those treated by interbody fusion, from 23% to 11% and from 21% to 11% respectively; p < 0.001; no significant difference between groups (mean follow-up 40.4\xa0months and 38.4 months respectively).\n\nThe RCT of 191 patients reported that subsequent laminectomy because of unresolved stenosis was required in 6% (6/100) of patients who had interspinous distraction and 26% (24/91) of patients in the control group (time of conversion not stated).\n\nThe RCT of 191 patients showed significantly better Short Form-36 scores for physical function, health-related physical limitations, bodily pain, energy levels, social functioning and mental health for patients treated by interspinous distraction compared with those who had conservative treatment at 2-year follow-up.\n\nThe Specialist Advisers listed key efficacy outcomes as relief of claudication pain in the leg and functional improvement.\n\n# Safety\n\nThe RCT of 191 patients reported 1 case of implant malpositioning (not otherwise described) and 1 of implant migration after a fall, requiring removal without sequelae. An RCT of 75 patients reported that 1 of the 42 patients treated by interspinous distraction had implant malpositioning, detected on 6‑month radiographic examination (not otherwise described). A case series of 69 patients (92 implantations) reported 4 cases of device dislocation (3 patients) at 4-day, 6-day and 2-week follow-up. The same study reported device malpositioning in 1\xa0patient at 6-week follow-up. All 4 patients had revision surgery.\n\nThe non-randomised study of 61 patients reported device fracture in 1 of the 30 patients treated by interspinous distraction (time of occurrence and further details not stated).\n\nA case series of 69 patients reported spinous process fracture in 1 patient intraoperatively and 3 patients postoperatively (at 1 week, 4 months and 6\xa0months). The postoperative fractures were treated by revision surgery. One was caused by trauma.\n\nAn unpublished abstract of 69 patients treated by interspinous distraction reported that 27% (18/66) of patients required removal of the spacer and revision surgery (timing of events not stated). A case series of 175 patients reported that 5% (8/175) of patients required removal of the device because the effect of the procedure was unsatisfactory.\n\nThe Specialist Advisers considered anecdotal adverse events to include infection and movement of the implant after placement.', 'Further information': "# Information for patients\n\nNICE has produced information on this procedure for patients and carers ('Understanding NICE guidance'). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.", 'About this guidance': 'NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland.\n\nThis guidance was developed using the NICE interventional procedure guidance process.\n\nIt updates and replaces NICE interventional procedure guidance 165.\n\nWe have produced a summary of this guidance for patients and carers. Information about the evidence it is based on is also available.\n\nChanges since publication\n\nJanuary 2012: minor maintenance.\n\nYour responsibility\n\nThis guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.\n\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.\n\nCopyright\n\n© National Institute for Health and Clinical Excellence 2010. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.\n\nContact NICE\n\nNational Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT\n\nwww.nice.org.uk\n \n nice@nice.org.uk\n 0845 033 7780'}	https://www.nice.org.uk/guidance/ipg365
aef806dee22cfd6826d236a4c2bb7a79840c90aa	nice	Imatinib for the treatment of unresectable and/or metastatic gastro-intestinal stromal tumours	Imatinib for the treatment of unresectable and/or metastatic gastro-intestinal stromal tumours Evidence-based recommendations on imatinib for treating unresectable or metastatic gastrointestinal stromal tumours in adults. # Guidance November 2010: This guidance has been partially updated by 'Imatinib for the treatment of unresectable and/or metastatic gastrointestinal stromal tumours' (NICE technology appraisal guidance 209), as shown below. Imatinib treatment at 400 mg/day is recommended as first-line management of people with KIT (CD117)-positive unresectable and/or KIT (CD117)-positive metastatic gastro-intestinal stromal tumours (GISTs). Continuation with imatinib therapy is recommended only if a response to initial treatment is achieved within 12 weeks. Responders should be assessed at intervals of approximately 12 weeks thereafter. Continuation of treatment is recommended at 400 mg/day until the tumour ceases to respond. An increase in the dose of imatinib is not recommended for people receiving imatinib who develop progressive disease after initially responding. This recommendation has been updated and replaced by NICE technology appraisal guidance 209. The use of imatinib should be supervised by cancer specialists with experience in the management of people with unresectable and/or metastatic GISTs.# Clinical need and practice Gastro-intestinal stromal tumours (GISTs) are rare connective tissue tumours that show a differentiation profile similar to the interstitial cells of Cajal. They represent less than 1% of the tumours arising in the gastro-intestinal (GI) tract. Although GISTs can occur along the length of the GI tract, the majority arise in the stomach (60–70%), small bowel (25–35%), colon and rectum (5%) and, to a lesser extent, the oesophagus. Presenting features of these tumours depend on the size and location of the tumour and include abdominal discomfort or pain, a feeling of abdominal fullness and the presence of a palpable mass. However, many people with GISTs are asymptomatic during early stages of the disease until tumours reach a large size, at which time the tumours rupture and bleed or obstruct the GI tract. Most GISTs express the tyrosine kinase growth factor receptor c-KIT, which is detected by immunostaining with the antibody for the cell-surface marker CD117. Under normal conditions, this receptor is activated by stem-cell factor, which stimulates signal transduction pathways such as cell growth, differentiation and apoptosis (cell death). Most GISTs express a form of the tyrosine kinase receptor that is permanently 'switched on' (constitutively activated), leading to unregulated cell proliferation. Until recently, there has been no appropriate test for the diagnosis of GIST. An immunohistochemical test for the presence of the cell-surface marker CD117 (present in 80–100% of GISTs) is now considered to be an appropriate diagnostic marker for the diagnosis of GIST. A diagnosis of GIST is made on the basis of histological characteristics of the tumour biopsy, clinical presentation and immunohistochemical profile, including a positive test for the CD117 marker. As a result of difficulties in the diagnosis of GIST, estimates of its incidence vary widely, from 4 to 40 cases per million population, which corresponds to between 200 and 2000 new cases per year in England and Wales. Recent epidemiological data from Sweden suggest that the incidence of GIST is in the region of 15 per million per year. Approximately half of new cases of GIST are likely to be metastatic and/or unresectable on first presentation. Although GIST can occur at any age, the mean age of presentation is between 50 and 70 years. The prognosis of people with GIST depends primarily on whether the tumour is resectable, although the size and location of the tumour and the stage of the tumour at initial diagnosis are also important prognostic indicators. A recent study suggested that the prognosis for unresectable and/or metastatic GIST is poor with few, if any, people surviving beyond 5 years. Complete surgical resection is the treatment of choice for people presenting with GISTs amenable to surgery, but there is currently no effective treatment for people with unresectable and/or metastatic tumours. As GISTs are particularly resistant to conventional cytotoxic chemotherapy and radiotherapy, current treatment normally comprises symptom relief and best supportive care. This includes palliative care for the management of pain, fever, GI obstruction, and anaemia caused by GI haemorrhage.# The technology Imatinib (Novartis) is a signal-transduction inhibitor designed to selectively inhibit certain classes of tyrosine kinase that include the c-KIT receptor expressed in GIST. Imatinib binds to activated c-KIT receptors and blocks the cell signalling pathway to prevent uncontrolled cell proliferation. Imatinib was first licensed for the treatment of chronic myeloid leukaemia, for which NICE guidance exists (NICE Technology Appraisal Guidance No. 70 'Imatinib for chronic myeloid leukaemia'). Imatinib received European marketing authorisation in May 2002 for the treatment of adult patients with KIT (CD117)-positive unresectable and/or metastatic malignant GIST. Licensing approval was based largely on a single, uncontrolled phase II study in 147 patients. Recent developments in pathology suggest that a small minority of GISTs that test negative for the c-KIT receptor may also respond to imatinib. However, the evidence to support this is currently limited and the UK marketing authorisation for imatinib does not include the treatment of this group of tumours. The manufacturer's summary of product characteristics recommends oral imatinib at a dose of 400 mg/day for the treatment of unresectable and/or metastatic GIST, to be taken with a large glass of water at meal times. The licence also states that there are limited data on the effect of dose increases from 400 mg/day to 600 mg/day in patients whose disease progresses at the lower dose. Imatinib costs £12.98 per 100 mg (excluding VAT; British National Formulary 47, March 2004). The approximate annual acquisition cost of imatinib is between £19,000 (400 mg/day) and £28,500 (600 mg/day).# Evidence and interpretation The Appraisal Committee (see Appendix A) considered evidence from a number of sources (see Appendix B). # Clinical effectiveness No randomised controlled trials (RCTs) were identified that compared imatinib treatment with best supportive care in patients with unresectable and/or metastatic GIST. In the absence of controlled studies, historical controls were identified to provide information on the natural history of advanced GIST. Many patients in these studies had received other treatments (such as chemotherapy or radiotherapy). These studies provide the most appropriate data for comparison with studies of imatinib treatment. The Assessment Group identified 15 studies of imatinib treatment of c-KIT-positive GIST, which included six ongoing uncontrolled trials. Four of the uncontrolled trials were only available in abstract form at the time of the review, but one was published during the course of the appraisal. The Assessment Group also identified eight single case studies and one case series. In the absence of any controlled trials, the Assessment Group also identified 14 uncontrolled case-series and cohort studies, that is, comparator studies (one of which is currently unpublished). Key study outcomes included: survival; tumour status (tumour mass measured by computerised tomography or magnetic resonance imaging and classified by response evaluation criteria in solid tumours or SWOG criteria); and Eastern Cooperative Oncology Group (ECOG) performance status (which measures functional status in everyday tasks, and which are also reported in quality-of-life measurement scales). Positron emission tomography (PET) imaging, reported in one study, provided information on the effect of imatinib on tumour metabolism. ## Imatinib treatment Study CSTI571-B2222 is a published ongoing phase II uncontrolled trial of imatinib treatment in 147 patients (91% of whom were c-KIT-positive) with unresectable and metastatic GIST, which formed the basis of the licence application. The manufacturer also provided updated results of this study, which are not yet fully published. Patients were randomly assigned to receive a single dose of 400 mg (n = 73) or 600 mg (n = 74) of imatinib. Patients received imatinib treatment for a median of 21 months (range 7 to 783 days). The study was not powered to distinguish statistically significant differences in the efficacy of imatinib treatment between the two study arms (400 and 600 mg/day). The combined survival rate from the start of treatment was 88% at 1-year follow-up and 78% at 2-year follow-up. Median survival had not been reached after 31 months of follow-up. Tumour response (based on SWOG criteria, Appendix D) evaluated at 21-month follow-up showed that 66% of patients achieved a partial response, 17% stable disease and 12% progressive disease (with 5% of patients being unevaluable). No patients achieved a complete response. The manufacturer's submission reported resistance to imatinib in 16 patients; 3 patients exhibited primary resistance (no response to imatinib) and a further 13 exhibited secondary resistance to imatinib (loss of response to imatinib). There were substantial improvements in patients' ECOG performance status. At the 4-month follow-up, the proportion of patients with normal functional status (grade 0) had increased from 42% at baseline to 64%, and the number of patients with impaired functional status of grade 2 (capable of self-care but unable to work) had decreased from 18% at baseline to 5%. These improvements were maintained in the 21% of patients who were followed up to 25 months. A published ongoing phase I study evaluated imatinib treatment at licensed doses of 400 and 600 mg/day and unlicensed higher doses in 40 patients with advanced GIST (35 of whom were c-KIT-positive). After 9 to 12 months of follow-up, survival from start of treatment was 90%. Tumour response was evaluated using RECIST criteria in the 35 patients who were c-KIT-positive: 51% achieved a partial response; 31% stable disease; and 8.5% progressive disease. Tumour function evaluated in 14 patients using PET imaging after 8 days of treatment showed that eight patients had achieved a complete response, two patients a partial response and one patient no change. The remaining three patients showed disease progression after 28 days. Of the four trials that were unpublished at the time of the Assessment Group's review, two were non-randomised studies and two were randomised dose-response studies based on large patient samples. An ongoing European study comparing 400 mg/day with (the unlicensed dose of) 800 mg/day in 946 patients reported progression-free survival at 2 years to be approximately 40% (400 mg/day) and 55% (800 mg/day). An interim analysis of this study published in abstract form (median follow-up of 8 months) showed no significant differences between the two treatment arms. A second interim analysis of this trial presented to the Committee (median follow-up of 17 months) showed that progression-free survival was significantly better with initial treatment at 800 mg/day. A study based in the USA, comparing the same daily doses in 746 patients, reported progression-free survival at 6 months to be 80% (400 mg/day) and 82% (800 mg/day). Study CSTI571-B2222 (registration study) reported that at least one adverse event had been experienced by all 147 patients by 21 months' follow-up. Of these, 37% were 'severe and undesirable' (grade 3) and 15% were 'life threatening and disabling' (grade 4). A total of 15 (10%) patients withdrew from the study because of adverse events; one third of these events were classed as drug-related. The most commonly reported side effects of imatinib include nausea, diarrhoea, periorbital oedema, muscle cramps, fatigue, rash and headache. The most common serious adverse events were unspecified haemorrhage and neutropenia, each event occurring in approximately 5% of patients. Overall, imatinib was well tolerated. Patient group submissions commented on the dramatic effect of imatinib, with the majority of patients experiencing improvements in disease-related symptoms (such as abdominal distension and pain) and reporting improved appetite and a feeling of well-being. Some patients were able to resume normal daily activities, which included a return to full-time employment. Expert testimony at the committee meeting provided evidence on the issue of resistance to imatinib. The clinical expert informed the Committee that, although data from the clinical trials are too premature to give definitive answers regarding resistance, they expect that approximately 40% of patients may become resistant to imatinib. ## Case-series and cohort studies on the natural history of disease progression Fourteen primary studies of alternative treatments (surgical resection, chemotherapy, radiotherapy and chemoembolisation) for patients with advanced GIST provided information on the natural history of disease. Median survival reported in 12 papers (983 patients) ranged from 2 to 39 months, with survival rates of 37–80% at 1-year follow-up, 6–45% at 3-year follow-up and 0–45% at 5-year follow-up. However, 12 out of 14 studies did not have the GIST diagnosis confirmed by c-KIT testing. Data from an unpublished cohort study were used to represent the natural history of patients with GIST. A total of 143 c-KIT-positive patients (132 patients with recurrent or metastatic GIST) were included in the retrospective analysis. Of these, 91% had previously undergone surgical resection of the tumour, and all patients had received chemotherapy for a median duration of 55 weeks. Patients surviving to the time when imatinib treatment became available were transferred to the treatment (n = 67). Survival outcomes were presented for all patients (irrespective of whether they received imatinib) and for patients who never received imatinib. # Cost effectiveness No published cost-effectiveness analyses or quality-of-life studies for patients with advanced GIST were identified in the literature. The manufacturer submitted an economic model, and the Assessment Group re-analysed this model to overcome identified shortcomings. The Assessment Group also developed its own economic model, which was revised after discussion at the committee meeting to answer questions raised about some of the assumptions underpinning all the models. The manufacturer's model estimated the incremental cost effectiveness of imatinib treatment compared with best supportive care. Patients in the control arm were assumed to start in a state of progressive disease, where they remained until death, on the basis of survival estimates extrapolated from the cohort study (using selected patients who never received imatinib only). All patients in the imatinib treatment arm were assumed to respond to imatinib treatment immediately. The probability of developing progressive disease after initial response was based on the results of the CSTI571-B2222 study. The data from both the trial and the cohort study were extrapolated to 10 years using exponential curves. Estimates of health-related utility were derived by using clinical judgement to map ECOG performance status to a generic measure of health status (the EuroQol EQ-5D). The results of the model showed the incremental cost-effectiveness ratio (ICER) estimates to be £59,000 at 2 years, £24,000 at 5 years and £14,000 at 10 years. The Assessment Group modified the manufacturer's model to overcome some concerns that the Group considered would overestimate the cost effectiveness of imatinib. The first of two key amendments was to the model structure; it sought to rectify the overestimation of benefit of imatinib by using both the survival and time-to-treatment-failure curves from the registration study to estimate the proportion of patients in the imatinib health state. The second key change was to estimate survival with progressive disease from all patients included in the cohort study, including those who later went on to receive imatinib. The ICER estimates following all the modifications were £41,000 at 2 years and £30,000 at 10 years. At the instruction of the Appraisal Committee, the Assessment Group, in conjunction with the NICE Decision Support Unit (DSU), was commissioned to develop its own economic model. Additional data from the cohort study (survival estimates, censored at the time imatinib became available) were sourced to improve the estimates of survival with progressive disease. One of the key differences between the DSU model and the other economic models was that the DSU model was structured so that all patients started in the same health state of progressive disease. Also, all the relevant censored data from the cohort study were used to estimate survival following progressive disease − that is, not just patients who died before they could be prescribed imatinib, but also survivors up to the point at which they were transferred to imatinib treatment. Another key difference was that the extrapolations of both the trial data and the censored cohort study data were based on all the data available and did not assume a constant hazard ratio. The estimates of utility were the same as those included in the manufacturer's economic model. The model was also structured to estimate the cost effectiveness of different policies regarding dose escalation. The results of the DSU model suggest that the incremental cost per additional quality-adjusted life year is approximately £32,000 for patients on 400 mg/day estimated over 10 years. The incremental cost effectiveness of a policy allowing dose escalation to 600 mg/day after failure of 400 mg/day is approximately £39,000 at 10 years compared with a policy of treatment with 400 mg/day and no dose escalation. # Consideration of the evidence The Committee reviewed the evidence available on the clinical and cost effectiveness of imatinib for the treatment of GIST, having considered evidence on the nature of the condition and the value placed by users on the benefits of imatinib from people with GIST, those who represent them, and clinical experts. It was also mindful of the need to ensure that its advice took account of the efficient use of NHS resources. The Committee heard evidence from experts on the current treatment of patients with GIST, and it was aware that imatinib is the only effective treatment for metastatic and/or unresectable GIST. Experts advised that about half of all patients with GIST have unresectable and/or metastatic disease at presentation. Experts also advised that tumour response is most commonly assessed by CT scan (tumour size and density) or MRI scan (tumour size). The Committee also heard that although PET assessment of tumour metabolism at 1 week post-treatment could provide early information on patients' responses to imatinib treatment, the PET technology is not currently routinely available. The Committee therefore considered that assessment of tumour response should be based principally on the SWOG criteria (Appendix D) because this classification of tumour response was reported in the published clinical study and formed the basis of all of the economic models. The Committee understood that estimates of SWOG response criteria are assessed by CT/MRI and that these include an element of assessment of symptoms and the need to note that tumour enlargement may be related to swelling associated with tissue necrosis. It was also persuaded that changes in the density of the tumour deposits as assessed by CT scanning may also indicate response to therapy, and that these changes should be included as part of the overall assessment of the response to imatinib. The Committee also concluded that further research into the use of PET for assessing tumour response would be beneficial. The experts informed the Committee that patients with multiple lesions may experience tumour growth in some sites while the bulk of the tumour remains under control. The Committee carefully considered the SWOG criteria in relation to these situations. It acknowledged that the criteria would allow for an increase in tumour size of up to 50% or 10 cm (whichever is smaller) in the sum of products of all measurable lesions over the smallest sum observed. The Committee also noted that lesions that appear to increase in size because of the presence of necrotic tissue are not considered to have progressed using the SWOG criteria. For these reasons, the Committee concluded that the use of SWOG criteria to assess response is appropriate. The experts advised the Committee on the difficulties involved in diagnosing metastatic and/or unresectable GISTs, the assessment of response to treatment and determining the appropriate mix and timing of treatments (surgery or drug therapy) for these patients. The Committee therefore concluded that imatinib therapy should be used only under the supervision of an expert with experience in the treatment of these patients. It is understood that this may also include shared care of the management of these patients between experts in GIST with other cancer centres. The Committee heard evidence that mutational analysis to determine whether patients have a mutation in KIT may enable clinicians to predict the patients who are most likely to respond to imatinib treatment, because patients with no mutations in KIT have a poorer prognosis. Although these tests are not widely available in the UK, the Committee believed that further research into their use to identify patients for whom imatinib may be particularly appropriate would be important. The Committee carefully considered the appropriate length of time for which patients should receive imatinib after initiation of treatment before first assessment of response, and at what stage treatment should be considered to have failed. Experts advised that patients are usually evaluated (by an assessment of diagnostic imaging and clinical symptoms) at about 12 weeks from the initiation of treatment, at which stage the disease is classified as complete response, partial response, stable disease or progressive disease. The experts also advised the Committee that a tumour response to imatinib, including stabilisation of disease, is usually seen within 12 weeks of initiation of treatment. The Committee also considered evidence from various sources that the maximum response of GIST to imatinib may not be reached for up to 6 to 12 months from initiation of treatment. The Committee was, however, persuaded that the time taken to achieve an initial response would be significantly less than that taken to achieve a maximum response, as is evidenced from the PET scanning studies, which show that response to imatinib can be achieved within the first 2 weeks of treatment. Additionally, the Committee noted that all of the clinical trials included early review of patients as part of the assessment of response to treatment. The Committee considered, therefore, that patients should initially receive imatinib treatment for up to 12 weeks before tumour response is evaluated, but that only patients responding to treatment (as defined in Section 1.5) by 12 weeks should continue to be treated with imatinib until there is further evidence of disease progression. In making this judgment, the Committee took into account the fact that the definition of tumour response allows for an increase in the size of tumour(s) due to necrosis and swelling, and for stabilisation (that is, no change) of disease within the SWOG criteria. The Committee considered the evidence on the effectiveness of the higher initial dose of imatinib of 600 mg/day from the CSTI571-B2222 study and the evidence published in abstract form on the daily dose of 800 mg. It concluded from the evidence reviewed that there was no difference in the effectiveness between initial doses of 400 mg/day and 600 mg/day. The Committee considered the early results from the two trials comparing initial doses of 400 mg/day and 800 mg/day. It acknowledged that the early interim results from one of these trials showed a non-significant benefit in progression-free survival from 800 mg/day compared with 400 mg/day, and that the later analysis of this trial showed a significant benefit from initial treatment at 800 mg/day. The Committee also noted that the other trial showed very little difference between the two daily dosages. The Committee concluded that the data from these studies were too premature to draw firm conclusions. The Committee was also aware that the safety and tolerability of a daily dose of imatinib of 800 mg has not yet been assessed by the Medicines and Healthcare products Regulatory Agency. The Committee concluded that it was unable to issue guidance on a dose of 800 mg/day because this dosage has not yet received a UK marketing authorisation, and it was persuaded that the licensed dosage of 400 mg/day was the most appropriate initial dose of imatinib. The Committee considered evidence from the trials, and new information provided by the manufacturer, regarding dose escalation in patients with progressive disease. The Committee considered that the data on dose escalation were limited because the number of patients involved was small, the length of follow-up for these patients was short, and patients were not allocated to dose escalation by randomisation, possibly leading to bias in the results. The Committee considered all the evidence on dose escalation in relation to the economic models and concluded that dose escalation is not cost effective. The Committee also considered views of the experts regarding dose escalation in patients with progressive disease following initial treatment. The experts advised that there is a lack of evidence supporting the effectiveness of dose escalation to 600 mg/day. The Committee acknowledged that studies were ongoing to evaluate the effectiveness of an 800 mg dose of imatinib, and it concluded that there is currently no robust evidence to suggest that continued treatment with imatinib (including dose escalation) in patients with progressive disease is cost effective. The Committee carefully considered the most appropriate estimates of survival for a control group for imatinib treatment in the cost-effectiveness modelling. All the models used data from the same unpublished historical control study to represent the natural history of GIST, but differed in the selection of patients and whether the data were censored for when imatinib treatment became available. The Committee considered this data to be the most appropriate because all patients' tumours were diagnosed as CD117-positive. The Committee concluded that data on the survival of the control group, censored for when imatinib became available, was the least prone to bias and the best estimate of prognosis of untreated GIST. The Committee considered the different methods of extrapolating the trial and cohort study data to a 10-year time horizon in the cost-effectiveness models. The DSU model, which did not assume constant hazard and used all of the available data for both the treatment and control groups, was considered to be the most appropriate method of extrapolation. The Committee concluded that the cost-effectiveness estimates based on a 10-year time horizon were the most appropriate, because this time horizon was likely to encompass the key costs and benefits. The Committee considered the results from extrapolating the data in relation to new information (at 152 weeks' follow-up) provided by the manufacturer. The Committee acknowledged that the extrapolated time to progression in the DSU model was shorter, and that the extrapolated time to progression in the manufacturer's model was longer, than the time to progression shown by the new data supplied by the manufacturer. However, the Committee also noted that overall survival predicted using the DSU model was longer than suggested by the new data provided by the manufacturer. Thus, the Committee concluded that the ICER produced using the DSU model was likely to be an underestimate when considering this new data. The Committee considered that the assumption that all patients would respond to imatinib immediately (as presented in the manufacturer's and Assessment Group model) was unlikely. The Committee concluded that the estimates of cost effectiveness based on the DSU model (in which all patients begin in the progressive phase) used the most appropriate available data and assumptions. The Committee heard evidence from experts regarding likely tumour response rate in the event of dose escalation. The DSU model assumed that patients who are escalated to 600 mg/day after disease progression on 400 mg/day have the same response as when they initially responded to the lower dose. The experts advised the Committee that the time to treatment failure following dose escalation is likely to be substantially shorter than the initial response at 400 mg/day. The Committee therefore considered that this assumption (of an equivalent length of response following dose escalation) used in the DSU economic model was more optimistic than suggested by the experts. The Committee also considered new evidence on response following dose escalation provided by the manufacturer. The Committee considered that the assumption about the proportion of patients responding to dose escalation in the economic model was more optimistic than supported by the evidence provided by the manufacturer. These conclusions supported their view on the inappropriateness of dose escalation in progressive disease, as in Sections 4.3.8 and 4.3.9. The Committee heard testimony from the representative for patients with GIST and the clinical experts about the dramatic improvement in health-related quality of life associated with successful imatinib treatment. In addition, the Committee considered advice from a clinical expert that, in a minority of patients, imatinib treatment may be given until unresectable tumours shrink to a size at which they can be surgically resected. The expected survival of these patients is better than the expected survival of patients whose tumours remain unresectable. The Committee considered that both of these factors may not have been fully represented in the economic modelling. The Committee concluded that if data were available to model these issues more robustly, the ICERs would be slightly lower. However, it concluded that these factors did not alter its overall view of the cost effectiveness of imatinib therapy for GIST. Experts commented that current practice sometimes includes the continuation of imatinib treatment in patients with progressive disease (as assessed by CT/MRI), provided that they report a symptomatic benefit without objective evidence of response. However, the Committee considered that, because there is a lack of robust evidence on the effectiveness of extended treatment in these patients, and because a decrease in the overall rate of response to imatinib treatment would increase the ICERs to an unacceptable level, the use of imatinib in this context should be undertaken only as part of clinical studies. The Committee was aware of the continuing research in this area and the emergence of new data published in abstract form during the consultation process. This new information included evidence relating to updated results from trials, dose escalation, assessment of response and discontinuation of imatinib therapy. The manufacturer also provided updated results for the CSTI571-B2222 study. The Committee considered that this evidence has not yet been fully peer reviewed and that much of the evidence relates to the unlicensed dose of imatinib of 800 mg/day. The Committee considered this evidence and its relation to the results of the economic models when making its recommendations. The Committee concluded that it would be important to re-evaluate the recommendations when new evidence becomes fully available or if substantial changes are made to the marketing authorisation of imatinib.# Recommendations for further research A national register of all patients receiving imatinib treatment for GIST should be maintained. Details could include patient characteristics, dose and duration of treatment, mutational analysis, tumour response rates and survival both with and after discontinuation of imatinib treatment. The response rates of patients who have received escalated doses of imatinib treatment in the context of clinical trials could also be included. The key dose-response trials for imatinib for metastatic and/or unresectable GIST are still in progress. There are also studies assessing the use of imatinib in patients with metastatic and/or unresectable GIST that have been published in abstract form, and many report interim results. The Institute recommends that further trials be undertaken to evaluate the benefit of maintenance therapy at 400 mg/day for patients with progressive disease, and the response rate of patients after switching to higher doses of imatinib treatment. The effectiveness of dose escalation should be evaluated for patients who do not respond to imatinib treatment at 400 mg/day, and for patients who initially respond to the lower dose but later develop progressive disease. These trials should incorporate measures of health-related quality of life. Information on survival following withdrawal of imatinib treatment should also be collected. The Institute considered that studies should be conducted to assess: the effectiveness of PET assessment for the measurement of tumour response the use of mutational analysis to predict individual responses to imatinib treatment.# Implications for the NHS The cost impact of this guidance will depend on: the number of patients with unresectable and/or metastatic GIST; the proportion of patients who receive imatinib; the proportion of patients who respond to imatinib treatment; the duration of treatment; the price of imatinib; and the number of patients already prescribed imatinib for GIST. Estimates of the annual incidence of GIST vary considerably. The manufacturer of imatinib estimated the number of new cases of unresectable and/or metastatic GIST to be between 80 and 240 people each year. It has also been suggested that current estimates of the incidence of GIST are underestimates, and these figures may increase as more tumours of patients with GIST are tested for c-KIT. The annual drug cost of imatinib is just under £19,000. Assuming that there will be 240 new patients eligible for imatinib treatment for GIST and that patients will be monitored by an average of four CT scans per year, the total cost of treating new patients in accordance with the guidance will be approximately £4.7 million in the first year. Assuming that the incidence rate does not change and that patients remain on imatinib treatment for an average of 1.44 years (as predicted by the DSU economic model), the total cost of treating patients with imatinib for GIST will be approximately £6.8 million when the number of patients receiving imatinib has reached a steady state. The resource impact of this guidance on the NHS will depend on the number of patients currently receiving NHS prescriptions for imatinib for the treatment of GIST. Using the assumptions set out in Section 6.2, if 25% of eligible patients currently receive NHS prescriptions for imatinib for GIST, the additional cost of implementing this guidance will be approximately £5.1 million. If 75% of eligible patients are currently being treated with imatinib, the impact of the guidance will be less, at about £1.7 million. These estimates are based on a number of assumptions and could be much less if switching to higher doses of imatinib is reduced. The estimates may also be reduced further if GIST patients receive imatinib treatment as a result of the guidance rather than receiving inappropriate surgery or chemotherapy treatment.# Related guidance National Institute for Clinical Excellence (2003) Guidance on the use of imatinib for chronic myeloid leukaemia.NICE Technology Appraisal Guidance No. 70. London: National Institute for Clinical Excellence.# Review of guidance The review date for a technology appraisal refers to the month and year in which the Guidance Executive will consider whether the technology should be reviewed. This decision will be taken in the light of information gathered by the Institute, and in consultation with consultees and commentators. The guidance on this technology will be reviewed in October 2007. Andrew DillonChief ExecutiveOctober 2004# Appendix C. Detail on criteria for audit of the use of imatinib for the treatment of unresectable and/or metastatic gastro-intestinal stromal tumours # Possible objectives for an audit An audit on the appropriateness and effectiveness of use of imatinib for the treatment of unresectable and/or metastatic GIST could be carried out to ensure the following. Imatinib is used appropriately for the treatment of unresectable and/or metastatic GISTs. The use of imatinib for the treatment of unresectable and/or metastatic GISTs is supervised by an appropriate cancer specialist. # Possible patients to be included in the audit An audit could be carried out on patients diagnosed with KIT (CD117)-positive unresectable and/or KIT (CD117)-positive metastatic GIST over a reasonable time period for audit. In view of the small number of patients who may be eligible for inclusion in the audit, all patients should be included in the audit and it may be desirable to collect data for the audit concurrent with treatment. # Measures that could be used as a basis for an audit The measures that could be used in an audit on the use of imatinib for the treatment of unresectable and/or metastatic GISTs are as follows. Criterion Standard Exception Definition of terms . For a person with KIT (CD117)-positive unresectable and/or KIT (CD117)-positive metastatic GIST, imatinib therapy is provided as first-line management as follows: a. at 400 mg/day and b. for up to 12 weeks % of people with KIT (CD117)-positive unresectable and/or KIT (CD117)-positive metastatic GIST None . Imatinib therapy at 400 mg/day is continued beyond the first 12 weeks only if the person's GIST has responded to treatment within 12 weeks % of people with KIT (CD117)-positive unresectable and/or KIT (CD117)-positive metastatic GIST who have been provided imatinib None 'GIST response to treatment' is assessed by imaging to assess the size and density of the tumour(s), patients' symptoms and other factors, and is classified as complete response, partial response or stable disease as defined by the SWOG criteria (see Appendix D). . A person whose GIST has responded to imatinib therapy is treated as follows: a. the person is assessed at intervals of approximately 12 weeks and b. imatinib therapy at 400 mg/day is continued until the GIST ceases to respond % of people with KIT (CD117)-positive unresectable and/or KIT (CD117)-positive metastatic GIST who have been provided imatinib and whose GIST has responded to imatinib therapy None See above for definition of GIST response to treatment. 'Assessment' includes review of the findings of diagnostic imaging and clinical symptoms. . If progressive disease develops in a person whose GIST initially responded to imatinib therapy, the dose of imatinib is not increased % of people in whom progressive disease develops when the GIST responded initially to imatinib therapy A. In cases for which initial tumour flare reaction is possible, either symptoms must persist beyond 4 weeks or there must be additional evidence of progression B. Lesions that appear to increase in size due to presence of necrotic tissue are not considered to have progressed See above for definition of progressive disease. . A cancer specialist with experience in the management of people with metastatic and/or unresectable GISTs supervises the use of imatinib % of people with KIT (CD117)-positive unresectable and/or KIT (CD117)-positive metastatic GIST who have been provided imatinib None Clinicians will need to agree locally on what constitutes supervision of the use of imatinib for people with KIT (CD117)-positive unresectable and/or KIT (CD 117) positive metastatic GIST, for audit purposes. # Calculation of compliance Compliance (%) with each measure described in the table above is calculated as follows. Number of patients whose care is consistent with the criterion plus number of patients who meet any exception listed x 100 Number of patients to whom the measure applies Clinicians should review the findings of measurement, identify whether practice can be improved, agree on a plan to achieve any desired improvement and repeat the measurement of actual practice to confirm that the desired improvement is being achieved.# Appendix D. Southwest Oncology Group (SWOG) criteria for assessing tumour response SWOG criteria Definition Complete response (CR) Complete disappearance of all measurable and evaluable disease. No new lesions. No disease-related symptoms. No evidence of non-evaluable disease, including normalisation of markers and other relevant abnormal lab values. All measurable, evaluable and non-evaluable lesions and sites must be assessed using the same technique as baseline. Partial response (PR) Greater than or equal to 50% decrease under baseline in the sum of products of perpendicular diameters of all measurable lesions. No progression of evaluable disease. No new lesions. All measurable and evaluable lesions and sites must be assessed using the same techniques as baseline. Stable disease (SD) Does not qualify for CR, PR, progression or unknown. All measurable and evaluable sites must be assessed using the same technique used at baseline. Progressive disease (PD) % increase or an increase of 10 cm² (whichever is smaller) in the sum of products of all measurable lesions over smallest sum observed (over baseline if no decrease) using the same techniques as baseline, or clear worsening from previous assessment of any evaluable disease, or reappearance of any lesion which had disappeared, or appearance of any new lesion/site, or failure to return for evaluation due to death or deteriorating condition (unless clearly unrelated to this cancer). For 'scan-only' bone disease, increased uptake does not constitute clear worsening. Worsening of existing non-evaluable disease does not constitute progression. Exceptions: (1) In cases for which initial tumour flare reaction is possible (hypercalcaemia, increased bone pain, erythema of skin lesions), either symptoms must persist beyond 4 weeks or there must be additional evidence of progression. (2) Lesions that appear to increase in size due to presence of necrotic tissue will not be considered to have progressed. Unknown Progression has not been documented and one or more measurable or evaluable sites have not been assessed.# Changes after publication September 2013: correction to show that recommendation 1.5 had been updated by TA209, rather than recommendation 1.4. March 2012: minor maintenance. November 2010: This guidance has been partially updated by 'Imatinib for the treatment of unresectable and/or metastatic gastrointestinal stromal tumours' (NICE technology appraisal guidance 209). The changes are shown in section 1.# About this guidance NICE technology appraisal guidance is about the use of new and existing medicines and treatments in the NHS in England and Wales. We have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available. Your responsibility This guidance represents the views of NICE and was arrived at after careful consideration of the evidence available. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. However, the guidance does not override the individual responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or guardian or carer. Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties. Copyright © National Institute for Health and Clinical Excellence 2005. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.	{'Guidance': "November 2010: This guidance has been partially updated by 'Imatinib for the treatment of unresectable and/or metastatic gastrointestinal stromal tumours' (NICE technology appraisal guidance 209), as shown below.\n\nImatinib treatment at 400\xa0mg/day is recommended as first-line management of people with KIT (CD117)-positive unresectable and/or KIT (CD117)-positive metastatic gastro-intestinal stromal tumours (GISTs).\n\nContinuation with imatinib therapy is recommended only if a response to initial treatment is achieved within 12\xa0weeks.\n\nResponders should be assessed at intervals of approximately 12\xa0weeks thereafter. Continuation of treatment is recommended at 400\xa0mg/day until the tumour ceases to respond.\n\nAn increase in the dose of imatinib is not recommended for people receiving imatinib who develop progressive disease after initially responding.\n\nThis recommendation has been updated and replaced by NICE technology appraisal guidance 209.\n\nThe use of imatinib should be supervised by cancer specialists with experience in the management of people with unresectable and/or metastatic GISTs.", 'Clinical need and practice': "Gastro-intestinal stromal tumours (GISTs) are rare connective tissue tumours that show a differentiation profile similar to the interstitial cells of Cajal. They represent less than 1% of the tumours arising in the gastro-intestinal (GI) tract. Although GISTs can occur along the length of the GI tract, the majority arise in the stomach (60–70%), small bowel (25–35%), colon and rectum (5%) and, to a lesser extent, the oesophagus. Presenting features of these tumours depend on the size and location of the tumour and include abdominal discomfort or pain, a feeling of abdominal fullness and the presence of a palpable mass. However, many people with GISTs are asymptomatic during early stages of the disease until tumours reach a large size, at which time the tumours rupture and bleed or obstruct the GI tract.\n\nMost GISTs express the tyrosine kinase growth factor receptor c-KIT, which is detected by immunostaining with the antibody for the cell-surface marker CD117. Under normal conditions, this receptor is activated by stem-cell factor, which stimulates signal transduction pathways such as cell growth, differentiation and apoptosis (cell death). Most GISTs express a form of the tyrosine kinase receptor that is permanently 'switched on' (constitutively activated), leading to unregulated cell proliferation.\n\nUntil recently, there has been no appropriate test for the diagnosis of GIST. An immunohistochemical test for the presence of the cell-surface marker CD117 (present in 80–100% of GISTs) is now considered to be an appropriate diagnostic marker for the diagnosis of GIST. A diagnosis of GIST is made on the basis of histological characteristics of the tumour biopsy, clinical presentation and immunohistochemical profile, including a positive test for the CD117 marker.\n\nAs a result of difficulties in the diagnosis of GIST, estimates of its incidence vary widely, from 4 to 40 cases per million population, which corresponds to between 200 and 2000 new cases per year in England and Wales. Recent epidemiological data from Sweden suggest that the incidence of GIST is in the region of 15 per million per year. Approximately half of new cases of GIST are likely to be metastatic and/or unresectable on first presentation. Although GIST can occur at any age, the mean age of presentation is between 50 and 70 years.\n\nThe prognosis of people with GIST depends primarily on whether the tumour is resectable, although the size and location of the tumour and the stage of the tumour at initial diagnosis are also important prognostic indicators. A recent study suggested that the prognosis for unresectable and/or metastatic GIST is poor with few, if any, people surviving beyond 5\xa0years.\n\nComplete surgical resection is the treatment of choice for people presenting with GISTs amenable to surgery, but there is currently no effective treatment for people with unresectable and/or metastatic tumours. As GISTs are particularly resistant to conventional cytotoxic chemotherapy and radiotherapy, current treatment normally comprises symptom relief and best supportive care. This includes palliative care for the management of pain, fever, GI obstruction, and anaemia caused by GI haemorrhage.", 'The technology': "Imatinib (Novartis) is a signal-transduction inhibitor designed to selectively inhibit certain classes of tyrosine kinase that include the c-KIT receptor expressed in GIST. Imatinib binds to activated c-KIT receptors and blocks the cell signalling pathway to prevent uncontrolled cell proliferation. Imatinib was first licensed for the treatment of chronic myeloid leukaemia, for which NICE guidance exists (NICE Technology Appraisal Guidance No. 70 'Imatinib for chronic myeloid leukaemia').\n\nImatinib received European marketing authorisation in May 2002 for the treatment of adult patients with KIT (CD117)-positive unresectable and/or metastatic malignant GIST. Licensing approval was based largely on a single, uncontrolled phase II study in 147 patients. Recent developments in pathology suggest that a small minority of GISTs that test negative for the c-KIT receptor may also respond to imatinib. However, the evidence to support this is currently limited and the UK marketing authorisation for imatinib does not include the treatment of this group of tumours.\n\nThe manufacturer's summary of product characteristics recommends oral imatinib at a dose of 400\xa0mg/day for the treatment of unresectable and/or metastatic GIST, to be taken with a large glass of water at meal times. The licence also states that there are limited data on the effect of dose increases from 400\xa0mg/day to 600\xa0mg/day in patients whose disease progresses at the lower dose.\n\nImatinib costs £12.98 per 100\xa0mg (excluding VAT; British National Formulary 47, March 2004). The approximate annual acquisition cost of imatinib is between £19,000 (400\xa0mg/day) and £28,500 (600\xa0mg/day).", 'Evidence and interpretation': "The Appraisal Committee (see Appendix A) considered evidence from a number of sources (see Appendix B).\n\n# Clinical effectiveness\n\nNo randomised controlled trials (RCTs) were identified that compared imatinib treatment with best supportive care in patients with unresectable and/or metastatic GIST. In the absence of controlled studies, historical controls were identified to provide information on the natural history of advanced GIST. Many patients in these studies had received other treatments (such as chemotherapy or radiotherapy). These studies provide the most appropriate data for comparison with studies of imatinib treatment.\n\nThe Assessment Group identified 15 studies of imatinib treatment of c-KIT-positive GIST, which included six ongoing uncontrolled trials. Four of the uncontrolled trials were only available in abstract form at the time of the review, but one was published during the course of the appraisal. The Assessment Group also identified eight single case studies and one case series. In the absence of any controlled trials, the Assessment Group also identified 14 uncontrolled case-series and cohort studies, that is, comparator studies (one of which is currently unpublished).\n\nKey study outcomes included: survival; tumour status (tumour mass measured by computerised tomography [CT] or magnetic resonance imaging [MRI] and classified by response evaluation criteria in solid tumours [RECIST] or SWOG criteria); and Eastern Cooperative Oncology Group (ECOG) performance status (which measures functional status in everyday tasks, and which are also reported in quality-of-life measurement scales). Positron emission tomography (PET) imaging, reported in one study, provided information on the effect of imatinib on tumour metabolism.\n\n## Imatinib treatment\n\nStudy CSTI571-B2222 is a published ongoing phase II uncontrolled trial of imatinib treatment in 147 patients (91% of whom were c-KIT-positive) with unresectable and metastatic GIST, which formed the basis of the licence application. The manufacturer also provided updated results of this study, which are not yet fully published. Patients were randomly assigned to receive a single dose of 400\xa0mg (n\xa0=\xa073) or 600\xa0mg (n\xa0=\xa074) of imatinib. Patients received imatinib treatment for a median of 21\xa0months (range 7 to 783\xa0days). The study was not powered to distinguish statistically significant differences in the efficacy of imatinib treatment between the two study arms (400 and 600\xa0mg/day). The combined survival rate from the start of treatment was 88% at 1-year follow-up and 78% at 2-year follow-up. Median survival had not been reached after 31 months of follow-up.\n\nTumour response (based on SWOG criteria, Appendix D) evaluated at 21-month follow-up showed that 66% of patients achieved a partial response, 17% stable disease and 12% progressive disease (with 5% of patients being unevaluable). No patients achieved a complete response. The manufacturer's submission reported resistance to imatinib in 16 patients; 3 patients exhibited primary resistance (no response to imatinib) and a further 13 exhibited secondary resistance to imatinib (loss of response to imatinib).\n\nThere were substantial improvements in patients' ECOG performance status. At the 4-month follow-up, the proportion of patients with normal functional status (grade\xa00) had increased from 42% at baseline to 64%, and the number of patients with impaired functional status of grade\xa02 (capable of self-care but unable to work) had decreased from 18% at baseline to 5%. These improvements were maintained in the 21% of patients who were followed up to 25\xa0months.\n\nA published ongoing phase I study evaluated imatinib treatment at licensed doses of 400 and 600\xa0mg/day and unlicensed higher doses in 40 patients with advanced GIST (35 of whom were c-KIT-positive). After 9 to 12\xa0months of follow-up, survival from start of treatment was 90%. Tumour response was evaluated using RECIST criteria in the 35 patients who were c-KIT-positive: 51% achieved a partial response; 31% stable disease; and 8.5% progressive disease. Tumour function evaluated in 14 patients using PET imaging after 8 days of treatment showed that eight patients had achieved a complete response, two patients a partial response and one patient no change. The remaining three patients showed disease progression after 28\xa0days.\n\nOf the four trials that were unpublished at the time of the Assessment Group's review, two were non-randomised studies and two were randomised dose-response studies based on large patient samples. An ongoing European study comparing 400\xa0mg/day with (the unlicensed dose of) 800\xa0mg/day in 946 patients reported progression-free survival at 2\xa0years to be approximately 40% (400\xa0mg/day) and 55% (800\xa0mg/day). An interim analysis of this study published in abstract form (median follow-up of 8\xa0months) showed no significant differences between the two treatment arms. A second interim analysis of this trial presented to the Committee (median follow-up of 17\xa0months) showed that progression-free survival was significantly better with initial treatment at 800\xa0mg/day. A study based in the USA, comparing the same daily doses in 746 patients, reported progression-free survival at 6\xa0months to be 80% (400\xa0mg/day) and 82% (800\xa0mg/day).\n\nStudy CSTI571-B2222 (registration study) reported that at least one adverse event had been experienced by all 147 patients by 21\xa0months' follow-up. Of these, 37% were 'severe and undesirable' (grade 3) and 15% were 'life threatening and disabling' (grade 4). A total of 15 (10%) patients withdrew from the study because of adverse events; one third of these events were classed as drug-related. The most commonly reported side effects of imatinib include nausea, diarrhoea, periorbital oedema, muscle cramps, fatigue, rash and headache. The most common serious adverse events were unspecified haemorrhage and neutropenia, each event occurring in approximately 5% of patients. Overall, imatinib was well tolerated.\n\nPatient group submissions commented on the dramatic effect of imatinib, with the majority of patients experiencing improvements in disease-related symptoms (such as abdominal distension and pain) and reporting improved appetite and a feeling of well-being. Some patients were able to resume normal daily activities, which included a return to full-time employment.\n\nExpert testimony at the committee meeting provided evidence on the issue of resistance to imatinib. The clinical expert informed the Committee that, although data from the clinical trials are too premature to give definitive answers regarding resistance, they expect that approximately 40% of patients may become resistant to imatinib.\n\n## Case-series and cohort studies on the natural history of disease progression\n\nFourteen primary studies of alternative treatments (surgical resection, chemotherapy, radiotherapy and chemoembolisation) for patients with advanced GIST provided information on the natural history of disease.\n\nMedian survival reported in 12 papers (983 patients) ranged from 2 to 39\xa0months, with survival rates of 37–80% at 1-year follow-up, 6–45% at 3-year follow-up and 0–45% at 5-year follow-up. However, 12 out of 14 studies did not have the GIST diagnosis confirmed by c-KIT testing.\n\nData from an unpublished cohort study were used to represent the natural history of patients with GIST. A total of 143 c-KIT-positive patients (132 patients with recurrent or metastatic GIST) were included in the retrospective analysis. Of these, 91% had previously undergone surgical resection of the tumour, and all patients had received chemotherapy for a median duration of 55\xa0weeks. Patients surviving to the time when imatinib treatment became available were transferred to the treatment (n\xa0=\xa067). Survival outcomes were presented for all patients (irrespective of whether they received imatinib) and for patients who never received imatinib.\n\n# Cost effectiveness\n\nNo published cost-effectiveness analyses or quality-of-life studies for patients with advanced GIST were identified in the literature. The manufacturer submitted an economic model, and the Assessment Group re-analysed this model to overcome identified shortcomings. The Assessment Group also developed its own economic model, which was revised after discussion at the committee meeting to answer questions raised about some of the assumptions underpinning all the models.\n\nThe manufacturer's model estimated the incremental cost effectiveness of imatinib treatment compared with best supportive care. Patients in the control arm were assumed to start in a state of progressive disease, where they remained until death, on the basis of survival estimates extrapolated from the cohort study (using selected patients who never received imatinib only). All patients in the imatinib treatment arm were assumed to respond to imatinib treatment immediately. The probability of developing progressive disease after initial response was based on the results of the CSTI571-B2222 study. The data from both the trial and the cohort study were extrapolated to 10\xa0years using exponential curves. Estimates of health-related utility were derived by using clinical judgement to map ECOG performance status to a generic measure of health status (the EuroQol EQ-5D). The results of the model showed the incremental cost-effectiveness ratio (ICER) estimates to be £59,000 at 2\xa0years, £24,000 at 5\xa0years and £14,000 at 10\xa0years.\n\nThe Assessment Group modified the manufacturer's model to overcome some concerns that the Group considered would overestimate the cost effectiveness of imatinib. The first of two key amendments was to the model structure; it sought to rectify the overestimation of benefit of imatinib by using both the survival and time-to-treatment-failure curves from the registration study to estimate the proportion of patients in the imatinib health state. The second key change was to estimate survival with progressive disease from all patients included in the cohort study, including those who later went on to receive imatinib. The ICER estimates following all the modifications were £41,000 at 2\xa0years and £30,000 at 10\xa0years.\n\nAt the instruction of the Appraisal Committee, the Assessment Group, in conjunction with the NICE Decision Support Unit (DSU), was commissioned to develop its own economic model. Additional data from the cohort study (survival estimates, censored at the time imatinib became available) were sourced to improve the estimates of survival with progressive disease. One of the key differences between the DSU model and the other economic models was that the DSU model was structured so that all patients started in the same health state of progressive disease. Also, all the relevant censored data from the cohort study were used to estimate survival following progressive disease − that is, not just patients who died before they could be prescribed imatinib, but also survivors up to the point at which they were transferred to imatinib treatment. Another key difference was that the extrapolations of both the trial data and the censored cohort study data were based on all the data available and did not assume a constant hazard ratio. The estimates of utility were the same as those included in the manufacturer's economic model. The model was also structured to estimate the cost effectiveness of different policies regarding dose escalation.\n\nThe results of the DSU model suggest that the incremental cost per additional quality-adjusted life year is approximately £32,000 for patients on 400\xa0mg/day estimated over 10\xa0years. The incremental cost effectiveness of a policy allowing dose escalation to 600\xa0mg/day after failure of 400\xa0mg/day is approximately £39,000 at 10\xa0years compared with a policy of treatment with 400\xa0mg/day and no dose escalation.\n\n# Consideration of the evidence\n\nThe Committee reviewed the evidence available on the clinical and cost effectiveness of imatinib for the treatment of GIST, having considered evidence on the nature of the condition and the value placed by users on the benefits of imatinib from people with GIST, those who represent them, and clinical experts. It was also mindful of the need to ensure that its advice took account of the efficient use of NHS resources.\n\nThe Committee heard evidence from experts on the current treatment of patients with GIST, and it was aware that imatinib is the only effective treatment for metastatic and/or unresectable GIST. Experts advised that about half of all patients with GIST have unresectable and/or metastatic disease at presentation. Experts also advised that tumour response is most commonly assessed by CT scan (tumour size and density) or MRI scan (tumour size). The Committee also heard that although PET assessment of tumour metabolism at 1\xa0week post-treatment could provide early information on patients' responses to imatinib treatment, the PET technology is not currently routinely available. The Committee therefore considered that assessment of tumour response should be based principally on the SWOG criteria (Appendix D) because this classification of tumour response was reported in the published clinical study and formed the basis of all of the economic models. The Committee understood that estimates of SWOG response criteria are assessed by CT/MRI and that these include an element of assessment of symptoms and the need to note that tumour enlargement may be related to swelling associated with tissue necrosis. It was also persuaded that changes in the density of the tumour deposits as assessed by CT scanning may also indicate response to therapy, and that these changes should be included as part of the overall assessment of the response to imatinib. The Committee also concluded that further research into the use of PET for assessing tumour response would be beneficial.\n\nThe experts informed the Committee that patients with multiple lesions may experience tumour growth in some sites while the bulk of the tumour remains under control. The Committee carefully considered the SWOG criteria in relation to these situations. It acknowledged that the criteria would allow for an increase in tumour size of up to 50% or 10\xa0cm (whichever is smaller) in the sum of products of all measurable lesions over the smallest sum observed. The Committee also noted that lesions that appear to increase in size because of the presence of necrotic tissue are not considered to have progressed using the SWOG criteria. For these reasons, the Committee concluded that the use of SWOG criteria to assess response is appropriate.\n\nThe experts advised the Committee on the difficulties involved in diagnosing metastatic and/or unresectable GISTs, the assessment of response to treatment and determining the appropriate mix and timing of treatments (surgery or drug therapy) for these patients. The Committee therefore concluded that imatinib therapy should be used only under the supervision of an expert with experience in the treatment of these patients. It is understood that this may also include shared care of the management of these patients between experts in GIST with other cancer centres.\n\nThe Committee heard evidence that mutational analysis to determine whether patients have a mutation in KIT may enable clinicians to predict the patients who are most likely to respond to imatinib treatment, because patients with no mutations in KIT have a poorer prognosis. Although these tests are not widely available in the UK, the Committee believed that further research into their use to identify patients for whom imatinib may be particularly appropriate would be important.\n\nThe Committee carefully considered the appropriate length of time for which patients should receive imatinib after initiation of treatment before first assessment of response, and at what stage treatment should be considered to have failed. Experts advised that patients are usually evaluated (by an assessment of diagnostic imaging and clinical symptoms) at about 12\xa0weeks from the initiation of treatment, at which stage the disease is classified as complete response, partial response, stable disease or progressive disease. The experts also advised the Committee that a tumour response to imatinib, including stabilisation of disease, is usually seen within 12\xa0weeks of initiation of treatment. The Committee also considered evidence from various sources that the maximum response of GIST to imatinib may not be reached for up to 6 to 12 months from initiation of treatment. The Committee was, however, persuaded that the time taken to achieve an initial response would be significantly less than that taken to achieve a maximum response, as is evidenced from the PET scanning studies, which show that response to imatinib can be achieved within the first 2 weeks of treatment. Additionally, the Committee noted that all of the clinical trials included early review of patients as part of the assessment of response to treatment. The Committee considered, therefore, that patients should initially receive imatinib treatment for up to 12\xa0weeks before tumour response is evaluated, but that only patients responding to treatment (as defined in Section 1.5) by 12\xa0weeks should continue to be treated with imatinib until there is further evidence of disease progression. In making this judgment, the Committee took into account the fact that the definition of tumour response allows for an increase in the size of tumour(s) due to necrosis and swelling, and for stabilisation (that is, no change) of disease within the SWOG criteria.\n\nThe Committee considered the evidence on the effectiveness of the higher initial dose of imatinib of 600\xa0mg/day from the CSTI571-B2222 study and the evidence published in abstract form on the daily dose of 800\xa0mg. It concluded from the evidence reviewed that there was no difference in the effectiveness between initial doses of 400\xa0mg/day and 600\xa0mg/day. The Committee considered the early results from the two trials comparing initial doses of 400\xa0mg/day and 800\xa0mg/day. It acknowledged that the early interim results from one of these trials showed a non-significant benefit in progression-free survival from 800\xa0mg/day compared with 400\xa0mg/day, and that the later analysis of this trial showed a significant benefit from initial treatment at 800\xa0mg/day. The Committee also noted that the other trial showed very little difference between the two daily dosages. The Committee concluded that the data from these studies were too premature to draw firm conclusions. The Committee was also aware that the safety and tolerability of a daily dose of imatinib of 800\xa0mg has not yet been assessed by the Medicines and Healthcare products Regulatory Agency. The Committee concluded that it was unable to issue guidance on a dose of 800\xa0mg/day because this dosage has not yet received a UK marketing authorisation, and it was persuaded that the licensed dosage of 400\xa0mg/day was the most appropriate initial dose of imatinib.\n\nThe Committee considered evidence from the trials, and new information provided by the manufacturer, regarding dose escalation in patients with progressive disease. The Committee considered that the data on dose escalation were limited because the number of patients involved was small, the length of follow-up for these patients was short, and patients were not allocated to dose escalation by randomisation, possibly leading to bias in the results. The Committee considered all the evidence on dose escalation in relation to the economic models and concluded that dose escalation is not cost effective.\n\nThe Committee also considered views of the experts regarding dose escalation in patients with progressive disease following initial treatment. The experts advised that there is a lack of evidence supporting the effectiveness of dose escalation to 600\xa0mg/day. The Committee acknowledged that studies were ongoing to evaluate the effectiveness of an 800\xa0mg dose of imatinib, and it concluded that there is currently no robust evidence to suggest that continued treatment with imatinib (including dose escalation) in patients with progressive disease is cost effective.\n\nThe Committee carefully considered the most appropriate estimates of survival for a control group for imatinib treatment in the cost-effectiveness modelling. All the models used data from the same unpublished historical control study to represent the natural history of GIST, but differed in the selection of patients and whether the data were censored for when imatinib treatment became available. The Committee considered this data to be the most appropriate because all patients' tumours were diagnosed as CD117-positive. The Committee concluded that data on the survival of the control group, censored for when imatinib became available, was the least prone to bias and the best estimate of prognosis of untreated GIST.\n\nThe Committee considered the different methods of extrapolating the trial and cohort study data to a 10-year time horizon in the cost-effectiveness models. The DSU model, which did not assume constant hazard and used all of the available data for both the treatment and control groups, was considered to be the most appropriate method of extrapolation. The Committee concluded that the cost-effectiveness estimates based on a 10-year time horizon were the most appropriate, because this time horizon was likely to encompass the key costs and benefits. The Committee considered the results from extrapolating the data in relation to new information (at 152\xa0weeks' follow-up) provided by the manufacturer. The Committee acknowledged that the extrapolated time to progression in the DSU model was shorter, and that the extrapolated time to progression in the manufacturer's model was longer, than the time to progression shown by the new data supplied by the manufacturer. However, the Committee also noted that overall survival predicted using the DSU model was longer than suggested by the new data provided by the manufacturer. Thus, the Committee concluded that the ICER produced using the DSU model was likely to be an underestimate when considering this new data.\n\nThe Committee considered that the assumption that all patients would respond to imatinib immediately (as presented in the manufacturer's and Assessment Group model) was unlikely. The Committee concluded that the estimates of cost effectiveness based on the DSU model (in which all patients begin in the progressive phase) used the most appropriate available data and assumptions.\n\nThe Committee heard evidence from experts regarding likely tumour response rate in the event of dose escalation. The DSU model assumed that patients who are escalated to 600\xa0mg/day after disease progression on 400\xa0mg/day have the same response as when they initially responded to the lower dose. The experts advised the Committee that the time to treatment failure following dose escalation is likely to be substantially shorter than the initial response at 400\xa0mg/day. The Committee therefore considered that this assumption (of an equivalent length of response following dose escalation) used in the DSU economic model was more optimistic than suggested by the experts. The Committee also considered new evidence on response following dose escalation provided by the manufacturer. The Committee considered that the assumption about the proportion of patients responding to dose escalation in the economic model was more optimistic than supported by the evidence provided by the manufacturer. These conclusions supported their view on the inappropriateness of dose escalation in progressive disease, as in Sections 4.3.8 and 4.3.9.\n\nThe Committee heard testimony from the representative for patients with GIST and the clinical experts about the dramatic improvement in health-related quality of life associated with successful imatinib treatment. In addition, the Committee considered advice from a clinical expert that, in a minority of patients, imatinib treatment may be given until unresectable tumours shrink to a size at which they can be surgically resected. The expected survival of these patients is better than the expected survival of patients whose tumours remain unresectable. The Committee considered that both of these factors may not have been fully represented in the economic modelling. The Committee concluded that if data were available to model these issues more robustly, the ICERs would be slightly lower. However, it concluded that these factors did not alter its overall view of the cost effectiveness of imatinib therapy for GIST.\n\nExperts commented that current practice sometimes includes the continuation of imatinib treatment in patients with progressive disease (as assessed by CT/MRI), provided that they report a symptomatic benefit without objective evidence of response. However, the Committee considered that, because there is a lack of robust evidence on the effectiveness of extended treatment in these patients, and because a decrease in the overall rate of response to imatinib treatment would increase the ICERs to an unacceptable level, the use of imatinib in this context should be undertaken only as part of clinical studies.\n\nThe Committee was aware of the continuing research in this area and the emergence of new data published in abstract form during the consultation process. This new information included evidence relating to updated results from trials, dose escalation, assessment of response and discontinuation of imatinib therapy. The manufacturer also provided updated results for the CSTI571-B2222 study. The Committee considered that this evidence has not yet been fully peer reviewed and that much of the evidence relates to the unlicensed dose of imatinib of 800\xa0mg/day. The Committee considered this evidence and its relation to the results of the economic models when making its recommendations. The Committee concluded that it would be important to re-evaluate the recommendations when new evidence becomes fully available or if substantial changes are made to the marketing authorisation of imatinib.", 'Recommendations for further research': 'A national register of all patients receiving imatinib treatment for GIST should be maintained. Details could include patient characteristics, dose and duration of treatment, mutational analysis, tumour response rates and survival both with and after discontinuation of imatinib treatment. The response rates of patients who have received escalated doses of imatinib treatment in the context of clinical trials could also be included.\n\nThe key dose-response trials for imatinib for metastatic and/or unresectable GIST are still in progress. There are also studies assessing the use of imatinib in patients with metastatic and/or unresectable GIST that have been published in abstract form, and many report interim results.\n\nThe Institute recommends that further trials be undertaken to evaluate the benefit of maintenance therapy at 400\xa0mg/day for patients with progressive disease, and the response rate of patients after switching to higher doses of imatinib treatment. The effectiveness of dose escalation should be evaluated for patients who do not respond to imatinib treatment at 400\xa0mg/day, and for patients who initially respond to the lower dose but later develop progressive disease. These trials should incorporate measures of health-related quality of life. Information on survival following withdrawal of imatinib treatment should also be collected.\n\nThe Institute considered that studies should be conducted to assess:\n\nthe effectiveness of PET assessment for the measurement of tumour response\n\nthe use of mutational analysis to predict individual responses to imatinib treatment.', 'Implications for the NHS ': 'The cost impact of this guidance will depend on: the number of patients with unresectable and/or metastatic GIST; the proportion of patients who receive imatinib; the proportion of patients who respond to imatinib treatment; the duration of treatment; the price of imatinib; and the number of patients already prescribed imatinib for GIST.\n\nEstimates of the annual incidence of GIST vary considerably. The manufacturer of imatinib estimated the number of new cases of unresectable and/or metastatic GIST to be between 80 and 240 people each year. It has also been suggested that current estimates of the incidence of GIST are underestimates, and these figures may increase as more tumours of patients with GIST are tested for c-KIT. The annual drug cost of imatinib is just under £19,000. Assuming that there will be 240 new patients eligible for imatinib treatment for GIST and that patients will be monitored by an average of four CT scans per year, the total cost of treating new patients in accordance with the guidance will be approximately £4.7\xa0million in the first year. Assuming that the incidence rate does not change and that patients remain on imatinib treatment for an average of 1.44\xa0years (as predicted by the DSU economic model), the total cost of treating patients with imatinib for GIST will be approximately £6.8\xa0million when the number of patients receiving imatinib has reached a steady state.\n\nThe resource impact of this guidance on the NHS will depend on the number of patients currently receiving NHS prescriptions for imatinib for the treatment of GIST. Using the assumptions set out in Section 6.2, if 25% of eligible patients currently receive NHS prescriptions for imatinib for GIST, the additional cost of implementing this guidance will be approximately £5.1\xa0million. If 75% of eligible patients are currently being treated with imatinib, the impact of the guidance will be less, at about £1.7\xa0million. These estimates are based on a number of assumptions and could be much less if switching to higher doses of imatinib is reduced. The estimates may also be reduced further if GIST patients receive imatinib treatment as a result of the guidance rather than receiving inappropriate surgery or chemotherapy treatment.', 'Related guidance': 'National Institute for Clinical Excellence (2003) Guidance on the use of imatinib for chronic myeloid leukaemia.NICE Technology Appraisal Guidance No. 70. London: National Institute for Clinical Excellence.', 'Review of guidance': 'The review date for a technology appraisal refers to the month and year in which the Guidance Executive will consider whether the technology should be reviewed.\xa0 This decision will be taken in the light of information gathered by the Institute, and in consultation with consultees and commentators.\n\nThe guidance on this technology will be reviewed in October 2007.\n\nAndrew DillonChief ExecutiveOctober 2004', 'Appendix C. Detail on criteria for audit of the use of imatinib for the treatment of unresectable and/or metastatic gastro-intestinal stromal tumours': "# Possible objectives for an audit\n\nAn audit on the appropriateness and effectiveness of use of imatinib for the treatment of unresectable and/or metastatic GIST could be carried out to ensure the following.\n\nImatinib is used appropriately for the treatment of unresectable and/or metastatic GISTs.\n\nThe use of imatinib for the treatment of unresectable and/or metastatic GISTs is supervised by an appropriate cancer specialist.\n\n# Possible patients to be included in the audit\n\nAn audit could be carried out on patients diagnosed with KIT (CD117)-positive unresectable and/or KIT (CD117)-positive metastatic GIST over a reasonable time period for audit. In view of the small number of patients who may be eligible for inclusion in the audit, all patients should be included in the audit and it may be desirable to collect data for the audit concurrent with treatment.\n\n# Measures that could be used as a basis for an audit\n\nThe measures that could be used in an audit on the use of imatinib for the treatment of unresectable and/or metastatic GISTs are as follows.\n\nCriterion\n\nStandard\n\nException\n\nDefinition of terms\n\n. For a person with KIT (CD117)-positive unresectable and/or KIT (CD117)-positive metastatic GIST, imatinib therapy is provided as first-line management as follows:\n\na. at 400\xa0mg/day and\n\nb. for up to 12\xa0weeks\n\n% of people with KIT (CD117)-positive unresectable and/or KIT (CD117)-positive metastatic GIST\n\nNone\n\n\n\n. Imatinib therapy at 400\xa0mg/day is continued beyond the first 12\xa0weeks only if the person's GIST has responded to treatment within 12\xa0weeks\n\n% of people with KIT (CD117)-positive unresectable and/or KIT (CD117)-positive metastatic GIST who have been provided imatinib\n\nNone\n\n'GIST response to treatment' is assessed by imaging to assess the size and density of the tumour(s), patients' symptoms and other factors, and is classified as complete response, partial response or stable disease as defined by the SWOG criteria (see Appendix D).\n\n. A person whose GIST has responded to imatinib therapy is treated as follows:\n\na. the person is assessed at intervals of approximately 12 weeks and\n\nb. imatinib therapy at 400 mg/day is continued until the GIST ceases to respond\n\n% of people with KIT (CD117)-positive unresectable and/or KIT (CD117)-positive metastatic GIST who have been provided imatinib and whose GIST has responded to imatinib therapy\n\nNone\n\nSee above for definition of GIST response to treatment.\n\n'Assessment' includes review of the findings of diagnostic imaging and clinical symptoms.\n\n. If progressive disease develops in a person whose GIST initially responded to imatinib therapy, the dose of imatinib is not increased\n\n% of people in whom progressive disease develops when the GIST responded initially to imatinib therapy\n\nA. In cases for which initial tumour flare reaction is possible, either symptoms must persist beyond 4 weeks or there must be additional evidence of progression\n\nB. Lesions that appear to increase in size due to presence of necrotic tissue are not considered to have progressed\n\nSee above for definition of progressive disease.\n\n. A cancer specialist with experience in the management of people with metastatic and/or unresectable GISTs supervises the use of imatinib\n\n% of people with KIT (CD117)-positive unresectable and/or KIT (CD117)-positive metastatic GIST who have been provided imatinib\n\nNone\n\nClinicians will need to agree locally on what constitutes supervision of the use of imatinib for people with KIT (CD117)-positive unresectable and/or KIT (CD 117) positive metastatic GIST, for audit purposes.\n\n# Calculation of compliance\n\nCompliance (%) with each measure described in the table above is calculated as follows.\n\nNumber of patients whose care is consistent with the criterion plus number of patients who meet any exception listed\n\n\n\nx 100\n\nNumber of patients to whom the measure applies\n\nClinicians should review the findings of measurement, identify whether practice can be improved, agree on a plan to achieve any desired improvement and repeat the measurement of actual practice to confirm that the desired improvement is being achieved.", 'Appendix D. Southwest Oncology Group (SWOG) criteria for assessing tumour response': "SWOG criteria\n\nDefinition\n\nComplete response (CR)\n\nComplete disappearance of all measurable and evaluable disease. No new lesions. No disease-related symptoms. No evidence of non-evaluable disease, including normalisation of markers and other relevant abnormal lab values. All measurable, evaluable and non-evaluable lesions and sites must be assessed using the same technique as baseline.\n\nPartial response (PR)\n\nGreater than or equal to 50% decrease under baseline in the sum of products of perpendicular diameters of all measurable lesions. No progression of evaluable disease. No new lesions. All measurable and evaluable lesions and sites must be assessed using the same techniques as baseline.\n\nStable disease (SD)\n\nDoes not qualify for CR, PR, progression or unknown. All measurable and evaluable sites must be assessed using the same technique used at baseline.\n\nProgressive disease (PD)\n\n% increase or an increase of 10 cm² (whichever is smaller) in the sum of products of all measurable lesions over smallest sum observed (over baseline if no decrease) using the same techniques as baseline, or clear worsening from previous assessment of any evaluable disease, or reappearance of any lesion which had disappeared, or appearance of any new lesion/site, or failure to return for evaluation due to death or deteriorating condition (unless clearly unrelated to this cancer). For 'scan-only' bone disease, increased uptake does not constitute clear worsening. Worsening of existing non-evaluable disease does not constitute progression.\n\nExceptions: (1) In cases for which initial tumour flare reaction is possible (hypercalcaemia, increased bone pain, erythema of skin lesions), either symptoms must persist beyond 4\xa0weeks or there must be additional evidence of progression. (2) Lesions that appear to increase in size due to presence of necrotic tissue will not be considered to have progressed.\n\nUnknown\n\nProgression has not been documented and one or more measurable or evaluable sites have not been assessed.", 'Changes after publication': "September 2013: correction to show that recommendation 1.5 had been updated by TA209, rather than recommendation 1.4.\n\nMarch 2012: minor maintenance.\n\nNovember 2010: This guidance has been partially updated by 'Imatinib for the treatment of unresectable and/or metastatic gastrointestinal stromal tumours' (NICE technology appraisal guidance 209). The changes are shown in section 1.", 'About this guidance': 'NICE technology appraisal guidance is about the use of new and existing medicines and treatments in the NHS in England and Wales.\n\nWe have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available.\n\nYour responsibility\n\nThis guidance represents the views of NICE and was arrived at after careful consideration of the evidence available. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. However, the guidance does not override the individual responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.\n\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.\n\nCopyright\n\n© National Institute for Health and Clinical Excellence 2005. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.'}	https://www.nice.org.uk/guidance/ta86	Evidence-based recommendations on imatinib for treating unresectable or metastatic gastrointestinal stromal tumours in adults.
82bd19556510f2d927f4371f065d3f5c2257c4e0	nice	Denosumab for the prevention of osteoporotic fractures in postmenopausal women	Denosumab for the prevention of osteoporotic fractures in postmenopausal women Evidence-based recommendations on denosumab (Prolia) for preventing osteoporotic fragility fractures in postmenopausal women. # Guidance Denosumab is recommended as a treatment option for the primary prevention of osteoporotic fragility fractures only in postmenopausal women at increased risk of fractures: who are unable to comply with the special instructions for administering alendronate and either risedronate or etidronate, or have an intolerance of, or a contraindication to, those treatments and who have a combination of T-score, age and number of independent clinical risk factors for fracture (see section 1.3) as indicated in the following table. T-scores (SD) at (or below) which denosumab is recommended when alendronate and either risedronate or etidronate are unsuitable Number of independent clinical risk factors for fracture Age (years) -r older Treatment with denosumab is not recommended. Denosumab is recommended as a treatment option for the secondary prevention of osteoporotic fragility fractures only in postmenopausal women at increased risk of fractures who are unable to comply with the special instructions for administering alendronate and either risedronate or etidronate, or have an intolerance of, or a contraindication to, those treatments. For the purposes of this guidance, independent clinical risk factors for fracture are parental history of hip fracture, alcohol intake of 4 or more units per day, and rheumatoid arthritis. People currently receiving denosumab for the primary or secondary prevention of osteoporotic fragility fractures who do not meet the criteria specified in recommendations 1.1 or 1.2 should have the option to continue treatment until they and their clinician consider it appropriate to stop. T-score measures bone mineral density using central (hip and/or spine) dual-energy X-ray (DXA) scanning, and is expressed as the number of standard deviations (SD) below peak bone mineral density.# The technology Denosumab (Prolia, Amgen) is a monoclonal antibody that reduces osteoclast activity, and so reduces bone breakdown. Denosumab has a UK marketing authorisation for the treatment of osteoporosis in postmenopausal women at increased risk of fractures. The summary of product characteristics states in the indication that denosumab significantly reduces the risk of vertebral, non-vertebral and hip fractures. The summary of product characteristics states that conditions associated with denosumab treatment include: urinary tract infection, upper respiratory tract infection, sciatica, cataracts, constipation, rash, pain in extremity and skin infections (predominantly cellulitis). However, there was no evidence of increased incidence of cataracts or diverticulitis in postmenopausal women with osteoporosis; these conditions occurred only in patients with prostate cancer. The summary of product characteristics states that osteonecrosis of the jaw has been reported in patients receiving denosumab or bisphosphonates, with most cases occurring in people with cancer, but some occurred in people with osteoporosis. For full details of side effects and contraindications, see the summary of product characteristics. Denosumab is administered as a single subcutaneous injection into the thigh, abdomen or back of the arm. The recommended dosage is 60 mg once every 6 months. The acquisition cost of denosumab is £183 for a 1 ml pre-filled syringe (60 mg per ml solution; excluding VAT, 'MIMS' September 2010 edition), which is equivalent to £366 for 1 year of treatment. Costs may vary in different settings because of negotiated procurement discounts.# The manufacturer's submission The Appraisal Committee (appendix A) considered evidence submitted by the manufacturer of denosumab and a review of this submission by the Evidence Review Group (ERG; appendix B). The manufacturer's submission presented data for clinical effectiveness from one main randomised trial, the FREEDOM (fracture reduction evaluation of denosumab in osteoporosis every 6 months) study. This multicentre, double-blind, placebo-controlled trial enrolled 7868 postmenopausal women aged 60–90 years with T-scores of less than −2.5 SD and greater than −4.0 SD at lumbar spine, total hip, or both locations. The T-score measures bone mineral density using central (hip and/or spine) DXA scanning and is expressed as the number of standard deviations (SD) below the mean bone mineral densityof young, healthy adults of the same gender at their peak bone mass. Lower T-scores indicate lower bone mineral density. Women were randomly assigned to receive a subcutaneous injection of either 60 mg denosumab or placebo twice a year for 3 years. All participants also took daily calcium and vitamin D supplements. The primary outcome was the incidence of new radiographically diagnosed vertebral fractures. Secondary outcomes were time to first non-vertebral fracture and time to first hip fracture. Health-related quality of life was assessed in terms of change from baseline in patient-reported outcomes using both the osteoporosis assessment questionnaire-short version (OPAQ-SV; physical function, emotional status and back pain score), and the EUROQOL-5D (EQ-5D) questionnaire. The results of the FREEDOM study demonstrated that, based on the number of people who underwent spinal radiography at baseline and during at least one visit after baseline, the 36-month incidence of new radiographically diagnosed vertebral fractures was 2.3% (86 of 3702 women) in the denosumab group compared with 7.2% (264 of 3691 women) in the placebo group (relative risk 0.32, 95% confidence interval 0.26 to 0.41; p < 0.001). The reduction in risk was similar during each year of the trial. Similar reductions in incidence were seen for clinically diagnosed vertebral fractures (0.8% for denosumab versus 2.6% for placebo; hazard ratio 0.31, 95% CI 0.20 to 0.47; p < 0.001) and for multiple new radiographically diagnosed vertebral fractures (0.6% for denosumab versus 1.6% for placebo; RR 0.39, 95% CI 0.24 to 0.63; p < 0.001). Denosumab also reduced the risk of non-vertebral fracture (6.5% for denosumab versus 8.0% for placebo; HR 0.80, 95% CI 0.67 to 0.95; p = 0.01) and hip fracture (0.7% for denosumab versus 1.2% for placebo; HR 0.60, 95% CI 0.37 to 0.97; p = 0.04). The manufacturer stated that dropout rates were similar between groups and no imbalances were observed. Health-related quality of life was assessed using the OPAQ-SV and EQ-5D questionnaire at baseline and every 6 months for 3 years. Among women who completed the study, completion rates for measures of health-related quality of life at year 3 were 83% for OPAQ-SV and 82% for EQ-5D. No significant differences were seen between treatment groups in measures of health-related quality of life at baseline compared with year 3, or between women without any fractures and those with incident clinical fractures. Changes from baseline to year 3 for each OPAQ-SV dimension and EQ-5D scores were positively correlated (all p < 0.0001). A statistically significant difference was noted in skin infections, which occurred in 12 women receiving denosumab compared with one woman receiving placebo (p = 0.002). However, when all studies of denosumab were pooled in the manufacturer's meta-analysis, the overall incidences of adverse events, serious adverse events and adverse events leading to treatment withdrawal were generally similar between denosumab and placebo groups. Further safety data were available from 30 studies, giving a total of 14,000 patients, including 11,000 postmenopausal women with low bone density or osteoporosis, as well as people taking denosumab for preventing bone loss in prostate or breast cancer. The manufacturer stated that it was mindful of the need for efficient use of NHS resources, and that, given the wide availability of generic oral bisphosphonates, denosumab was expected to be an option for women in whom oral bisphosphonates are unsuitable (reasons for unsuitability are that the woman is unable to comply with the special instructions for the administration of oral bisphosphonates, or has a contraindication to or is intolerant of oral bisphosphonates). Therefore denosumab was not expected to compete with oral bisphosphonates in clinical practice. In the absence of head-to-head clinical trials comparing denosumab with all relevant comparators (denosumab, strontium ranelate, raloxifene, teriparatide and zoledronate), the manufacturer carried out a random-effects meta-analysis of the relative risks (RRs) for all fracture endpoints directly comparing each treatment against placebo. The fracture incidence data (and RRs) for strontium ranelate for hip and wrist fracture were taken from the publication by Reginster et al. (2008) which reported 5-year data from the TROPOS study. As outlined in the table 1 below, the results of the manufacturer's meta-analysis showed that all treatments were associated with statistically significant decreases in the risk of morphometric vertebral fractures compared with placebo. Denosumab, strontium ranelate and zoledronate were associated with statistically significant decreases in the risk of clinical vertebral fractures, but raloxifene was not (no data were available for teriparatide). Similarly, denosumab, strontium ranelate, teriparatide and zoledronate were associated with statistically significant decreases in the risk of non-vertebral fractures, but raloxifene was not. Denosumab and zoledronate were associated with statistically significant decreases in the risk of hip fractures but strontium ranelate, and teriparatide were not (no data were available for raloxifene). None of the treatments were associated with a statistically significant decrease in the risk of wrist fracture. Table 1 Manufacturer's direct comparison of each comparator with placebo from the random effects meta-analysis Comparator Clinically diagnosed vertebral fracture (relative risk ) Non-vertebral fractures (relative risk ) Hip fracture(relative risk ) Wrist fracture(relative risk ) Denosumab (0.21 to 0.48)* (0.69 to 0.96)* (0.37 to 1.0)* (0.64 to 1.1) Zoledronate (0.14 to 0.37)* (0.65 to 0.87)* (0.42 to 0.83)* Raloxifene (0.05 to 3.82) (0.16 to 2.65) Strontium ranelate (0.50 to 0.84)* (0.78 to 0.99)* (0.67 to 1.2) (0.73 to 1.31) CI, confidence interval. *Statistically significant (p ≤ 0.05). The manufacturer's submission included a systematic review of the cost-effectiveness evidence for denosumab. The manufacturer carried out Markov cohort modelling to assess the cost effectiveness of denosumab against primary and secondary comparators. Primary comparators were strontium ranelate, raloxifene and no treatment (placebo). Secondary comparators were intravenous ibandronate, zoledronate and teriparatide. The manufacturer stated that denosumab is expected to be a treatment option for women with osteoporosis for whom oral bisphosphonates are unsuitable. Therefore, comparisons with oral bisphosphonates were not directly relevant to this appraisal and were included in appendices to the manufacturer's submission. The manufacturer stated that 71.6% of women receiving treatment for osteoporosis in England and Wales receive alendronate, 15.8% receive risedronate, 1.5% receive etidronate and 4.3% receive oral ibandronate, meaning that 93.2% of this population receive oral bisphosphonates (2009 figures). This means an estimated 6.8% of women receiving treatment for osteoporosis in England and Wales receive drugs other than oral bisphosphonates (2.8% strontium ranelate, 2.2% raloxifene, 0.6% intravenous ibandronate, 0.7% zoledronate, 0.2% calcitonin, 0.2% calcitriol and 0.1% teriparatide). The manufacturer stated that persistence and compliance with oral bisphosphonates are poor because of the strict and complex dosing regimen and side effects of treatment. The manufacturer's submission stated that at least 42% of patients taking oral bisphosphonates stop within 1 year, and the median duration of treatment is estimated to be as low as 1.2 years. The manufacturer stated that few people (< 1%) permanently discontinued denosumab treatment because of treatment-related adverse events over 2–3 years in the FREEDOM study. The model assessed the cost effectiveness of denosumab against the primary and secondary comparators for two separate cohorts. The first investigated the primary prevention of fragility fractures in women (70 years and over) with osteoporosis (T-score of −2.5 SD or below) for whom oral bisphosphonates are unsuitable. The second investigated the secondary prevention of subsequent fragility fractures in women (70 years and over) with osteoporosis (T-scores of −2.5 SD or below) and prior fragility fractures in whom oral bisphosphonates are unsuitable. The model had a cycle length of 6 months and a lifetime horizon (defined as until time of death or age of 100 years), including a half-cycle correction, with a treatment duration of 5 years. The model included six discrete health states: well, hip fracture, clinically diagnosed vertebral fracture, wrist fracture, other types of fracture (pelvic, femur shaft, tibia, fibular, humerus, scapula, clavicle, rib or sternum), and death. It included two additional health states (post-hip fracture and post-vertebral fracture) to account for the long-term costs and effects associated with these fractures (no long-term costs or effects were assumed for women with wrist or other fractures). When a fracture occurred, women were modelled to remain in the respective fracture state for two cycles (1 year). After this period, women with a wrist fracture or other types of fracture were modelled to return to the well state. Women with a vertebral fracture or hip fracture were modelled to enter a post-fracture state. Women who had a vertebral fracture could no longer incur a wrist fracture or other type of osteoporotic fracture (other than a subsequent vertebral fracture or hip fracture). Women who had a hip fracture could only incur further hip fractures. The manufacturer's model was not a treatment-sequencing model because of the lack of clinical evidence for such use. The manufacturer's base-case analysis assumed that women continued osteoporosis therapy for 5 years, and costs and quality-adjusted life years (QALYs) were tracked over the lifetime of the cohorts (consistent with economic modelling in 'Alendronate, etidronate, risedronate, raloxifene and strontium ranelate for the primary prevention of osteoporotic fragility fractures in postmenopausal women' and 'Alendronate, etidronate, risedronate, raloxifene, strontium ranelate and teriparatide for the secondary prevention of osteoporotic fragility fractures in postmenopausal women' ). This assumption was examined in a sensitivity analysis. Subgroup analysis was undertaken for women with and without prior fracture by age (55–75, 5-year age bands) and T-score (between −2.5 to −4.0 SD). Sensitivity analysis assessed the effect on cost effectiveness of the presence or absence of additional independent clinical risk factors for fracture in women of 70 years of age, with and without prior fragility fractures. Sensitivity analysis also assessed the effects on cost effectiveness of differences in treatment persistence and compliance. In the manufacturer's base-case analysis, fracture risks were estimated on the basis of epidemiological literature, and were based on three main elements: general population fracture risk, increased fracture risk associated with osteoporosis, and risk reduction attributed to treatment (if any). A systematic review of the literature was undertaken to identify appropriate UK studies or systematic reviews for all three model parameters. Age-specific fracture risks were estimated for women in the general population (using a study by Singer et al. to estimate risk of wrist and hip fractures, and a study by Kanis et al. to derive estimates for the incidence of clinically diagnosed vertebral and other fractures). Next, age-matched Z-scores (that is, the estimate of the number of SD below the mean bone mineral density of the general population for the patient's age and sex) were estimated for a cohort with osteoporosis using the National Health and Nutrition Examination Survey (NHANES) III database. Evidence from the systematic review was then used to attribute age-specific relative risks for the different types of fracture. Treatment was modelled to continue for 5 years by applying relative risks to the estimated baseline risks of fracture in the cohort with osteoporosis. An assumption was made that, on stopping treatment after 5 years, women would return in a linear fashion to baseline risk levels over 1 year (a return to baseline over 5 years was assumed in NICE technology appraisal guidance 160 and 161). The relative risks of fracture for each treatment for clinical vertebral, hip and wrist fractures were estimated from the manufacturer's direct comparison for each treatment against placebo if data were available. If evidence was not available for a comparator, the following explicit assumptions were made: that for interventions without data for the relative risk of clinical vertebral fracture, this was equivalent to the relative risk of morphometric vertebral fracture that the relative risk for interventions for which data for wrist and hip fractures were not available was 1.00. that since no efficacy evidence was identified for intravenous ibandronate compared with placebo, efficacy was equivalent to that of oral ibandronate that the relative risk for other fractures was 1.00 for all treatments, because 'other fracture' was not defined consistently across studies. The model accounted for observed increases in the risk of mortality after fracture by applying relative risks for mortality obtained from a review of the literature. An increased risk was modelled for the first year and subsequent years after hip fracture or vertebral fracture. For other types of fracture, women were modelled to be at increased risk of mortality for 1 year only. The relative risks of mortality after all types of fracture were adjusted downwards to account for the observation that a proportion of mortality after fracture is explained by comorbidity. It was assumed that 30% of all mortality after all types of fracture is causally related, which is consistent with similar assumptions in NICE technology appraisal guidance 160 and 161. The manufacturer's model also took into account persistence and compliance. Persistence is defined as the duration of time from start to end of therapy, and compliance is defined as conforming to the recommendations made by the provider with respect to timing, dosage and frequency of medication taking. Persistence and compliance were assumed to be 100% for the 5-year treatment period for all modelled treatments. Sensitivity analysis was carried out for oral therapies and denosumab. Women completed the EQ-5D questionnaire in the FREEDOM study, but the number of fracture events with associated EQ-5D scores recorded was low and the trial design precluded assessment of health status immediately after fracture events. Therefore, evidence from the manufacturer's systematic review of the literature on health-related quality of life in osteoporosis was considered to be more meaningful and was applied in the economic analysis. The disutilities associated with fracture were obtained from a systematic review of the literature and applied to population norms in the form of utility multipliers. Utility loss associated with hip and vertebral fractures was modelled in a two-stage process, with a larger decrease in the first year after fracture and an ongoing but less severe utility loss in subsequent years. Utility multipliers for the first and subsequent years after hip fracture were obtained from a meta-analysis of studies using the EQ-5D responses. Utility loss associated with clinically diagnosed vertebral fracture was estimated separately for women managed in hospital and in primary care. The disutilities for women in hospital were derived from the EQ-5D scores of a cohort that were predominantly in hospital. The disutilities for women who were not in hospital were obtained from cohorts with prevalent morphometric fractures. Utility multipliers associated with wrist fracture were also obtained from the literature and applied in the model for 1 year after the event. Because of an absence of evidence, the same multiplier and the same approach were also used to model utility loss associated with other types of fractures. Finally, utility losses associated with selected adverse events were also included in the model. Treatment costs and quality-of-life losses associated with wrist fracture or other types of fracture were modelled to last 1 year. Clinically diagnosed vertebral fractures and hip fractures were modelled to incur ongoing costs and loss of quality of life. Costs of drug treatment were estimated using the 'British national formulary' (edition 58), with assumptions about the costs of administration and monitoring for the comparators. Fracture costs were estimated using hospital episode statistics for England and Wales in conjunction with the Department of Health's Healthcare Resource Group tariff; assumptions about the proportion of women treated in hospital, with and without surgery, for the different fracture types were informed by a combination of expert opinion, review of the literature and analysis of routine data. Costs associated with severe adverse events (such as gastrointestinal adverse events associated with oral therapies and cellulitis associated with denosumab) were included. Other types of adverse events associated with denosumab and its comparators were not included. The results of the manufacturer's base-case analysis (pairwise comparisons) for the primary comparators showed that, for primary prevention, the incremental cost-effectiveness ratios (ICERs) for denosumab were £29,223 per QALY gained compared with no treatment and £9289 per QALY gained compared with raloxifene, and denosumab dominated strontium ranelate (that is, denosumab was less costly and more effective). For secondary prevention, the ICERs for denosumab were £12,381 per QALY gained compared with no treatment, £2046 per QALY gained compared with raloxifene, and denosumab dominated strontium ranelate. ICERs compared with no treatment for primary prevention were £74,239 per QALY gained for raloxifene and £102,592 per QALY gained for strontium ranelate. ICERs compared with no treatment for secondary prevention were £24,524 per QALY gained for raloxifene and £37,123 per QALY for strontium ranelate. The results of the manufacturer's base-case analysis (pairwise comparisons) for the secondary comparators showed that denosumab was the lowest-cost treatment. For primary prevention, the ICERs for the other treatments compared with denosumab were £70,900 per QALY gained for zoledronate, £772,424 per QALY gained for teriparatide, and denosumab dominated ibandronate. For secondary prevention, the ICERs for the other treatments compared with denosumab were £29,029 per QALY gained for zoledronate, £451,269 per QALY gained for teriparatide, and denosumab dominated ibandronate. The manufacturer presented a subgroup analysis to demonstrate how the cost effectiveness of denosumab varied when using different treatment cut-offs (that is, all women with a T-score at or below −2.5, −3, −3.5 SD and so on). The manufacturer provided further subgroup analyses for women with and without prior fracture by age and T-score. The results of the manufacturer's subgroup analyses showed that the cost effectiveness of denosumab improved as age increases and as T-score decreases, and with the presence of a prior fragility fracture. For primary prevention, in circumstances in which none of the treatments appraised by NICE are recommended, and oral bisphosphonates are unsuitable, the ICER for denosumab compared with no treatment varied between £19,313 and £71,319 per QALY gained. In circumstances in which strontium ranelate is recommended for primary prevention, denosumab dominated strontium ranelate (that is, denosumab was more effective and less costly). For secondary prevention, in circumstances in which no treatment is currently recommended in the NHS, the ICER for denosumab compared with no treatment varied between £12,289 and £22,957 per QALY gained. In circumstances in which strontium ranelate is recommended for secondary prevention, denosumab dominated strontium ranelate, and in circumstances in which raloxifene is recommended for secondary prevention, denosumab dominated raloxifene or had an ICER of £2046 per QALY gained. The manufacturer also provided a subgroup analysis using the FRAX algorithm (an internet-based tool developed by the World Health Organization to calculate a 10-year absolute risk of fracture). This showed how cost effectiveness varied depending on T-score and the presence or absence of independent clinical risk factors for fracture. The results demonstrated that the presence of independent clinical risk factors for fracture, particularly rheumatoid arthritis, also improved the cost effectiveness of denosumab compared with the primary comparators (strontium ranelate, raloxifene and no treatment). The manufacturer conducted a range of deterministic and probabilistic sensitivity analyses. The results of the deterministic sensitivity analyses showed that alterations to most key parameters had limited impact on comparisons of denosumab with raloxifene, strontium ranelate and no treatment. The impact on comparisons with intravenous ibandronate, zoledronate and teriparatide were most sensitive to changes in assumptions about the cost of denosumab administration. The manufacturer carried out sensitivity analyses that assumed one administration of denosumab in secondary care per year. Under this scenario, the ICER for denosumab compared with no treatment rose to £36,185 per QALY gained in women with no prior fragility fracture, and to £15,720 per QALY gained in women with a prior fragility fracture. This change led to zoledronate dominating denosumab in women with and without a prior fragility fracture. Following a request from the ERG, the manufacturer also carried out a sensitivity analysis in which denosumab treatment was assumed to be started in secondary care and thereafter delivered in general practice. This analysis showed that the additional cost associated with initiating treatment with denosumab in a secondary care setting had a marginal impact on the cost-effectiveness of denosumab compared with both primary and secondary comparators. The ERG also requested that the manufacturer provided further analysis assuming equal efficacy of denosumab and zoledronate for the prevention of wrist fractures. This analysis showed that the ICER for denosumab was moderately sensitive to assumptions about the relative efficacy of the two drugs for the prevention of wrist fractures. After consultation, the manufacturer carried out additional sensitivity analyses on the long-term effects of fractures on mortality and nursing home care using the conservative assumption that nursing home admission was zero. These analyses showed no substantial impact on the cost-effectiveness results with the ICER for denosumab compared with strontium ranelate going from denosumab being dominant (that is, denosumab was less costly and more effective than strontium ranelate) to £2040 per QALY gained for primary prevention, and denosumab remaining dominant for secondary prevention. The ICER for denosumab compared with raloxifene went from £9289 (£11,135 costs, 8.0 QALYs) to £12,438 per QALY gained for primary prevention, and from £2,046 (£13,543 costs, 7.9 QALYs) to £5,120 for secondary prevention. The results of the manufacturer's probabilistic sensitivity analysis showed that denosumab had approximately 50% probability of being considered cost effective at a threshold of £30,000 per QALY gained compared with the primary comparators (strontium ranelate, raloxifene and no treatment) in the base-case population of women aged 70 years with a T-score at or below −2.5 SD for primary prevention. The probability for secondary prevention was 90%. Against the secondary comparators (ibandronate, zoledronate and teriparatide), denosumab had a 60% probability of being considered cost effective at a threshold of £30,000 per QALY gained in the base-case population of women aged 70 years without prior fracture. The probability in women with prior fracture was 70%. The ERG considered that the evidence of clinical effectiveness presented in the manufacturer's submission was derived from a large high-quality trial of adequate duration. The ERG stated that it did not consider the evidence presented in the manufacturer's submission on the effects of drugs on bone mineral density to be relevant because fracture data were available for all drugs. The ERG also noted that the data for morphometric vertebral fractures were not relevant, and so were not used in the modelling. The ERG noted that the results for the direct comparison of strontium ranelate with placebo (RR for hip fracture of 0.89 and RR for non-vertebral fracture of 0.88) were similar to the meta-analysis provided in NICE technology appraisal 160 (RR for hip fracture of 0.85 and RR for all non-vertebral fractures of 0.84), which provided some confidence in the results. The ERG expressed concern about the relevant comparator for denosumab (see 3.29) and the methodology of the meta-regression to determine whether mean age and bone mineral density were associated with different effects of treatments. The ERG noted that the manufacturer provided multiple comparisons of cost effectiveness using a high-quality validated model that took into account a wide range of costs, such as short-term drug costs and long-term nursing home costs, and that the analysis met the NICE reference case. The ERG considered that the appendices to the manufacturer's submission also provided very detailed accounts of underlying model assumptions and sensitivity analyses. The ERG identified several issues with the manufacturer's economic model, specifically: the choice of comparator cost assumptions for denosumab the validity of assumptions used for modelling utilities, costs, persistence and compliance variations in cost effectiveness in subgroups of the cohort modelled -mission of underlying fracture risk estimates from the probabilistic sensitivity analysis treatment setting and administration of denosumab. First, the ERG believed that zoledronate should be a key comparator. The manufacturer's submission did not consider zoledronate or intravenous ibandronate to be primary comparators for denosumab because they are used by only 0.7% and 0.6% of currently treated women respectively (according to Intercontinental Marketing Services data), and neither comparator had been appraised by NICE. However, the ERG stated that intravenous ibandronate and zoledronate are licensed and used routinely in UK secondary care for treating osteoporosis in postmenopausal women. The ERG noted that intravenous ibandronate and zoledronate were similar in effectiveness but that intravenous ibandronate was given more frequently than zoledronate, and would be associated with greater administration costs. Therefore, given both its effectiveness and the same method of intravenous administration, zoledronate was a key comparator in the ERG's view. The second issue raised by the ERG was that the relative cost effectiveness of denosumab compared with zoledronate depended on assumptions made about administration costs. The manufacturer assumed that denosumab would be given twice a year in general practice at the average cost of two standard visits to a GP, whereas zoledronate was assumed to be given once a year in hospital clinics (with some monitoring incorporated into the visit). The ERG believed that this approach made denosumab much less costly than zoledronate. Therefore, the ERG believed that, given the similar effectiveness of denosumab and zoledronate, the cost-effectiveness comparison depended largely on the relative costs used in the model. The ERG carried out additional exploratory analyses assuming that denosumab was given entirely in secondary care, which demonstrated that for primary prevention the ICER for denosumab compared with no treatment was £40,627 per QALY gained. For primary prevention, the ICER for denosumab compared with raloxifene was £25,743 per QALY gained and for denosumab compared with strontium ranelate was £15,866 per QALY gained. For secondary prevention, the ICER for denosumab compared with no treatment was £17,851 per QALY gained, the ICER for denosumab compared with raloxifene was £12,171 per QALY gained, and the ICER for denosumab compared with strontium ranelate was £6606 per QALY gained. After comments on the appraisal consultation document, which reported a change in cost of zoledronate and that an alternative relative risk could be used for the effect of zoledronate on wrist fracture, the ERG were requested to carry out additional sensitivity analyses. These demonstrated that the change in the cost of zoledronate (which reduced from £283.74 to £266.72 in January 2010) resulted in ICERs for zoledronate compared with denosumab decreasing from £70,900 to £55,885 per QALY gained for primary prevention, and from £29,029 to £22,966 per QALY gained for secondary prevention. Additional sensitivity analyses were also carried out using an alternate relative risk value of 0.81 for risk of wrist fracture for zoledronate (instead of 1.0 in the manufacturer's base case, and 0.84 in the ERGs original sensitivity analyses). The results showed that the ICER for zoledronate compared with denosumab decreased from £70,900 to £58,764 per QALY gained for primary prevention, and from £29,029 to £24,454 for secondary prevention. The ERG carried out analyses using the manufacturer's assumptions in their economic model by combining both the above zoledronate changes simultaneously. These resulted in an ICER for zoledronate compared with denosumab of £44,804 per QALY gained for primary prevention, and £18,606 per QALY gained for secondary prevention. The ERG identified that a simplifying assumption was used for transitions in the model. Women experiencing a vertebral fracture could no longer experience a wrist fracture or other type of fracture (apart from a clinical vertebral fracture or hip fracture). After a hip fracture, women could no longer experience any type of fracture other than a hip fracture. The ERG believed that this assumption was unrealistic because experience of a hip fracture or clinical vertebral fracture would put women at higher risk of further fracture. However, the extent of the effect of these assumptions on the cost-effectiveness estimates was unclear. The ERG noted that in the manufacturer's base-case analysis, the assumption that fracture risk would return linearly to baseline levels over the course of 1 year after stopping treatment was conservative and would favour oral therapies. Persistence and compliance were assumed to be 100% for all treatments in the base-case analysis, which was also a conservative assumption. The ERG noted that after initial administration of denosumab, both compliance and persistence would be 100% for 6 months. However, in the long term, persistence with denosumab therapy may be less than 100%. The manufacturer carried out sensitivity analyses that examined variations in persistence for oral therapies and denosumab. The ERG noted that the manufacturer's quality-of-life review methodology and the primary studies included in the review suggested that suitable utility multipliers were applied in the model. However, many of the multipliers were derived from observational time-series studies without independent control groups and therefore did not control for all potential confounding factors. The ERG noted that costs and utility losses associated with wrist fractures and other types of fracture were assumed to last for 1 year, whereas hip fractures and clinical vertebral fractures were modelled to incur ongoing costs and utility losses. The ERG also noted that utility loss relative to population norms remained constant in the second and subsequent years after hip fracture or vertebral fracture. This assumption may have slightly overestimated utility loss associated with hip and vertebral fracture if the observed trend towards improved quality of life in the second year after fracture continued in subsequent years. The ERG noted that the manufacturer's ICERs varied substantially within subgroups of the cohorts, and that the appropriate comparator also varied by subgroup according to existing NICE guidance. Furthermore, neither raloxifene or strontium ranelate compared favourably with no treatment (ICERs of £74,239 and £102,592 per QALY gained respectively for 70-year-old women with a T-score of −2.5 SD and no prior fragility fracture, and £24,524 and £37,123 per QALY gained respectively for those with a prior fragility fracture), which is consistent with the modelling in NICE technology appraisal guidance 160 and 161. The ERG expressed the view that demonstrating cost effectiveness against these comparators did not allow the conclusion that denosumab is cost effective. The ERG also believed that, for the comparison between denosumab and zoledronate, there was uncertainty about the costs of administering these two drugs and their relative efficacy for the prevention of wrist fracture. The manufacturer conducted a range of deterministic and probabilistic sensitivity analyses. The ERG noted that an important omission from the probabilistic sensitivity analysis was the underlying estimates of fracture risk. The manufacturer stated that data limitation meant that distributions could not be estimated for these parameters. The ERG believed that this would have the effect of overestimating the probability of denosumab being considered cost effective at different payment thresholds. It also noted that deterministic sensitivity analysis showed that the cost-effectiveness estimates were sensitive to underlying fracture risk. Following consultation the manufacturer carried out additional sensitivity analyses in which beta distributions were assigned to baseline fracture incidence based on an assumed sample size of 10,000. Probabilistic sensitivity analysis showed that for denosumab compared with no treatment the ICER was £30,422 per QALY gained which was similar to the deterministic ICER of £29,233 per QALY gained. The ERG had concerns about the treatment setting and administration of denosumab in the model. The subcutaneous injection of denosumab is simple and could be carried out by a general practitioner, a practice nurse or the woman herself. However, the ERG believed that denosumab treatment would probably not be started in general practice because it is a new biological agent that has effects on other body systems (including the immune system), and that long-term adverse events could not be ruled out. The ERG stated that it would expect at least one outpatient visit to be needed and, in many cases, continued hospital follow-up would be necessary. Additionally, if follow-up was partly or mainly in general practice, the ERG believed that administration of denosumab would probably not be provided in primary care as part of general medical services, but would be regarded as an enhanced service for which an additional payment would be negotiated (the size of which is currently unknown, but may be greater than the manufacturer's assumption of the average cost of two visits to a GP per patient per year). Therefore, the marginal costs per patient of administering denosumab in primary care may be greater than the average cost of two visits to a GP per patient per year as presented in the manufacturer's model. The ERG noted that although denosumab could be self-administered by the woman, the average age of women taking medication for the prevention of fracture in the General Practice Research Database dataset was 71.4 years, and many would be older. Such women might not be able to give themselves a subcutaneous injection because of poor eyesight, poor manual dexterity or cognitive impairment. The oldest age groups also have the highest proportion of women treated with oral bisphosphonates. Furthermore, training women to self-administer denosumab might not be regarded as worthwhile because they would have to visit a general practice to obtain the pre-filled pen injection device, and after 6 months some may have forgotten how to administer it (which is unlikely to occur with drugs given daily, such as teriparatide). The ERG also expressed the view that an equality issue exists for women who have had a stroke in the past and who are at increased risk of falls and fracture, together with bone loss because of reduced mobility. Such women might have difficulty swallowing or standing to take oral bisphosphonates, and therefore, intravenous or subcutaneous drugs may be more suitable. Full details of all the evidence are in the manufacturer's submission and the ERG report.# Consideration of the evidence The Appraisal Committee reviewed the data available for the clinical and cost effectiveness of denosumab, having considered evidence on the nature of osteoporotic fractures and the value placed on the benefits of denosumab by postmenopausal women with the condition, those who represent them, and clinical specialists. It also took into account the effective use of NHS resources. The Committee discussed the clinical need of postmenopausal women for the prevention of osteoporotic fragility fractures. It heard from the clinical specialists that the main aim of primary prevention is the opportunistic identification of postmenopausal women who are at risk of osteoporotic fragility fractures, and the aim of secondary prevention is to provide the most effective treatment for women who have already had an osteoporotic fragility fracture and are at risk of further fractures. The Committee heard from the clinical specialists that current UK clinical practice is to start treatment with oral bisphosphonates (first with alendronate and then either risedronate or etidronate if alendronate is unsuitable). These treatments are not suitable for all women because some women are unable to comply with the special instructions for the administration of oral bisphosphonates, or have a contraindication to or are intolerant of oral bisphosphonates. The Committee also heard from the clinical specialists that women for whom oral bisphosphonates are unsuitable receive either no treatment or strontium ranelate for primary prevention (as set out in NICE technology appraisal guidance 160), or no treatment, strontium ranelate or raloxifene for secondary prevention (as set out in NICE technology appraisal guidance 161). The clinical specialists stated that the management of osteoporosis usually takes place in primary care (both strontium ranelate and raloxifene are given in primary care). Women who have severe osteoporosis may receive more potent agents such as zoledronate or intravenous ibandronate but there is limited capacity for treatment in secondary care because of the need for day-case facilities for these intravenous treatments. The patient experts stated that some women who cannot take or cannot tolerate oral bisphosphonates have a preference for strontium ranelate or raloxifene as they do not like the intravenous infusion used for zoledronate treatment, whereas others prefer the convenience of a 12-monthly intravenous infusion (zoledronate) over taking oral treatments daily (strontium ranelate and raloxifene). The Committee accepted that the great majority of treatment for the primary and secondary prevention of osteoporotic fragility fractures is provided in primary care. It also accepted that women for whom oral therapies are unsuitable or who have severe osteoporosis may receive more potent agents such as zoledronate or intravenous ibandronate in secondary care and that teriparatide is also used for secondary prevention when women are unable to take other therapies. The Committee concluded that the relevant comparators for primary prevention are no treatment and strontium ranelate, and for secondary prevention are no treatment, strontium ranelate and raloxifene, because both the administration and supervision of strontium ranelate and raloxifene are organised in primary care. The Committee also concluded that potential comparators for denosumab are zoledronate (for severe osteoporosis) and teriparatide (for women who have sustained a clinically apparent osteoporotic fracture and who are defined by age, T score and number of osteoporotic fractures and who are unable to take all oral bisphosphonates, strontium and raloxifene, as defined in NICE Technology Appraisal 161). The Committee was aware that the licensed indication for denosumab is for the treatment of osteoporosis in postmenopausal women at increased risk of fractures. The Committee noted that the manufacturer's decision problem focused on postmenopausal women diagnosed with osteoporosis for whom oral bisphosphonates are unsuitable. The manufacturer stated that denosumab was not expected to compete with oral bisphosphonates in clinical practice, given the wide availability of generic oral bisphosphonates in the UK and the need for efficient use of NHS resources. The Committee also noted that the manufacturer did provide an analysis of denosumab compared with oral bisphosphonates for completeness. It accepted that it was reasonable to base its considerations on women for whom oral bisphosphonates are unsuitable and the subsequent discussion focused on this population only. The Committee heard from the clinical specialists that denosumab is a monoclonal antibody that reduces osteoclast activity and hence reduces bone breakdown, that it is the first drug of its class, and that its biological mechanism of action results in targeted therapy with fewer adverse events than other treatments. The Committee considered that a treatment administered by subcutaneous injection once every 6 months, such as denosumab, offers an advantage because it may improve adherence with therapy, particularly for women who have problems swallowing or standing to take oral bisphosphonates. The Committee also accepted evidence from the patient experts that many women stop taking oral bisphosphonates because of adverse events, and often do not go back to their GP. Therefore a 6-monthly subcutaneous injection of denosumab could provide women with a pre-arranged opportunity to discuss their treatment and any adverse events with a healthcare professional, and this support may improve compliance and persistence with treatment. # Clinical effectiveness The Committee accepted that the clinical-effectiveness evidence presented in the manufacturer's submission was derived from a large, high-quality trial of adequate duration (FREEDOM) that studied treatment with denosumab compared with placebo. The Committee noted that, because the FREEDOM study did not provide a head-to-head comparison of denosumab against all relevant comparators, the manufacturer carried out a random-effects meta-analysis to obtain direct estimates for each treatment compared with placebo (denosumab, strontium ranelate, raloxifene, teriparatide and zoledronate). The Committee noted that the FREEDOM trial showed a statistically significant 68% reduction in the relative risk p < 0.001) of the 36-month incidence of new radiographically diagnosed vertebral fractures. The Committee also noted that denosumab significantly reduced the risk of non-vertebral fracture (HR 0.80; 95% CI 0.67 to 0.95; relative reduction of 20%) and of hip fracture (HR 0.60, 95% CI 0.37 to 0.97; relative reduction of 40%). The Committee concluded that the evidence from the FREEDOM trial demonstrated that denosumab was effective in reducing the risk of fracture in postmenopausal women compared with placebo. The Committee discussed the meta-analysis that was undertaken by the manufacturer to obtain direct estimates for each treatment compared with placebo. However, the Committee noted the lack of a direct comparison of denosumab with active comparators. It was, therefore, unable to make a conclusion about the relative clinical effectiveness of denosumab, but was satisfied with the evidence on the direct estimates for each treatment compared with placebo and concluded that the methods used in the meta-analysis were sufficiently robust for use in the economic analysis. The Committee discussed the adverse events experienced by postmenopausal women receiving denosumab for the prevention of osteoporotic fragility fractures. The Committee noted that in the FREEDOM trial treatment with denosumab was associated with fewer adverse events than placebo. The patient experts stated that the main concern women have about treatment for osteoporosis is the duration for which therapies are taken and whether they will experience adverse events over a long period of time. The Committee heard that there may be a risk of infection associated with denosumab treatment; however, it accepted evidence from the clinical specialists that this risk was low and that if substantial evidence became available, it may be necessary to assess women with severe infections before considering the use of denosumab. The Committee noted that studies of denosumab for other indications have shown that treatment may be associated with osteonecrosis of the jaw, but it was satisfied with the clinical specialists' statement that there was no evidence of this from the clinical studies of denosumab in women with osteoporosis. The clinical specialists confirmed that 14,000 women have received denosumab and that it was well tolerated. The Committee concluded that the available clinical evidence on the adverse effects associated with denosumab indicated that it was a well tolerated treatment for the prevention of osteoporotic fragility fractures in postmenopausal women. # Cost effectiveness The Committee considered the manufacturer's economic model, and the critique and exploratory sensitivity analyses performed by the ERG. It noted that the manufacturer used a Markov economic model to evaluate the cost effectiveness of denosumab compared with a range of comparators, and that the clinical data were derived from the manufacturer's direct comparison of each comparator with placebo in their random-effects meta-analysis. The Committee considered that the methods used in the analysis were robust. The Committee considered the ERG's concerns about a number of aspects of the economic model, such as the long-term effects of fractures on mortality, the setting where denosumab is likely to be given, and the associated administration and monitoring costs modelled. The Committee also discussed issues raised from consultation on the appraisal consultation document: the use of quality of life data from the FREEDOM study in the economic model, the use of the FRAX tool to estimate fracture risk, the cost and setting of care for women receiving denosumab, the cost of zoledronate, the relative risk for wrist fracture for zoledronate, and the relative risk for hip fracture with strontium ranelate. The Committee considered the long-term effects of fractures on mortality and the need for nursing home care. It noted that the manufacturer assumed that 30% of observed mortality for all fracture types is causally related to osteoporotic fracture, and this estimate was varied to 100% in sensitivity analyses. The Committee was aware that the manufacturer's model also assumed that women were at increased risk of entry into nursing home care following hip fracture and that the lowest cost of private residential care was applied. The Committee noted that some women may already be in a nursing home, and some may also be self-funding their nursing home care. After consultation, the manufacturer carried out additional sensitivity analyses, using the assumption that nursing home admission was zero. The Committee concluded that the long-term effects of fractures on mortality and nursing home care had only a minor impact on the cost-effectiveness estimates for denosumab. The Committee noted that the manufacturer's model assumed treatment duration of 5 years, and that the FREEDOM study was of 3 years' duration. The Committee accepted that the 5-year treatment duration assumption was appropriate and reflected clinical practice. The Committee noted that the manufacturer's model assumed that women would return in a linear fashion to baseline fracture risk levels over 1 year after treatment stops. It considered whether the return to baseline fracture risk should be different according to treatment type, and heard from the ERG that the duration of benefit in terms of fracture risk (as opposed to bone mineral density) is unknown after cessation of osteoporosis treatments. The Committee concluded that there was little evidence on the duration of effect on fracture risk for osteoporosis treatments and that this was an area of uncertainty. The Committee discussed health-related quality-of-life benefits and utility values in the economic model. The Committee noted that no significant differences were seen in health-related quality of life between the denosumab and placebo arms of the FREEDOM trial. The manufacturer justified the omission from the economic model of EQ-5D data from FREEDOM on the grounds that the number of fracture events with associated EQ-5D scores was low and there was relative infrequency of health-related quality of life measurement. The ERG accepted that the lack of statistical difference in EQ-5D scores between the denosumab and placebo arms of the trial was explained by the above factors (low number of fracture events with associated EQ-5D scores and relative infrequency of health-related quality of life measurement), rather than an adverse effect of denosumab masking the health benefit of fracture prevention. The ERG stated that omitting the FREEDOM trial EQ-5D data from the economic analysis was justified given the quality and depth of the manufacturer's systematic review of health-related quality-of-life data. The Committee concluded that the manufacturer's approach to modelling health-related quality of life was acceptable. The Committee considered that the manufacturer's model allowed sensitivity analyses to be carried out using the FRAX tool. The Committee accepted that FRAX is a potentially useful tool in clinical practice, but it was mindful that the tool is presently unvalidated. The Committee was not persuaded that recommendations about treatment should be based on absolute risk as calculated using FRAX and that the stepped approach of assessing fracture risk is needed to ensure the effective allocation of NHS resources. This is because absolute fracture risk is the total risk for all fracture sites, but different fracture sites have different impacts on quality of life, costs and mortality. Therefore, cost effectiveness is dependent on the contribution from each fracture site to the total fracture risk. The Committee concluded that using a combination of T-score, age and a number of independent clinical risk factors for fracture remained more appropriate for defining treatment recommendations in this appraisal. The Committee considered the key drivers of cost effectiveness and noted that alterations to most key parameters in the manufacturer's sensitivity analyses had limited impact on comparisons of denosumab with raloxifene, strontium ranelate and no treatment. Comparisons with ibandronate, zoledronate and teriparatide were most sensitive to changes in the assumptions about the cost of administering denosumab. When the manufacturer increased the cost of administering denosumab (by assuming that one administration per year would be delivered in secondary care), this increased the ICER for denosumab compared with no treatment from £29,200 to £36,200 per QALY gained for primary prevention, and from £12,400 to £15,700 per QALY gained for secondary prevention. The Committee noted that given the similar cost and efficacy of denosumab and zoledronate, changes to this assumption also resulted in zoledronate dominating denosumab (that is, zoledronate was less costly and more effective than denosumab) for both primary and secondary prevention. The Committee concluded that with the exception of administration costs for denosumab, alterations to most key parameters had limited impact on comparisons between denosumab and the primary and secondary comparators. The Committee noted the ERG's view that administration of denosumab may not be provided in primary care. However, the clinical specialists stated that there is no reason why denosumab should only be used in secondary care. The clinical specialists highlighted that because denosumab is a new biological agent they expected that, initially, treatment would be started in secondary care, but with follow-up almost exclusively in primary care (except for women with severe osteoporosis, who may be followed up in secondary care in line with current UK clinical practice). The Committee discussed whether administering denosumab would be part of general medical services or whether it would be regarded as an enhanced service for which an additional payment would be negotiated, and it noted the comments received during consultation on the ACD. The clinical specialists stated that women would not need to go through a screening process before starting treatment with denosumab, and that women receiving denosumab are not likely to be at high risk of side effects and so follow-up in secondary care would not be necessary. The clinical specialists also stated that although denosumab is a biological agent and also has effects on the immune system, it is specifically targeted for regulating bone cells. The clinical specialists, therefore, thought that the potential safety concerns associated with other biological agents (such as those targeting tumour necrosis factor) may not be applicable to denosumab. The clinical specialists stated that because treatment with denosumab would not involve substantial additional activities to standard practice in managing osteoporosis, it would probably be provided as part of general medical services. The Committee accepted the views of the clinical specialists that there were no specific safety concerns around the use of denosumab and that follow-up in secondary care would not be necessary. Therefore, it was not persuaded to alter its opinion that denosumab is likely to be provided as part of general medical services in primary care. The Committee concluded that while treatment with denosumab may be started in secondary care, it would be subsequently delivered almost exclusively in primary care. The relatively small proportion of women with severe osteoporosis would continue to be followed-up in secondary care, in line with current UK clinical practice. After consultation on the appraisal consultation document, the Committee discussed comments that outlined a change in the cost of zoledronate and that an alternative relative risk could be used for the effect of zoledronate on wrist fracture. The ERG was requested to carry out exploratory analyses that showed that denosumab was less effective and less costly than zoledronate. The Committee had already concluded that although treatment with denosumab may be started in secondary care, it will be subsequently delivered almost exclusively in primary care, unlike the administration of zoledronate, use of which will remain in secondary care. As the Committee regarded the main comparators for denosumab to be those treatments delivered in primary care when oral bisphosphonates were unsuitable (no treatment, strontium ranelate, raloxifene), it did not regard these issues to be central to the decision problem. The Committee, therefore, accepted that the most likely cost-effectiveness estimates would lie between the manufacturer's base case (using primary care assumptions) and the ERG's additional analyses (using secondary care assumptions), and that the most plausible ICERs were likely to be closer to the manufacturer's base case estimates given that care would mostly be in the primary setting. The Committee considered the relative risks for hip fracture that were used in the manufacturer's meta-analysis. The Committee was aware that NICE recommendations on strontium ranelate are due to be reconsidered following a court of appeal judgement related to assumptions about relative risk of hip fracture. It noted that the figure that the manufacturer used as the 5-year relative risk of hip fracture for strontium ranelate was 0.89 compared with placebo and this was derived from the published TROPOS study, but that alternative relative risk figures of 0.64 (obtained over 3 years) or 0.57 (obtained over 5 years) for the effect of strontium ranelate on hip fracture were suggested during consultation. These alternative, and lower relative risk values, were based on a post-hoc subgroup analysis in the TROPOS study of women over the age of 74 with a T score of −2.4. The Committee also noted a suggestion by the manufacturer of denosumab that if a subgroup relative risk figure for hip fracture was to be used for one treatment in comparative analysis, then similar subgroup figures should also be used for denosumab for this and other outcomes. The Committee noted that when using a relative risk of hip fracture of 0.89 for strontium ranelate in the manufacturer's base case, denosumab was dominant compared with strontium ranelate for both primary and secondary prevention. The Committee heard from the ERG that exploratory analyses applying the relative risk estimate of 0.64 over the modelled 5-year treatment period in the manufacturer's model resulted in a base-case ICER of £10,200 per QALY gained for denosumab compared with strontium ranelate for primary prevention and an ICER of £5100 per QALY gained for secondary prevention. When the relative risk estimate of 0.57 for strontium ranelate was applied over the modelled 5-year treatment period in the manufacturer's model, this resulted in an ICER of £16,300 per QALY gained for denosumab compared with strontium ranelate for primary prevention and an ICER of £8600 per QALY gained for denosumab compared with strontium ranelate for secondary prevention. The Committee considered these exploratory analyses and concluded that it did not need to make a decision on which relative risk for strontium ranelate was the most appropriate one to apply, because for any of the suggested relative risk values for hip fracture for strontium ranelate, the ICERs for denosumab compared with strontium ranelate fell within a range that was still considered to be a cost effective use of NHS resources. The Committee noted that for the primary prevention of osteoporotic fragility fractures, denosumab dominated strontium ranelate in the manufacturer's base case, and the ICER was £15,900 per QALY gained for denosumab compared with strontium ranelate in the ERG's additional analyses (assuming denosumab is always given in secondary care). The Committee noted that in NICE technology appraisal guidance 160, strontium ranelate is recommended for postmenopausal women: who are unable to comply with the special instructions for the administration of alendronate and either risedronate or etidronate, or have a contraindication to or are intolerant of alendronate and either risedronate or etidronate and who also have a combination of T-score, age and number of independent clinical risk factors for fracture as indicated in the following table. T-scores (SD) at (or below) which strontium ranelate is recommended when alendronate and either risedronate or etidronate cannot be taken Age (years) Number of independent clinical risk factors for fracture -r older Treatment with strontium ranelate is not recommended. For the purposes of technology appraisal guidance 160, independent clinical risk factors for fracture are parental history of hip fracture, alcohol intake of 4 or more units per day, and rheumatoid arthritis. The Committee accepted that the above were appropriate when making recommendations on treatment with denosumab for the prevention of primary and secondary osteoporotic fractures. The Committee was mindful that the clinical effectiveness evidence was based on a meta-analysis of each treatment compared with placebo rather than a direct comparison of denosumab with active comparators, and of the areas of uncertainty it had discussed in the economic modelling. However it was satisfied with the robustness of the clinical evidence and, when taken together with the low ICERs presented, the Committee concluded that, as an option, denosumab was a cost-effective use of NHS resources for the primary prevention of osteoporotic fragility fractures only for postmenopausal women at increased risk of fractures for whom oral bisphosphonates are unsuitable, and who have the same level of fracture risk as described in the recommendations for strontium ranelate in NICE technology appraisal guidance 160. The Committee was aware that for women for whom oral bisphosphonates are unsuitable and who do not currently fulfil the criteria for treatment with strontium ranelate, there is no treatment currently recommended by NICE for the primary prevention of osteoporotic fragility fractures. The Committee noted that the ICER for denosumab compared with no treatment was £29,200 per QALY gained in the manufacturer's base-case analysis, and this increased to £40,600 per QALY gained in the ERG's additional analyses. It concluded that the ICER for the base-case population (women 70 years and over with a T-score of −2.5 SD or below) for denosumab compared with no treatment was likely to lie within this range. The Committee explored the results for subgroups of women at higher risk by age and T-score, for whom oral bisphosphonates are unsuitable and in circumstances in which none of the treatments appraised by NICE are recommended. The ICERs for denosumab compared with no treatment from the manufacturers model varied between £19,300 and £71,300 per QALY gained. The Committee agreed that the most plausible ICERs were likely to be higher, based on the ERG's amended assumptions. Taking into account the uncertainties around the long-term effects of fractures on mortality and nursing home care, and the setting where denosumab is likely to be given, the Committee concluded that denosumab was not a cost-effective use of NHS resources for women for whom oral bisphosphonates are unsuitable and the treatments appraised by NICE are not recommended. For the secondary prevention of osteoporotic fragility fractures, the Committee noted that the ICER for denosumab compared with no treatment in women for whom oral bisphosphonates are unsuitable was £12,400 per QALY gained in the manufacturer's base-case analysis, which increased to £17,900 per QALY gained in the ERG's additional analyses. Denosumab dominated raloxifene or had an ICER of £2000 per QALY gained in the manufacturer's base-case analysis, which increased to £12,200 per QALY gained in the ERG's additional analyses. The cost-effectiveness results for denosumab compared with strontium ranelate ranged from strontium ranelate being dominated by denosumab in the manufacturer's base-case analysis to an ICER of £6600 per QALY gained in the ERG's exploratory analyses. The Committee also noted the results of the subgroup analysis by age and T-score for women for whom oral bisphosphonates are unsuitable and in circumstances in which the treatments appraised by NICE are not recommended, in which the ICER for denosumab compared with no treatment varied between £12,289 and £22,957 per QALY gained. The Committee noted that teriparatide is recommended in NICE technology appraisal guidance 161 as a treatment option for the secondary prevention of osteoporotic fragility fractures in women with severe osteoporosis for whom oral bisphosphonates and strontium ranelate are unsuitable. The Committee noted that in the manufacturer's base-case analysis, denosumab was slightly less effective and much less costly than teriparatide. The Committee concluded that treatment with denosumab was a cost-effective use of NHS resources and may be an option for the secondary prevention of osteoporotic fragility fractures in women for whom oral bisphosphonates are unsuitable (that is, in women who are unable to comply with the special instructions for administering alendronate and either risedronate or etidronate, or have an intolerance of, or a contraindication to, those treatments). The Committee also concluded that denosumab may provide an alternative treatment option that would be a cost-effective use of NHS resources for women who are eligible for treatment with teriparatide as defined in NICE technology appraisal guidance 161. The Committee considered whether its recommendations were associated with any potential issues related to equality. Following consultation on the appraisal consultation document, the Committee was aware that one area of potential discrimination was the primary prevention of osteoporotic fractures in postmenopausal women with swallowing problems as a result of disabling stroke disease, who would otherwise be eligible for treatment with oral bisphosphonates, but do not fulfil the criteria for denosumab or other treatments. The Committee concluded that its considerations were based on the population of postmenopausal women for whom oral bisphosphonates are unsuitable which included women with and without a disability. # Summary of Appraisal Committee's key conclusions TA204 STA Appraisal Title: Denosumab for the prevention of osteoporotic fractures in postmenopausal women FAD section Key conclusion Denosumab is recommended as a treatment option for the primary prevention of osteoporotic fragility fractures only in postmenopausal women at increased risk of fractures: who are unable to comply with the special instructions for administering alendronate and either risedronate or etidronate, or have an intolerance of or a contraindication to those treatments and who have a combination of T-score, age and number of independent clinical risk factors for fracture (see section 1.3) as indicated in the following table. T-scores (SD) at (or below) which denosumab is recommended when alendronate and either risedronate or etidronate are unsuitable Age (years) Number of independent clinical risk factors for fracture -r older Treatment with denosumab is not recommended. Denosumab is recommended as a treatment option for the secondary prevention of osteoporotic fragility fractures only in postmenopausal women at increased risk of fractures who are unable to comply with the special instructions for administering alendronate and either risedronate or etidronate, or have an intolerance or contraindication to those treatments. For the purposes of this guidance, independent clinical risk factors for fracture are parental history of hip fracture, alcohol intake of 4 or more units per day, and rheumatoid arthritis. The Committee accepted that there was good quality evidence to support the clinical effectiveness of denosumab compared with placebo and that denosumab would be a clinically effective alternative to existing treatment options for the prevention of osteoporotic fragility fractures in postmenopausal women. The Committee concluded that treatment with denosumab was a cost-effective use of NHS resources for the primary prevention of osteoporotic fragility fractures only in postmenopausal women at increased risk of fractures for whom oral bisphosphonates are unsuitable, and who have the same level of fracture risk as described in the recommendations of NICE technology appraisal 160 for strontium ranelate. The Committee concluded that treatment with denosumab was a cost-effective use of NHS resources for the secondary prevention of osteoporotic fragility fractures in postmenopausal women at increased risk of fractures for whom oral bisphosphonates are unsuitable. Current practice Clinical need of patients including the availability of alternative treatments The main aim of primary prevention is the opportunistic identification of postmenopausal women who are at risk of osteoporotic fragility fractures, and the aim of secondary prevention is to provide the most effective treatment for women who have already had an osteoporotic fragility fracture and are at risk of further fractures. The Committee accepted that current UK clinical practice is to start treatment with oral bisphosphonates (first with alendronate and then either risedronate or etidronate if alendronate is unsuitable), but that these are not suitable for all women. Reasons for unsuitability are that the woman is unable to comply with the special instructions for the administration of oral bisphosphonates, or has a contraindication to or is intolerant of oral bisphosphonates. Women for whom oral bisphosphonates are unsuitable receive either no treatment or strontium ranelate for primary prevention (as set out in NICE technology appraisal guidance 160), or strontium ranelate or raloxifene for secondary prevention (as set out in NICE technology appraisal guidance 161). Treatment usually takes place in primary care (both strontium ranelate and raloxifene are given in primary care). Women who have severe osteoporosis may receive more potent agents such as zoledronate or intravenous ibandronate. The Committee also noted that zoledronate is sometimes used in secondary care for the prevention of fractures, and that teriparatide is also used for secondary prevention when women are unable to take other therapies. The technology Proposed benefits of the technology How innovative is the technology in its potential to make a significant and substantial impact on health-related benefits? The Committee considered that a treatment that is administered by subcutaneous injection once every 6 months, such as denosumab, offers an advantage because it may improve adherence with therapy, particularly for women who have problems swallowing or standing to take oral bisphosphonates. The Committee noted that denosumab is a monoclonal antibody that reduces osteoclast activity and hence reduces bone breakdown. It also heard from the clinical specialists that it is the first drug in its class, and that its targeted biological mechanism of action results in fewer adverse events than other treatments. What is the position of the treatment in the pathway of care for the condition? The Committee noted that the manufacturer's decision problem focused on postmenopausal women diagnosed with osteoporosis for whom oral bisphosphonates are unsuitable, and that the manufacturer stated that denosumab was not expected to compete with oral bisphosphonates in clinical practice, given the wide availability of generic oral bisphosphonates in the UK. The Committee also noted that the manufacturer did provide an analysis of denosumab compared with oral bisphosphonates for completeness. It accepted that it was reasonable to base its considerations on women for whom oral bisphosphonates are unsuitable and the subsequent discussion focused on this population only. Adverse effects The Committee heard that there may be a risk of infection associated with denosumab treatment, however it accepted evidence from the clinical specialists that this risk was low and that if substantial evidence became available, it may be necessary to assess women with severe infections before considering the use of denosumab. The Committee concluded that the available clinical evidence on the adverse effects associated with denosumab indicated that it was a well tolerated treatment for the prevention of osteoporotic fragility fractures in postmenopausal women. Evidence for clinical effectiveness Availability, nature and quality of evidence The Committee considered that the clinical effectiveness evidence presented in the manufacturer's submission was derived from a large, high-quality trial of adequate duration (FREEDOM). Because the FREEDOM study did not provide a head-to-head comparison of denosumab against all relevant comparators, the manufacturer carried out a random-effects meta-analysis to obtain direct estimates for each treatment compared with placebo. Relevance to general clinical practice in the NHS The Committee accepted that denosumab is not expected to compete with oral bisphosphonates in clinical practice, given the wide availability of generic oral bisphosphonates in the UK as stated by the manufacturer. Uncertainties generated by the evidence There was no head-to-head clinical trial evidence comparing denosumab with active relevant comparators (the comparator in the FREEDOM trial was placebo). The manufacturer carried out a random-effects meta-analysis to obtain direct estimates for each treatment compared with placebo. However, the Committee noted the lack of a direct comparison of denosumab with active comparators. It was, therefore, unable to make a conclusion about the relative clinical effectiveness of denosumab, but was satisfied with the evidence on the direct estimates for each treatment compared with placebo and concluded that the methods used in the meta-analysis were sufficiently robust for use in the economic analysis. The Committee heard that there may be a risk of infection associated with denosumab treatment; however, it accepted evidence from the clinical specialists that this risk was low and that if substantial evidence became available, it may be necessary to assess women with severe infections before considering the use of denosumab. Are there any clinically relevant subgroups for which there is evidence of differential effectiveness Subgroups by T-score, age and clinical risk factors were explored in the economic model and considered by the Appraisal Committee (see below). Estimate of the size of the clinical effectiveness including strength of supporting evidence The Committee concluded that the evidence from the FREEDOM trial demonstrated that denosumab was effective in reducing the risk of fracture in postmenopausal women compared with placebo. The Committee discussed the meta-analysis that was undertaken by the manufacturer to obtain direct estimates for each treatment compared with placebo. However, the Committee noted the lack of a direct comparison of denosumab with active comparators. It was therefore unable to make a conclusion about the relative clinical effectiveness of denosumab, but was satisfied with the evidence on the direct estimates for each treatment compared with placebo and concluded that the methods used in the meta-analysis were sufficiently robust for use in the economic analysis. The Committee accepted that there was good evidence to support the clinical effectiveness of denosumab compared with placebo and that denosumab it would be a clinically effective alternative to existing treatment options for the prevention of osteoporotic fragility fractures in postmenopausal women. For details of treatment effect size see relative risks reported in sections 3.3, 3.6 and 4.7. Evidence for cost effectiveness Availability and nature of evidence The Committee accepted that the manufacturer used a Markov economic model to evaluate the cost effectiveness of denosumab compared with a range of comparators (split into primary and secondary comparators). The clinical data were derived from the manufacturer's direct comparison of each comparator with placebo from their random-effects meta-analysis. Uncertainties around and plausibility of assumptions and inputs in the economic model The Committee was mindful of the ERG's concerns around a number of aspects of the economic model, such as the long term effects of fractures on mortality, the setting where denosumab is likely to be given, and the associated administration and monitoring costs modelled. The Committee also discussed issues raised from consultation on the appraisal consultation document: the use of the FRAX tool to estimate fracture risk, the cost and setting of care for women receiving denosumab, the cost of zoledronate, the relative risk for hip fracture with strontium ranelate. The Committee concluded that the long term effects of fractures on mortality and nursing home care did not have a substantial impact on the cost effectiveness estimates for denosumab. The Committee noted that the manufacturer's model assumed treatment duration of 5 years, and that the FREEDOM study was of 3 years' duration. The Committee accepted that the 5-year treatment duration assumption was appropriate and reflected clinical practice. The Committee heard from the ERG that the duration of benefit in terms of fracture risk (as opposed to bone mineral density) is unknown after cessation of osteoporosis treatments. The Committee concluded that there was little evidence on the duration of effect on fracture risk for osteoporosis treatments and that this was an area of uncertainty. The Committee considered that the manufacturer's model allowed sensitivity analyses to be carried out using the FRAX tool and accepted that it is potentially useful in clinical practice. However, it was not persuaded that recommendations about treatment should be based on absolute risk as calculated using FRAX and that the stepped approach of assessing fracture risk is needed to ensure the effective allocation of NHS resources. Therefore, the Committee concluded that using a combination of T-score, age and a number of independent clinical risk factors for fracture remained more appropriate for defining treatment recommendations in this appraisal. The Committee concluded that with the exception of administration costs for denosumab, alterations to most key parameters had limited impact on comparisons between denosumab and the primary and secondary comparators. The Committee considered the change in cost of zoledronate and that an alternative relative risk could be used for the effect of zoledronate on wrist fracture. The Committee concluded that although treatment with denosumab may be started in secondary care, it will be subsequently delivered almost exclusively in primary care, unlike the administration of zoledronate, use of which will remain in a secondary care setting. As the Committee regarded the main comparators for denosumab to be those treatments delivered in primary care when oral bisphosphonates were unsuitable, it did not regard these issues to be central to the decision problem. The Committee considered the relative risks for hip fracture that were used in the manufacturer's meta-analysis. The Committee was aware that NICE recommendations on strontium ranelate are due to be reconsidered following a court of appeal judgement related to assumptions about relative risk of hip fracture. It noted that the figure that the manufacturer used as the 5-year relative risk of hip fracture for strontium ranelate was 0.89 compared with placebo and this was derived from the published TROPOS study, but that alternative relative risk figures of 0.64 (obtained over 3 years) or 0.57 (obtained over 5 years) for the effect of strontium ranelate on hip fracture were suggested during consultation. The Committee noted that when using a relative risk of hip fracture of 0.89 for strontium ranelate in the manufacturer's base case, denosumab was dominant compared with strontium ranelate for both primary and secondary prevention. The Committee heard from the ERG that exploratory analyses applying the relative risk estimate of 0.64 over the modelled 5-year treatment period in the manufacturer's model resulted in a base-case ICER of £10,200 per QALY gained for denosumab compared with strontium ranelate for primary prevention and an ICER of £5100 per QALY gained for secondary prevention. When the relative risk estimate of 0.57 for strontium ranelate was applied over the modelled 5-year treatment period in the manufacturer's model, this resulted in an ICER of £16,300 per QALY gained for denosumab compared with strontium ranelate for primary prevention and an ICER of £8600 per QALY gained for denosumab compared with strontium ranelate for secondary prevention. The Committee considered these exploratory analyses and concluded that it did not need to make a decision on which relative risk for strontium ranelate was the most appropriate one to apply, because for any of the suggested relative risk values for hip fracture for strontium ranelate, the ICERs for denosumab compared with strontium ranelate fell within a range that was still considered to be a cost effective use of NHS resources. Incorporation of health-related quality of life benefits and utility values Have any potential significant and substantial health-related benefits been identified that were not included in the economic model, and how have they been considered? The Committee noted that no significant differences were seen in health-related quality of life between the denosumab and placebo arms of FREEDOM. The ERG stated that the omission of the FREEDOM trial EQ-5D data from the economic analysis was justified given the quality and depth of the manufacturer's systematic review of health-related quality of life data. The Committee concluded that the manufacturer's approach to modelling health-related quality of life was acceptable. Are there specific groups of people for whom the technology is particularly cost-effective? The Committee noted that for the primary prevention of osteoporotic fragility fractures, denosumab dominated strontium ranelate in the manufacturer's base case, and the ICER was £15,900 per QALY gained for denosumab compared with strontium ranelate in the ERG's additional analyses (assuming denosumab is always given in secondary care). The Committee noted that in NICE technology appraisal guidance 160, strontium ranelate is recommended for postmenopausal women: - who are unable to comply with the special instructions for the administration of alendronate and either risedronate or etidronate, or have a contraindication to or are intolerant of alendronate and either risedronate or etidronate and - who also have a combination of T-score, age and number of independent clinical risk factors for fracture is as indicated in the following table. T-scores (SD) at (or below) which strontium ranelate is recommended when alendronate and either risedronate or etidronate cannot be taken Age (years) Number of independent clinical risk factors for fracture -r older Treatment with strontium ranelate is not recommended. - For the purposes of technology appraisal guidance 160, independent clinical risk factors for fracture are parental history of hip fracture, alcohol intake of 4 or more units per day, and rheumatoid arthritis. The Committee accepted that the above were appropriate when making recommendations on treatment with denosumab for the prevention of primary and secondary osteoporotic fractures. The Committee was mindful that the clinical effectiveness evidence was based on a meta-analysis of each treatment compared with placebo rather than with active comparators. However, it was satisfied that the robustness of the clinical evidence and, when taken together with the low ICERs presented, the Committee concluded that for the primary prevention of osteoporotic fragility fractures, denosumab was a cost-effective use of NHS resources as a treatment option only for postmenopausal women at increased risk of fractures for whom oral bisphosphonates are unsuitable, and who have the same level of fracture risk as described in the recommendations of NICE technology appraisal 160 for strontium ranelate. For the secondary prevention of osteoporotic fragility fractures, the Committee also noted the results of the subgroup analysis by age and T-score, for women for whom oral bisphosphonates are unsuitable and in circumstances in which the treatments appraised by NICE are not recommended, in which the ICER for denosumab compared with no treatment varied between £12,289 and £22,957 per QALY gained. The Committee concluded that treatment with denosumab was considered to be a cost-effective use of NHS resources for the secondary prevention of osteoporotic fragility fractures in women for whom oral bisphosphonates are unsuitable. What are the key drivers of cost effectiveness? The Committee concluded that with the exception of administration costs for denosumab, alterations to most key parameters had limited impact on comparisons between denosumab and the primary and secondary comparators. Most likely cost-effectiveness estimate (given as an ICER) The Committee accepted that the most likely cost-effectiveness estimates would lie between the manufacturer's base case (using primary care assumptions) and the ERG's additional analyses (using secondary care assumptions), and that the most plausible ICERs were likely to be closer to the manufacturer's base case estimates, given that care would mostly be in the primary setting. The Committee noted that for the primary prevention of osteoporotic fragility fractures, denosumab dominated strontium ranelate in the manufacturer's base case, and the ICER was £15,900 per QALY gained for denosumab compared with strontium ranelate in the ERG's additional analyses (assuming denosumab is always given in secondary care). The Committee concluded that for the primary prevention of osteoporotic fragility fractures, denosumab was a cost-effective use of NHS resources as a treatment option only for postmenopausal women at increased risk of fractures for whom oral bisphosphonates are unsuitable, and who have the same level of fracture risk as described in the recommendations of NICE technology appraisal 160 for strontium ranelate. The Committee was aware that for women for whom oral bisphosphonates are unsuitable and who do not currently fulfil the criteria for treatment with strontium ranelate, no treatment is currently recommended by NICE for the primary prevention of osteoporotic fragility fractures. The Committee noted that the ICER for denosumab compared with no treatment was £29,200 per QALY gained in the manufacturer's base-case analysis, and this increased to £40,600 per QALY gained in the ERG's additional analyses. It concluded that the ICER for the base-case population (women 70 years and over with T-score of −2.5 SD or below) for denosumab compared with no treatment was likely to lie within this range. For the secondary prevention of osteoporotic fragility fractures, the Committee noted that the ICER for denosumab compared with no treatment in women for whom oral bisphosphonates are unsuitable was £12,400 per QALY gained in the manufacturer's base-case analysis, which increased to £17,900 per QALY gained in the ERG's additional analyses. Denosumab dominated raloxifene or had an ICER of £2000 per QALY gained (age 70, T-score −2.5) in the manufacturer's base-case analysis, which increased to £12,200 per QALY gained in the ERG's additional analyses. The ICER for denosumab compared with strontium ranelate ranged from strontium ranelate being dominated by denosumab in the manufacturer's base-case analysis to £6600 per QALY gained in the ERG's additional analyses. The Committee concluded that treatment with denosumab was considered to be a cost-effective use of NHS resources for the secondary prevention of osteoporotic fragility fractures in women for whom oral bisphosphonates are unsuitable. The Committee noted that in the manufacturer's base-case analysis, denosumab was slightly less effective and much less costly than teriparatide. Therefore the Committee concluded that denosumab may provide an alternative treatment option that would be a cost-effective use of NHS resources for women who are eligible for treatment with teriparatide as defined in NICE technology appraisal guidance 161. Additional factors taken into account Patient access schemes (PPRS) Not applicable. No patient access scheme was submitted. End of life considerations Not applicable to this disease area. Equalities considerations Following consultation on the appraisal consultation document, the Committee was aware that one area of potential discrimination was the primary prevention of osteoporotic fractures in postmenopausal women with swallowing problems as a result of disabling stroke disease, who would otherwise be eligible for treatment with oral bisphosphonates, but do not fulfil the criteria for denosumab or other treatments. The Committee concluded that its considerations were based on the population of postmenopausal women for whom oral bisphosphonates are unsuitable which included women with and without a disability. T-score relates to the measurement of bone mineral density using central (hip and/or spine) DXA scanning, and is expressed as the number of standard deviations (SD) below peak bone mineral density. Treatment with denosumab is not recommended. Treatment with strontium ranelate is not recommended.# Related NICE guidance Alendronate, etidronate, risedronate, raloxifene and strontium ranelate for the primary prevention of osteoporotic fragility fractures in postmenopausal women (amended).NICE technology appraisal guidance 160 (2008; amended 2010). Alendronate, etidronate, risedronate, raloxifene, strontium ranelate and teriparatide for the secondary prevention of osteoporotic fragility fractures in postmenopausal women (amended).NICE technology appraisal guidance 161 (2008; amended 2010).# Review of guidance The guidance on this technology will be considered for review at the same time that NICE technology appraisal guidance 160 and 161 (2008; amended 2010) are considered for review. The Guidance Executive will decide whether the technology should be reviewed based on information gathered by NICE, and in consultation with consultees and commentators. Andrew DillonChief ExecutiveOctober 2010# Changes after publication February 2014: implementation section updated to clarify that denosumab is recommended as an option for preventing osteoporotic fractures in postmenopausal women. Additional minor maintenance update also carried out. March 2012: minor maintenance# About this guidance NICE technology appraisal guidance is about the use of new and existing medicines and treatments in the NHS in England and Wales. This guidance was developed using the NICE single technology appraisal process. We have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available. Your responsibility This guidance represents the views of NICE and was arrived at after careful consideration of the evidence available. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. However, the guidance does not override the individual responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or guardian or carer. Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties. Copyright © National Institute for Health and Clinical Excellence 2010. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.	{'Guidance': 'Denosumab is recommended as a treatment option for the primary prevention of osteoporotic fragility fractures only in postmenopausal women at increased risk of fractures:\n\nwho are unable to comply with the special instructions for administering alendronate and either risedronate or etidronate, or have an intolerance of, or a contraindication to, those treatments and\n\nwho have a combination of T-score, age and number of independent clinical risk factors for fracture (see section 1.3) as indicated in the following table.\n\nT-scores (SD) at (or below) which denosumab is recommended when alendronate and either risedronate or etidronate are unsuitable\n\n\n\nNumber of independent clinical risk factors for fracture\n\nAge (years)\n\n\n\n\n\n\n\n-69\n\n–[a]\n\n−4.5\n\n−4.0\n\n-74\n\n−4.5\n\n−4.0\n\n−3.5\n\nor older\n\n−4.0\n\n−4.0\n\n−3.0\n\n[a] Treatment with denosumab is not recommended.\n\nDenosumab is recommended as a treatment option for the secondary prevention of osteoporotic fragility fractures only in postmenopausal women at increased risk of fractures who are unable to comply with the special instructions for administering alendronate and either risedronate or etidronate, or have an intolerance of, or a contraindication to, those treatments.\n\nFor the purposes of this guidance, independent clinical risk factors for fracture are parental history of hip fracture, alcohol intake of 4 or more units per day, and rheumatoid arthritis.\n\nPeople currently receiving denosumab for the primary or secondary prevention of osteoporotic fragility fractures who do not meet the criteria specified in recommendations 1.1 or 1.2 should have the option to continue treatment until they and their clinician consider it appropriate to stop.\n\n T-score measures bone mineral density using central (hip and/or spine) dual-energy X-ray (DXA) scanning, and is expressed as the number of standard deviations (SD) below peak bone mineral density.', 'The technology ': "Denosumab (Prolia, Amgen) is a monoclonal antibody that reduces osteoclast activity, and so reduces bone breakdown. Denosumab has a UK marketing authorisation for the treatment of osteoporosis in postmenopausal women at increased risk of fractures. The summary of product characteristics states in the indication that denosumab significantly reduces the risk of vertebral, non-vertebral and hip fractures.\n\nThe summary of product characteristics states that conditions associated with denosumab treatment include: urinary tract infection, upper respiratory tract infection, sciatica, cataracts, constipation, rash, pain in extremity and skin infections (predominantly cellulitis). However, there was no evidence of increased incidence of cataracts or diverticulitis in postmenopausal women with osteoporosis; these conditions occurred only in patients with prostate cancer. The summary of product characteristics states that osteonecrosis of the jaw has been reported in patients receiving denosumab or bisphosphonates, with most cases occurring in people with cancer, but some occurred in people with osteoporosis. For full details of side effects and contraindications, see the summary of product characteristics.\n\nDenosumab is administered as a single subcutaneous injection into the thigh, abdomen or back of the arm. The recommended dosage is 60\xa0mg once every 6 months.\n\nThe acquisition cost of denosumab is £183 for a 1\xa0ml pre-filled syringe (60\xa0mg per ml solution; excluding VAT, 'MIMS' September 2010 edition), which is equivalent to £366 for 1\xa0year of treatment. Costs may vary in different settings because of negotiated procurement discounts.", "The manufacturer's submission": "The Appraisal Committee (appendix A) considered evidence submitted by the manufacturer of denosumab and a review of this submission by the Evidence Review Group (ERG; appendix B).\n\nThe manufacturer's submission presented data for clinical effectiveness from one main randomised trial, the FREEDOM (fracture reduction evaluation of denosumab in osteoporosis every 6 months) study. This multicentre, double-blind, placebo-controlled trial enrolled 7868 postmenopausal women aged 60–90 years with T-scores of less than −2.5 SD and greater than −4.0 SD at lumbar spine, total hip, or both locations. The T-score measures bone mineral density using central (hip and/or spine) DXA scanning and is expressed as the number of standard deviations (SD) below the mean bone mineral densityof young, healthy adults of the same gender at their peak bone mass. Lower T-scores indicate lower bone mineral density. Women were randomly assigned to receive a subcutaneous injection of either 60\xa0mg denosumab or placebo twice a year for 3\xa0years. All participants also took daily calcium and vitamin D supplements.\n\nThe primary outcome was the incidence of new radiographically diagnosed vertebral fractures. Secondary outcomes were time to first non-vertebral fracture and time to first hip fracture. Health-related quality of life was assessed in terms of change from baseline in patient-reported outcomes using both the osteoporosis assessment questionnaire-short version (OPAQ-SV; physical function, emotional status and back pain score), and the EUROQOL-5D (EQ-5D) questionnaire.\n\nThe results of the FREEDOM study demonstrated that, based on the number of people who underwent spinal radiography at baseline and during at least one visit after baseline, the 36-month incidence of new radiographically diagnosed vertebral fractures was 2.3% (86 of 3702 women) in the denosumab group compared with 7.2% (264 of 3691 women) in the placebo group (relative risk [RR] 0.32, 95% confidence interval [CI] 0.26 to 0.41; p\xa0< 0.001). The reduction in risk was similar during each year of the trial. Similar reductions in incidence were seen for clinically diagnosed vertebral fractures (0.8% for denosumab versus 2.6% for placebo; hazard ratio [HR] 0.31, 95% CI 0.20 to 0.47; p\xa0< 0.001) and for multiple new radiographically diagnosed vertebral fractures (0.6% for denosumab versus 1.6% for placebo; RR 0.39, 95% CI 0.24 to 0.63; p\xa0< 0.001). Denosumab also reduced the risk of non-vertebral fracture (6.5% for denosumab versus 8.0% for placebo; HR 0.80, 95% CI 0.67 to 0.95; p\xa0=\xa00.01) and hip fracture (0.7% for denosumab versus 1.2% for placebo; HR 0.60, 95% CI 0.37 to 0.97; p\xa0=\xa00.04). The manufacturer stated that dropout rates were similar between groups and no imbalances were observed.\n\nHealth-related quality of life was assessed using the OPAQ-SV and EQ-5D questionnaire at baseline and every 6 months for 3 years. Among women who completed the study, completion rates for measures of health-related quality of life at year 3 were 83% for OPAQ-SV and 82% for EQ-5D. No significant differences were seen between treatment groups in measures of health-related quality of life at baseline compared with year 3, or between women without any fractures and those with incident clinical fractures. Changes from baseline to year\xa03 for each OPAQ-SV dimension and EQ-5D scores were positively correlated (all p\xa0<\xa00.0001).\n\nA statistically significant difference was noted in skin infections, which occurred in 12 women receiving denosumab compared with one woman receiving placebo (p = 0.002). However, when all studies of denosumab were pooled in the manufacturer's meta-analysis, the overall incidences of adverse events, serious adverse events and adverse events leading to treatment withdrawal were generally similar between denosumab and placebo groups. Further safety data were available from 30 studies, giving a total of 14,000 patients, including 11,000 postmenopausal women with low bone density or osteoporosis, as well as people taking denosumab for preventing bone loss in prostate or breast cancer.\n\nThe manufacturer stated that it was mindful of the need for efficient use of NHS resources, and that, given the wide availability of generic oral bisphosphonates, denosumab was expected to be an option for women in whom oral bisphosphonates are unsuitable (reasons for unsuitability are that the woman is unable to comply with the special instructions for the administration of oral bisphosphonates, or has a contraindication to or is intolerant of oral bisphosphonates). Therefore denosumab was not expected to compete with oral bisphosphonates in clinical practice. In the absence of head-to-head clinical trials comparing denosumab with all relevant comparators (denosumab, strontium ranelate, raloxifene, teriparatide and zoledronate), the manufacturer carried out a random-effects meta-analysis of the relative risks (RRs) for all fracture endpoints directly comparing each treatment against placebo. The fracture incidence data (and RRs) for strontium ranelate for hip and wrist fracture were taken from the publication by Reginster et al. (2008) which reported 5-year data from the TROPOS study. As outlined in the table 1 below, the results of the manufacturer's meta-analysis showed that all treatments were associated with statistically significant decreases in the risk of morphometric vertebral fractures compared with placebo. Denosumab, strontium ranelate and zoledronate were associated with statistically significant decreases in the risk of clinical vertebral fractures, but raloxifene was not (no data were available for teriparatide). Similarly, denosumab, strontium ranelate, teriparatide and zoledronate were associated with statistically significant decreases in the risk of non-vertebral fractures, but raloxifene was not. Denosumab and zoledronate were associated with statistically significant decreases in the risk of hip fractures but strontium ranelate, and teriparatide were not (no data were available for raloxifene). None of the treatments were associated with a statistically significant decrease in the risk of wrist fracture.\n\nTable 1 Manufacturer's direct comparison of each comparator with placebo from the random effects meta-analysis\n\nComparator\n\nClinically diagnosed vertebral fracture (relative risk [95% CI])\n\nNon-vertebral fractures (relative risk [95% CI])\n\nHip fracture(relative risk [95% CI])\n\nWrist fracture(relative risk [95% CI])\n\nDenosumab\n\n(0.21 to 0.48)\n\n(0.69 to 0.96)\n\n(0.37 to 1.0)\n\n(0.64 to 1.1)\n\nZoledronate\n\n(0.14 to 0.37)\n\n(0.65 to 0.87)\n\n(0.42 to 0.83)\n\n–\n\nRaloxifene\n\n(0.05 to 3.82)\n\n(0.16 to 2.65)\n\n–\n\n–\n\nStrontium ranelate\n\n(0.50 to 0.84)\n\n(0.78 to 0.99)\n\n(0.67 to 1.2)\n\n(0.73 to 1.31)\n\nCI, confidence interval.\n\n*Statistically significant (p\xa0≤\xa00.05).\n\nThe manufacturer's submission included a systematic review of the cost-effectiveness evidence for denosumab. The manufacturer carried out Markov cohort modelling to assess the cost effectiveness of denosumab against primary and secondary comparators. Primary comparators were strontium ranelate, raloxifene and no treatment (placebo). Secondary comparators were intravenous ibandronate, zoledronate and teriparatide. The manufacturer stated that denosumab is expected to be a treatment option for women with osteoporosis for whom oral bisphosphonates are unsuitable. Therefore, comparisons with oral bisphosphonates were not directly relevant to this appraisal and were included in appendices to the manufacturer's submission. The manufacturer stated that 71.6% of women receiving treatment for osteoporosis in England and Wales receive alendronate, 15.8% receive risedronate, 1.5% receive etidronate and 4.3% receive oral ibandronate, meaning that 93.2% of this population receive oral bisphosphonates (2009 figures). This means an estimated 6.8% of women receiving treatment for osteoporosis in England and Wales receive drugs other than oral bisphosphonates (2.8% strontium ranelate, 2.2% raloxifene, 0.6% intravenous ibandronate, 0.7% zoledronate, 0.2% calcitonin, 0.2% calcitriol and 0.1% teriparatide).\n\nThe manufacturer stated that persistence and compliance with oral bisphosphonates are poor because of the strict and complex dosing regimen and side effects of treatment. The manufacturer's submission stated that at least 42% of patients taking oral bisphosphonates stop within 1 year, and the median duration of treatment is estimated to be as low as 1.2\xa0years. The manufacturer stated that few people (<\xa01%) permanently discontinued denosumab treatment because of treatment-related adverse events over 2–3 years in the FREEDOM study.\n\nThe model assessed the cost effectiveness of denosumab against the primary and secondary comparators for two separate cohorts. The first investigated the primary prevention of fragility fractures in women (70\xa0years and over) with osteoporosis (T-score of −2.5\xa0SD or below) for whom oral bisphosphonates are unsuitable. The second investigated the secondary prevention of subsequent fragility fractures in women (70\xa0years and over) with osteoporosis (T-scores of −2.5\xa0SD or below) and prior fragility fractures in whom oral bisphosphonates are unsuitable. The model had a cycle length of 6\xa0months and a lifetime horizon (defined as until time of death or age of 100\xa0years), including a half-cycle correction, with a treatment duration of 5\xa0years.\n\nThe model included six discrete health states: well, hip fracture, clinically diagnosed vertebral fracture, wrist fracture, other types of fracture (pelvic, femur shaft, tibia, fibular, humerus, scapula, clavicle, rib or sternum), and death. It included two additional health states (post-hip fracture and post-vertebral fracture) to account for the long-term costs and effects associated with these fractures (no long-term costs or effects were assumed for women with wrist or other fractures). When a fracture occurred, women were modelled to remain in the respective fracture state for two cycles (1\xa0year). After this period, women with a wrist fracture or other types of fracture were modelled to return to the well state. Women with a vertebral fracture or hip fracture were modelled to enter a post-fracture state. Women who had a vertebral fracture could no longer incur a wrist fracture or other type of osteoporotic fracture (other than a subsequent vertebral fracture or hip fracture). Women who had a hip fracture could only incur further hip fractures. The manufacturer's model was not a treatment-sequencing model because of the lack of clinical evidence for such use.\n\nThe manufacturer's base-case analysis assumed that women continued osteoporosis therapy for 5 years, and costs and quality-adjusted life years (QALYs) were tracked over the lifetime of the cohorts (consistent with economic modelling in 'Alendronate, etidronate, risedronate, raloxifene and strontium ranelate for the primary prevention of osteoporotic fragility fractures in postmenopausal women' [NICE technology appraisal guidance 160] and 'Alendronate, etidronate, risedronate, raloxifene, strontium ranelate and teriparatide for the secondary prevention of osteoporotic fragility fractures in postmenopausal women' [NICE technology appraisal guidance\xa0161]). This assumption was examined in a sensitivity analysis.\n\nSubgroup analysis was undertaken for women with and without prior fracture by age (55–75, 5-year age bands) and T-score (between −2.5 to −4.0 SD). Sensitivity analysis assessed the effect on cost effectiveness of the presence or absence of additional independent clinical risk factors for fracture in women of 70 years of age, with and without prior fragility fractures. Sensitivity analysis also assessed the effects on cost effectiveness of differences in treatment persistence and compliance.\n\nIn the manufacturer's base-case analysis, fracture risks were estimated on the basis of epidemiological literature, and were based on three main elements: general population fracture risk, increased fracture risk associated with osteoporosis, and risk reduction attributed to treatment (if any). A systematic review of the literature was undertaken to identify appropriate UK studies or systematic reviews for all three model parameters. Age-specific fracture risks were estimated for women in the general population (using a study by Singer et al. to estimate risk of wrist and hip fractures, and a study by Kanis et al. to derive estimates for the incidence of clinically diagnosed vertebral and other fractures). Next, age-matched Z-scores (that is, the estimate of the number of SD below the mean bone mineral density of the general population for the patient's age and sex) were estimated for a cohort with osteoporosis using the National Health and Nutrition Examination Survey (NHANES) III database. Evidence from the systematic review was then used to attribute age-specific relative risks for the different types of fracture. Treatment was modelled to continue for 5 years by applying relative risks to the estimated baseline risks of fracture in the cohort with osteoporosis. An assumption was made that, on stopping treatment after 5 years, women would return in a linear fashion to baseline risk levels over 1 year (a return to baseline over 5 years was assumed in NICE technology appraisal guidance 160 and 161). The relative risks of fracture for each treatment for clinical vertebral, hip and wrist fractures were estimated from the manufacturer's direct comparison for each treatment against placebo if data were available. If evidence was not available for a comparator, the following explicit assumptions were made:\n\nthat for interventions without data for the relative risk of clinical vertebral fracture, this was equivalent to the relative risk of morphometric vertebral fracture\n\nthat the relative risk for interventions for which data for wrist and hip fractures were not available was 1.00.\n\nthat since no efficacy evidence was identified for intravenous ibandronate compared with placebo, efficacy was equivalent to that of oral ibandronate\n\nthat the relative risk for other fractures was 1.00 for all treatments, because 'other fracture' was not defined consistently across studies.\n\nThe model accounted for observed increases in the risk of mortality after fracture by applying relative risks for mortality obtained from a review of the literature. An increased risk was modelled for the first year and subsequent years after hip fracture or vertebral fracture. For other types of fracture, women were modelled to be at increased risk of mortality for 1 year only. The relative risks of mortality after all types of fracture were adjusted downwards to account for the observation that a proportion of mortality after fracture is explained by comorbidity. It was assumed that 30% of all mortality after all types of fracture is causally related, which is consistent with similar assumptions in NICE technology appraisal guidance 160 and 161.\n\nThe manufacturer's model also took into account persistence and compliance. Persistence is defined as the duration of time from start to end of therapy, and compliance is defined as conforming to the recommendations made by the provider with respect to timing, dosage and frequency of medication taking. Persistence and compliance were assumed to be 100% for the 5-year treatment period for all modelled treatments. Sensitivity analysis was carried out for oral therapies and denosumab.\n\nWomen completed the EQ-5D questionnaire in the FREEDOM study, but the number of fracture events with associated EQ-5D scores recorded was low and the trial design precluded assessment of health status immediately after fracture events. Therefore, evidence from the manufacturer's systematic review of the literature on health-related quality of life in osteoporosis was considered to be more meaningful and was applied in the economic analysis. The disutilities associated with fracture were obtained from a systematic review of the literature and applied to population norms in the form of utility multipliers. Utility loss associated with hip and vertebral fractures was modelled in a two-stage process, with a larger decrease in the first year after fracture and an ongoing but less severe utility loss in subsequent years. Utility multipliers for the first and subsequent years after hip fracture were obtained from a meta-analysis of studies using the EQ-5D responses. Utility loss associated with clinically diagnosed vertebral fracture was estimated separately for women managed in hospital and in primary care. The disutilities for women in hospital were derived from the EQ-5D scores of a cohort that were predominantly in hospital. The disutilities for women who were not in hospital were obtained from cohorts with prevalent morphometric fractures. Utility multipliers associated with wrist fracture were also obtained from the literature and applied in the model for 1 year after the event. Because of an absence of evidence, the same multiplier and the same approach were also used to model utility loss associated with other types of fractures. Finally, utility losses associated with selected adverse events were also included in the model.\n\nTreatment costs and quality-of-life losses associated with wrist fracture or other types of fracture were modelled to last 1\xa0year. Clinically diagnosed vertebral fractures and hip fractures were modelled to incur ongoing costs and loss of quality of life.\n\nCosts of drug treatment were estimated using the 'British national formulary' (edition 58), with assumptions about the costs of administration and monitoring for the comparators. Fracture costs were estimated using hospital episode statistics for England and Wales in conjunction with the Department of Health's Healthcare Resource Group tariff; assumptions about the proportion of women treated in hospital, with and without surgery, for the different fracture types were informed by a combination of expert opinion, review of the literature and analysis of routine data. Costs associated with severe adverse events (such as gastrointestinal adverse events associated with oral therapies and cellulitis associated with denosumab) were included. Other types of adverse events associated with denosumab and its comparators were not included.\n\nThe results of the manufacturer's base-case analysis (pairwise comparisons) for the primary comparators showed that, for primary prevention, the incremental cost-effectiveness ratios (ICERs) for denosumab were £29,223 per QALY gained compared with no treatment and £9289 per QALY gained compared with raloxifene, and denosumab dominated strontium ranelate (that is, denosumab was less costly and more effective). For secondary prevention, the ICERs for denosumab were £12,381 per QALY gained compared with no treatment, £2046 per QALY gained compared with raloxifene, and denosumab dominated strontium ranelate. ICERs compared with no treatment for primary prevention were £74,239 per QALY gained for raloxifene and £102,592 per QALY gained for strontium ranelate. ICERs compared with no treatment for secondary prevention were £24,524 per QALY gained for raloxifene and £37,123 per QALY for strontium ranelate.\n\nThe results of the manufacturer's base-case analysis (pairwise comparisons) for the secondary comparators showed that denosumab was the lowest-cost treatment. For primary prevention, the ICERs for the other treatments compared with denosumab were £70,900 per QALY gained for zoledronate, £772,424 per QALY gained for teriparatide, and denosumab dominated ibandronate. For secondary prevention, the ICERs for the other treatments compared with denosumab were £29,029 per QALY gained for zoledronate, £451,269 per QALY gained for teriparatide, and denosumab dominated ibandronate.\n\nThe manufacturer presented a subgroup analysis to demonstrate how the cost effectiveness of denosumab varied when using different treatment cut-offs (that is, all women with a T-score at or below −2.5, −3, −3.5\xa0SD and so on). The manufacturer provided further subgroup analyses for women with and without prior fracture by age and T-score. The results of the manufacturer's subgroup analyses showed that the cost effectiveness of denosumab improved as age increases and as T-score decreases, and with the presence of a prior fragility fracture. For primary prevention, in circumstances in which none of the treatments appraised by NICE are recommended, and oral bisphosphonates are unsuitable, the ICER for denosumab compared with no treatment varied between £19,313 and £71,319 per QALY gained. In circumstances in which strontium ranelate is recommended for primary prevention, denosumab dominated strontium ranelate (that is, denosumab was more effective and less costly). For secondary prevention, in circumstances in which no treatment is currently recommended in the NHS, the ICER for denosumab compared with no treatment varied between £12,289 and £22,957 per QALY gained. In circumstances in which strontium ranelate is recommended for secondary prevention, denosumab dominated strontium ranelate, and in circumstances in which raloxifene is recommended for secondary prevention, denosumab dominated raloxifene or had an ICER of £2046 per QALY gained.\n\nThe manufacturer also provided a subgroup analysis using the FRAX algorithm (an internet-based tool developed by the World Health Organization to calculate a 10-year absolute risk of fracture). This showed how cost effectiveness varied depending on T-score and the presence or absence of independent clinical risk factors for fracture. The results demonstrated that the presence of independent clinical risk factors for fracture, particularly rheumatoid arthritis, also improved the cost effectiveness of denosumab compared with the primary comparators (strontium ranelate, raloxifene and no treatment).\n\nThe manufacturer conducted a range of deterministic and probabilistic sensitivity analyses. The results of the deterministic sensitivity analyses showed that alterations to most key parameters had limited impact on comparisons of denosumab with raloxifene, strontium ranelate and no treatment. The impact on comparisons with intravenous ibandronate, zoledronate and teriparatide were most sensitive to changes in assumptions about the cost of denosumab administration. The manufacturer carried out sensitivity analyses that assumed one administration of denosumab in secondary care per year. Under this scenario, the ICER for denosumab compared with no treatment rose to £36,185 per QALY gained in women with no prior fragility fracture, and to £15,720 per QALY gained in women with a prior fragility fracture. This change led to zoledronate dominating denosumab in women with and without a prior fragility fracture. Following a request from the ERG, the manufacturer also carried out a sensitivity analysis in which denosumab treatment was assumed to be started in secondary care and thereafter delivered in general practice. This analysis showed that the additional cost associated with initiating treatment with denosumab in a secondary care setting had a marginal impact on the cost-effectiveness of denosumab compared with both primary and secondary comparators. The ERG also requested that the manufacturer provided further analysis assuming equal efficacy of denosumab and zoledronate for the prevention of wrist fractures. This analysis showed that the ICER for denosumab was moderately sensitive to assumptions about the relative efficacy of the two drugs for the prevention of wrist fractures.\n\nAfter consultation, the manufacturer carried out additional sensitivity analyses on the long-term effects of fractures on mortality and nursing home care using the conservative assumption that nursing home admission was zero. These analyses showed no substantial impact on the cost-effectiveness results with the ICER for denosumab compared with strontium ranelate going from denosumab being dominant (that is, denosumab was less costly and more effective than strontium ranelate) to £2040 per QALY gained for primary prevention, and denosumab remaining dominant for secondary prevention. The ICER for denosumab compared with raloxifene went from £9289 (£11,135 costs, 8.0 QALYs) to £12,438 per QALY gained for primary prevention, and from £2,046 (£13,543 costs, 7.9 QALYs) to £5,120 for secondary prevention.\n\nThe results of the manufacturer's probabilistic sensitivity analysis showed that denosumab had approximately 50% probability of being considered cost effective at a threshold of £30,000 per QALY gained compared with the primary comparators (strontium ranelate, raloxifene and no treatment) in the base-case population of women aged 70 years with a T-score at or below −2.5\xa0SD for primary prevention. The probability for secondary prevention was 90%. Against the secondary comparators (ibandronate, zoledronate and teriparatide), denosumab had a 60% probability of being considered cost effective at a threshold of £30,000 per QALY gained in the base-case population of women aged 70 years without prior fracture. The probability in women with prior fracture was 70%.\n\nThe ERG considered that the evidence of clinical effectiveness presented in the manufacturer's submission was derived from a large high-quality trial of adequate duration. The ERG stated that it did not consider the evidence presented in the manufacturer's submission on the effects of drugs on bone mineral density to be relevant because fracture data were available for all drugs. The ERG also noted that the data for morphometric vertebral fractures were not relevant, and so were not used in the modelling.\n\nThe ERG noted that the results for the direct comparison of strontium ranelate with placebo (RR for hip fracture of 0.89 and RR for non-vertebral fracture of 0.88) were similar to the meta-analysis provided in NICE technology appraisal 160 (RR for hip fracture of 0.85 and RR for all non-vertebral fractures of 0.84), which provided some confidence in the results. The ERG expressed concern about the relevant comparator for denosumab (see 3.29) and the methodology of the meta-regression to determine whether mean age and bone mineral density were associated with different effects of treatments.\n\nThe ERG noted that the manufacturer provided multiple comparisons of cost effectiveness using a high-quality validated model that took into account a wide range of costs, such as short-term drug costs and long-term nursing home costs, and that the analysis met the NICE reference case. The ERG considered that the appendices to the manufacturer's submission also provided very detailed accounts of underlying model assumptions and sensitivity analyses.\n\nThe ERG identified several issues with the manufacturer's economic model, specifically:\n\nthe choice of comparator\n\ncost assumptions for denosumab\n\nthe validity of assumptions used for modelling utilities, costs, persistence and compliance\n\nvariations in cost effectiveness in subgroups of the cohort modelled\n\nomission of underlying fracture risk estimates from the probabilistic sensitivity analysis\n\ntreatment setting and administration of denosumab.\n\nFirst, the ERG believed that zoledronate should be a key comparator. The manufacturer's submission did not consider zoledronate or intravenous ibandronate to be primary comparators for denosumab because they are used by only 0.7% and 0.6% of currently treated women respectively (according to Intercontinental Marketing Services data), and neither comparator had been appraised by NICE. However, the ERG stated that intravenous ibandronate and zoledronate are licensed and used routinely in UK secondary care for treating osteoporosis in postmenopausal women. The ERG noted that intravenous ibandronate and zoledronate were similar in effectiveness but that intravenous ibandronate was given more frequently than zoledronate, and would be associated with greater administration costs. Therefore, given both its effectiveness and the same method of intravenous administration, zoledronate was a key comparator in the ERG's view.\n\nThe second issue raised by the ERG was that the relative cost effectiveness of denosumab compared with zoledronate depended on assumptions made about administration costs. The manufacturer assumed that denosumab would be given twice a year in general practice at the average cost of two standard visits to a GP, whereas zoledronate was assumed to be given once a year in hospital clinics (with some monitoring incorporated into the visit). The ERG believed that this approach made denosumab much less costly than zoledronate. Therefore, the ERG believed that, given the similar effectiveness of denosumab and zoledronate, the cost-effectiveness comparison depended largely on the relative costs used in the model. The ERG carried out additional exploratory analyses assuming that denosumab was given entirely in secondary care, which demonstrated that for primary prevention the ICER for denosumab compared with no treatment was £40,627 per QALY gained. For primary prevention, the ICER for denosumab compared with raloxifene was £25,743 per QALY gained and for denosumab compared with strontium ranelate was £15,866 per QALY gained. For secondary prevention, the ICER for denosumab compared with no treatment was £17,851 per QALY gained, the ICER for denosumab compared with raloxifene was £12,171 per QALY gained, and the ICER for denosumab compared with strontium ranelate was £6606 per QALY gained.\n\nAfter comments on the appraisal consultation document, which reported a change in cost of zoledronate and that an alternative relative risk could be used for the effect of zoledronate on wrist fracture, the ERG were requested to carry out additional sensitivity analyses. These demonstrated that the change in the cost of zoledronate (which reduced from £283.74 to £266.72 in January 2010) resulted in ICERs for zoledronate compared with denosumab decreasing from £70,900 to £55,885 per QALY gained for primary prevention, and from £29,029 to £22,966 per QALY gained for secondary prevention. Additional sensitivity analyses were also carried out using an alternate relative risk value of 0.81 for risk of wrist fracture for zoledronate (instead of 1.0 in the manufacturer's base case, and 0.84 in the ERGs original sensitivity analyses). The results showed that the ICER for zoledronate compared with denosumab decreased from £70,900 to £58,764 per QALY gained for primary prevention, and from £29,029 to £24,454 for secondary prevention. The ERG carried out analyses using the manufacturer's assumptions in their economic model by combining both the above zoledronate changes simultaneously. These resulted in an ICER for zoledronate compared with denosumab of £44,804 per QALY gained for primary prevention, and £18,606 per QALY gained for secondary prevention.\n\nThe ERG identified that a simplifying assumption was used for transitions in the model. Women experiencing a vertebral fracture could no longer experience a wrist fracture or other type of fracture (apart from a clinical vertebral fracture or hip fracture). After a hip fracture, women could no longer experience any type of fracture other than a hip fracture. The ERG believed that this assumption was unrealistic because experience of a hip fracture or clinical vertebral fracture would put women at higher risk of further fracture. However, the extent of the effect of these assumptions on the cost-effectiveness estimates was unclear.\n\nThe ERG noted that in the manufacturer's base-case analysis, the assumption that fracture risk would return linearly to baseline levels over the course of 1\xa0year after stopping treatment was conservative and would favour oral therapies. Persistence and compliance were assumed to be 100% for all treatments in the base-case analysis, which was also a conservative assumption. The ERG noted that after initial administration of denosumab, both compliance and persistence would be 100% for 6\xa0months. However, in the long term, persistence with denosumab therapy may be less than 100%. The manufacturer carried out sensitivity analyses that examined variations in persistence for oral therapies and denosumab.\n\nThe ERG noted that the manufacturer's quality-of-life review methodology and the primary studies included in the review suggested that suitable utility multipliers were applied in the model. However, many of the multipliers were derived from observational time-series studies without independent control groups and therefore did not control for all potential confounding factors. The ERG noted that costs and utility losses associated with wrist fractures and other types of fracture were assumed to last for 1\xa0year, whereas hip fractures and clinical vertebral fractures were modelled to incur ongoing costs and utility losses. The ERG also noted that utility loss relative to population norms remained constant in the second and subsequent years after hip fracture or vertebral fracture. This assumption may have slightly overestimated utility loss associated with hip and vertebral fracture if the observed trend towards improved quality of life in the second year after fracture continued in subsequent years.\n\nThe ERG noted that the manufacturer's ICERs varied substantially within subgroups of the cohorts, and that the appropriate comparator also varied by subgroup according to existing NICE guidance. Furthermore, neither raloxifene or strontium ranelate compared favourably with no treatment (ICERs of £74,239 and £102,592 per QALY gained respectively for 70-year-old women with a T-score of −2.5 SD and no prior fragility fracture, and £24,524 and £37,123 per QALY gained respectively for those with a prior fragility fracture), which is consistent with the modelling in NICE technology appraisal guidance 160 and 161. The ERG expressed the view that demonstrating cost effectiveness against these comparators did not allow the conclusion that denosumab is cost effective. The ERG also believed that, for the comparison between denosumab and zoledronate, there was uncertainty about the costs of administering these two drugs and their relative efficacy for the prevention of wrist fracture.\n\nThe manufacturer conducted a range of deterministic and probabilistic sensitivity analyses. The ERG noted that an important omission from the probabilistic sensitivity analysis was the underlying estimates of fracture risk. The manufacturer stated that data limitation meant that distributions could not be estimated for these parameters. The ERG believed that this would have the effect of overestimating the probability of denosumab being considered cost effective at different payment thresholds. It also noted that deterministic sensitivity analysis showed that the cost-effectiveness estimates were sensitive to underlying fracture risk. Following consultation the manufacturer carried out additional sensitivity analyses in which beta distributions were assigned to baseline fracture incidence based on an assumed sample size of 10,000. Probabilistic sensitivity analysis showed that for denosumab compared with no treatment the ICER was £30,422 per QALY gained which was similar to the deterministic ICER of £29,233 per QALY gained.\n\nThe ERG had concerns about the treatment setting and administration of denosumab in the model. The subcutaneous injection of denosumab is simple and could be carried out by a general practitioner, a practice nurse or the woman herself. However, the ERG believed that denosumab treatment would probably not be started in general practice because it is a new biological agent that has effects on other body systems (including the immune system), and that long-term adverse events could not be ruled out. The ERG stated that it would expect at least one outpatient visit to be needed and, in many cases, continued hospital follow-up would be necessary. Additionally, if follow-up was partly or mainly in general practice, the ERG believed that administration of denosumab would probably not be provided in primary care as part of general medical services, but would be regarded as an enhanced service for which an additional payment would be negotiated (the size of which is currently unknown, but may be greater than the manufacturer's assumption of the average cost of two visits to a GP per patient per year). Therefore, the marginal costs per patient of administering denosumab in primary care may be greater than the average cost of two visits to a GP per patient per year as presented in the manufacturer's model.\n\nThe ERG noted that although denosumab could be self-administered by the woman, the average age of women taking medication for the prevention of fracture in the General Practice Research Database dataset was 71.4 years, and many would be older. Such women might not be able to give themselves a subcutaneous injection because of poor eyesight, poor manual dexterity or cognitive impairment. The oldest age groups also have the highest proportion of women treated with oral bisphosphonates. Furthermore, training women to self-administer denosumab might not be regarded as worthwhile because they would have to visit a general practice to obtain the pre-filled pen injection device, and after 6 months some may have forgotten how to administer it (which is unlikely to occur with drugs given daily, such as teriparatide). The ERG also expressed the view that an equality issue exists for women who have had a stroke in the past and who are at increased risk of falls and fracture, together with bone loss because of reduced mobility. Such women might have difficulty swallowing or standing to take oral bisphosphonates, and therefore, intravenous or subcutaneous drugs may be more suitable.\n\nFull details of all the evidence are in the manufacturer's submission and the ERG report.", 'Consideration of the evidence': "The Appraisal Committee reviewed the data available for the clinical and cost effectiveness of denosumab, having considered evidence on the nature of osteoporotic fractures and the value placed on the benefits of denosumab by postmenopausal women with the condition, those who represent them, and clinical specialists. It also took into account the effective use of NHS resources.\n\nThe Committee discussed the clinical need of postmenopausal women for the prevention of osteoporotic fragility fractures. It heard from the clinical specialists that the main aim of primary prevention is the opportunistic identification of postmenopausal women who are at risk of osteoporotic fragility fractures, and the aim of secondary prevention is to provide the most effective treatment for women who have already had an osteoporotic fragility fracture and are at risk of further fractures.\n\nThe Committee heard from the clinical specialists that current UK clinical practice is to start treatment with oral bisphosphonates (first with alendronate and then either risedronate or etidronate if alendronate is unsuitable). These treatments are not suitable for all women because some women are unable to comply with the special instructions for the administration of oral bisphosphonates, or have a contraindication to or are intolerant of oral bisphosphonates. The Committee also heard from the clinical specialists that women for whom oral bisphosphonates are unsuitable receive either no treatment or strontium ranelate for primary prevention (as set out in NICE technology appraisal guidance\xa0160), or no treatment, strontium ranelate or raloxifene for secondary prevention (as set out in NICE technology appraisal guidance\xa0161). The clinical specialists stated that the management of osteoporosis usually takes place in primary care (both strontium ranelate and raloxifene are given in primary care). Women who have severe osteoporosis may receive more potent agents such as zoledronate or intravenous ibandronate but there is limited capacity for treatment in secondary care because of the need for day-case facilities for these intravenous treatments. The patient experts stated that some women who cannot take or cannot tolerate oral bisphosphonates have a preference for strontium ranelate or raloxifene as they do not like the intravenous infusion used for zoledronate treatment, whereas others prefer the convenience of a 12-monthly intravenous infusion (zoledronate) over taking oral treatments daily (strontium ranelate and raloxifene). The Committee accepted that the great majority of treatment for the primary and secondary prevention of osteoporotic fragility fractures is provided in primary care. It also accepted that women for whom oral therapies are unsuitable or who have severe osteoporosis may receive more potent agents such as zoledronate or intravenous ibandronate in secondary care and that teriparatide is also used for secondary prevention when women are unable to take other therapies. The Committee concluded that the relevant comparators for primary prevention are no treatment and strontium ranelate, and for secondary prevention are no treatment, strontium ranelate and raloxifene, because both the administration and supervision of strontium ranelate and raloxifene are organised in primary care. The Committee also concluded that potential comparators for denosumab are zoledronate (for severe osteoporosis) and teriparatide (for women who have sustained a clinically apparent osteoporotic fracture and who are defined by age, T score and number of osteoporotic fractures and who are unable to take all oral bisphosphonates, strontium and raloxifene, as defined in NICE Technology Appraisal 161).\n\nThe Committee was aware that the licensed indication for denosumab is for the treatment of osteoporosis in postmenopausal women at increased risk of fractures. The Committee noted that the manufacturer's decision problem focused on postmenopausal women diagnosed with osteoporosis for whom oral bisphosphonates are unsuitable. The manufacturer stated that denosumab was not expected to compete with oral bisphosphonates in clinical practice, given the wide availability of generic oral bisphosphonates in the UK and the need for efficient use of NHS resources. The Committee also noted that the manufacturer did provide an analysis of denosumab compared with oral bisphosphonates for completeness. It accepted that it was reasonable to base its considerations on women for whom oral bisphosphonates are unsuitable and the subsequent discussion focused on this population only.\n\nThe Committee heard from the clinical specialists that denosumab is a monoclonal antibody that reduces osteoclast activity and hence reduces bone breakdown, that it is the first drug of its class, and that its biological mechanism of action results in targeted therapy with fewer adverse events than other treatments. The Committee considered that a treatment administered by subcutaneous injection once every 6\xa0months, such as denosumab, offers an advantage because it may improve adherence with therapy, particularly for women who have problems swallowing or standing to take oral bisphosphonates. The Committee also accepted evidence from the patient experts that many women stop taking oral bisphosphonates because of adverse events, and often do not go back to their GP. Therefore a 6-monthly subcutaneous injection of denosumab could provide women with a pre-arranged opportunity to discuss their treatment and any adverse events with a healthcare professional, and this support may improve compliance and persistence with treatment.\n\n# Clinical effectiveness\n\nThe Committee accepted that the clinical-effectiveness evidence presented in the manufacturer's submission was derived from a large, high-quality trial of adequate duration (FREEDOM) that studied treatment with denosumab compared with placebo. The Committee noted that, because the FREEDOM study did not provide a head-to-head comparison of denosumab against all relevant comparators, the manufacturer carried out a random-effects meta-analysis to obtain direct estimates for each treatment compared with placebo (denosumab, strontium ranelate, raloxifene, teriparatide and zoledronate).\n\nThe Committee noted that the FREEDOM trial showed a statistically significant 68% reduction in the relative risk p < 0.001) of the 36-month incidence of new radiographically diagnosed vertebral fractures. The Committee also noted that denosumab significantly reduced the risk of non-vertebral fracture (HR 0.80; 95% CI 0.67 to 0.95; relative reduction of 20%) and of hip fracture (HR 0.60, 95% CI 0.37 to 0.97; relative reduction of 40%). The Committee concluded that the evidence from the FREEDOM trial demonstrated that denosumab was effective in reducing the risk of fracture in postmenopausal women compared with placebo.\n\nThe Committee discussed the meta-analysis that was undertaken by the manufacturer to obtain direct estimates for each treatment compared with placebo. However, the Committee noted the lack of a direct comparison of denosumab with active comparators. It was, therefore, unable to make a conclusion about the relative clinical effectiveness of denosumab, but was satisfied with the evidence on the direct estimates for each treatment compared with placebo and concluded that the methods used in the meta-analysis were sufficiently robust for use in the economic analysis.\n\nThe Committee discussed the adverse events experienced by postmenopausal women receiving denosumab for the prevention of osteoporotic fragility fractures. The Committee noted that in the FREEDOM trial treatment with denosumab was associated with fewer adverse events than placebo. The patient experts stated that the main concern women have about treatment for osteoporosis is the duration for which therapies are taken and whether they will experience adverse events over a long period of time. The Committee heard that there may be a risk of infection associated with denosumab treatment; however, it accepted evidence from the clinical specialists that this risk was low and that if substantial evidence became available, it may be necessary to assess women with severe infections before considering the use of denosumab. The Committee noted that studies of denosumab for other indications have shown that treatment may be associated with osteonecrosis of the jaw, but it was satisfied with the clinical specialists' statement that there was no evidence of this from the clinical studies of denosumab in women with osteoporosis. The clinical specialists confirmed that 14,000 women have received denosumab and that it was well tolerated. The Committee concluded that the available clinical evidence on the adverse effects associated with denosumab indicated that it was a well tolerated treatment for the prevention of osteoporotic fragility fractures in postmenopausal women.\n\n# Cost effectiveness\n\nThe Committee considered the manufacturer's economic model, and the critique and exploratory sensitivity analyses performed by the ERG. It noted that the manufacturer used a Markov economic model to evaluate the cost effectiveness of denosumab compared with a range of comparators, and that the clinical data were derived from the manufacturer's direct comparison of each comparator with placebo in their random-effects meta-analysis. The Committee considered that the methods used in the analysis were robust.\n\nThe Committee considered the ERG's concerns about a number of aspects of the economic model, such as the long-term effects of fractures on mortality, the setting where denosumab is likely to be given, and the associated administration and monitoring costs modelled. The Committee also discussed issues raised from consultation on the appraisal consultation document: the use of quality of life data from the FREEDOM study in the economic model, the use of the FRAX tool to estimate fracture risk, the cost and setting of care for women receiving denosumab, the cost of zoledronate, the relative risk for wrist fracture for zoledronate, and the relative risk for hip fracture with strontium ranelate.\n\nThe Committee considered the long-term effects of fractures on mortality and the need for nursing home care. It noted that the manufacturer assumed that 30% of observed mortality for all fracture types is causally related to osteoporotic fracture, and this estimate was varied to 100% in sensitivity analyses. The Committee was aware that the manufacturer's model also assumed that women were at increased risk of entry into nursing home care following hip fracture and that the lowest cost of private residential care was applied. The Committee noted that some women may already be in a nursing home, and some may also be self-funding their nursing home care. After consultation, the manufacturer carried out additional sensitivity analyses, using the assumption that nursing home admission was zero. The Committee concluded that the long-term effects of fractures on mortality and nursing home care had only a minor impact on the cost-effectiveness estimates for denosumab.\n\nThe Committee noted that the manufacturer's model assumed treatment duration of 5 years, and that the FREEDOM study was of 3 years' duration. The Committee accepted that the 5-year treatment duration assumption was appropriate and reflected clinical practice. The Committee noted that the manufacturer's model assumed that women would return in a linear fashion to baseline fracture risk levels over 1\xa0year after treatment stops. It considered whether the return to baseline fracture risk should be different according to treatment type, and heard from the ERG that the duration of benefit in terms of fracture risk (as opposed to bone mineral density) is unknown after cessation of osteoporosis treatments. The Committee concluded that there was little evidence on the duration of effect on fracture risk for osteoporosis treatments and that this was an area of uncertainty.\n\nThe Committee discussed health-related quality-of-life benefits and utility values in the economic model. The Committee noted that no significant differences were seen in health-related quality of life between the denosumab and placebo arms of the FREEDOM trial. The manufacturer justified the omission from the economic model of EQ-5D data from FREEDOM on the grounds that the number of fracture events with associated EQ-5D scores was low and there was relative infrequency of health-related quality of life measurement. The ERG accepted that the lack of statistical difference in EQ-5D scores between the denosumab and placebo arms of the trial was explained by the above factors (low number of fracture events with associated EQ-5D scores and relative infrequency of health-related quality of life measurement), rather than an adverse effect of denosumab masking the health benefit of fracture prevention. The ERG stated that omitting the FREEDOM trial EQ-5D data from the economic analysis was justified given the quality and depth of the manufacturer's systematic review of health-related quality-of-life data. The Committee concluded that the manufacturer's approach to modelling health-related quality of life was acceptable.\n\nThe Committee considered that the manufacturer's model allowed sensitivity analyses to be carried out using the FRAX tool. The Committee accepted that FRAX is a potentially useful tool in clinical practice, but it was mindful that the tool is presently unvalidated. The Committee was not persuaded that recommendations about treatment should be based on absolute risk as calculated using FRAX and that the stepped approach of assessing fracture risk is needed to ensure the effective allocation of NHS resources. This is because absolute fracture risk is the total risk for all fracture sites, but different fracture sites have different impacts on quality of life, costs and mortality. Therefore, cost effectiveness is dependent on the contribution from each fracture site to the total fracture risk. The Committee concluded that using a combination of T-score, age and a number of independent clinical risk factors for fracture remained more appropriate for defining treatment recommendations in this appraisal.\n\nThe Committee considered the key drivers of cost effectiveness and noted that alterations to most key parameters in the manufacturer's sensitivity analyses had limited impact on comparisons of denosumab with raloxifene, strontium ranelate and no treatment. Comparisons with ibandronate, zoledronate and teriparatide were most sensitive to changes in the assumptions about the cost of administering denosumab. When the manufacturer increased the cost of administering denosumab (by assuming that one administration per year would be delivered in secondary care), this increased the ICER for denosumab compared with no treatment from £29,200 to £36,200 per QALY gained for primary prevention, and from £12,400 to £15,700 per QALY gained for secondary prevention. The Committee noted that given the similar cost and efficacy of denosumab and zoledronate, changes to this assumption also resulted in zoledronate dominating denosumab (that is, zoledronate was less costly and more effective than denosumab) for both primary and secondary prevention. The Committee concluded that with the exception of administration costs for denosumab, alterations to most key parameters had limited impact on comparisons between denosumab and the primary and secondary comparators.\n\nThe Committee noted the ERG's view that administration of denosumab may not be provided in primary care. However, the clinical specialists stated that there is no reason why denosumab should only be used in secondary care. The clinical specialists highlighted that because denosumab is a new biological agent they expected that, initially, treatment would be started in secondary care, but with follow-up almost exclusively in primary care (except for women with severe osteoporosis, who may be followed up in secondary care in line with current UK clinical practice). The Committee discussed whether administering denosumab would be part of general medical services or whether it would be regarded as an enhanced service for which an additional payment would be negotiated, and it noted the comments received during consultation on the ACD. The clinical specialists stated that women would not need to go through a screening process before starting treatment with denosumab, and that women receiving denosumab are not likely to be at high risk of side effects and so follow-up in secondary care would not be necessary. The clinical specialists also stated that although denosumab is a biological agent and also has effects on the immune system, it is specifically targeted for regulating bone cells. The clinical specialists, therefore, thought that the potential safety concerns associated with other biological agents (such as those targeting tumour necrosis factor) may not be applicable to denosumab. The clinical specialists stated that because treatment with denosumab would not involve substantial additional activities to standard practice in managing osteoporosis, it would probably be provided as part of general medical services. The Committee accepted the views of the clinical specialists that there were no specific safety concerns around the use of denosumab and that follow-up in secondary care would not be necessary. Therefore, it was not persuaded to alter its opinion that denosumab is likely to be provided as part of general medical services in primary care. The Committee concluded that while treatment with denosumab may be started in secondary care, it would be subsequently delivered almost exclusively in primary care. The relatively small proportion of women with severe osteoporosis would continue to be followed-up in secondary care, in line with current UK clinical practice.\n\nAfter consultation on the appraisal consultation document, the Committee discussed comments that outlined a change in the cost of zoledronate and that an alternative relative risk could be used for the effect of zoledronate on wrist fracture. The ERG was requested to carry out exploratory analyses that showed that denosumab was less effective and less costly than zoledronate. The Committee had already concluded that although treatment with denosumab may be started in secondary care, it will be subsequently delivered almost exclusively in primary care, unlike the administration of zoledronate, use of which will remain in secondary care. As the Committee regarded the main comparators for denosumab to be those treatments delivered in primary care when oral bisphosphonates were unsuitable (no treatment, strontium ranelate, raloxifene), it did not regard these issues to be central to the decision problem.\n\nThe Committee, therefore, accepted that the most likely cost-effectiveness estimates would lie between the manufacturer's base case (using primary care assumptions) and the ERG's additional analyses (using secondary care assumptions), and that the most plausible ICERs were likely to be closer to the manufacturer's base case estimates given that care would mostly be in the primary setting.\n\nThe Committee considered the relative risks for hip fracture that were used in the manufacturer's meta-analysis. The Committee was aware that NICE recommendations on strontium ranelate are due to be reconsidered following a court of appeal judgement related to assumptions about relative risk of hip fracture. It noted that the figure that the manufacturer used as the 5-year relative risk of hip fracture for strontium ranelate was 0.89 compared with placebo and this was derived from the published TROPOS study, but that alternative relative risk figures of 0.64 (obtained over 3 years) or 0.57 (obtained over 5 years) for the effect of strontium ranelate on hip fracture were suggested during consultation. These alternative, and lower relative risk values, were based on a post-hoc subgroup analysis in the TROPOS study of women over the age of 74 with a T score of −2.4. The Committee also noted a suggestion by the manufacturer of denosumab that if a subgroup relative risk figure for hip fracture was to be used for one treatment in comparative analysis, then similar subgroup figures should also be used for denosumab for this and other outcomes.\n\nThe Committee noted that when using a relative risk of hip fracture of 0.89 for strontium ranelate in the manufacturer's base case, denosumab was dominant compared with strontium ranelate for both primary and secondary prevention. The Committee heard from the ERG that exploratory analyses applying the relative risk estimate of 0.64 over the modelled 5-year treatment period in the manufacturer's model resulted in a base-case ICER of £10,200 per QALY gained for denosumab compared with strontium ranelate for primary prevention and an ICER of £5100 per QALY gained for secondary prevention. When the relative risk estimate of 0.57 for strontium ranelate was applied over the modelled 5-year treatment period in the manufacturer's model, this resulted in an ICER of £16,300 per QALY gained for denosumab compared with strontium ranelate for primary prevention and an ICER of £8600 per QALY gained for denosumab compared with strontium ranelate for secondary prevention. The Committee considered these exploratory analyses and concluded that it did not need to make a decision on which relative risk for strontium ranelate was the most appropriate one to apply, because for any of the suggested relative risk values for hip fracture for strontium ranelate, the ICERs for denosumab compared with strontium ranelate fell within a range that was still considered to be a cost effective use of NHS resources.\n\nThe Committee noted that for the primary prevention of osteoporotic fragility fractures, denosumab dominated strontium ranelate in the manufacturer's base case, and the ICER was £15,900 per QALY gained for denosumab compared with strontium ranelate in the ERG's additional analyses (assuming denosumab is always given in secondary care). The Committee noted that in NICE technology appraisal guidance 160, strontium ranelate is recommended for postmenopausal women:\n\nwho are unable to comply with the special instructions for the administration of alendronate and either risedronate or etidronate, or have a contraindication to or are intolerant of alendronate and either risedronate or etidronate and\n\nwho also have a combination of T-score, age and number of independent clinical risk factors for fracture as indicated in the following table.\n\nT-scores (SD) at (or below) which strontium ranelate is recommended when alendronate and either risedronate or etidronate cannot be taken\n\nAge (years)\n\nNumber of independent clinical risk factors for fracture\n\n\n\n\n\n\n\n–69\n\n– [a]\n\n−4.5\n\n−4.0\n\n–74\n\n−4.5\n\n−4.0\n\n−3.5\n\nor older\n\n−4.0\n\n−4.0\n\n−3.0\n\n[a] Treatment with strontium ranelate is not recommended.\n\nFor the purposes of technology appraisal guidance 160, independent clinical risk factors for fracture are parental history of hip fracture, alcohol intake of 4 or more units per day, and rheumatoid arthritis. The Committee accepted that the above were appropriate when making recommendations on treatment with denosumab for the prevention of primary and secondary osteoporotic fractures. The Committee was mindful that the clinical effectiveness evidence was based on a meta-analysis of each treatment compared with placebo rather than a direct comparison of denosumab with active comparators, and of the areas of uncertainty it had discussed in the economic modelling. However it was satisfied with the robustness of the clinical evidence and, when taken together with the low ICERs presented, the Committee concluded that, as an option, denosumab was a cost-effective use of NHS resources for the primary prevention of osteoporotic fragility fractures only for postmenopausal women at increased risk of fractures for whom oral bisphosphonates are unsuitable, and who have the same level of fracture risk as described in the recommendations for strontium ranelate in NICE technology appraisal guidance 160.\n\nThe Committee was aware that for women for whom oral bisphosphonates are unsuitable and who do not currently fulfil the criteria for treatment with strontium ranelate, there is no treatment currently recommended by NICE for the primary prevention of osteoporotic fragility fractures. The Committee noted that the ICER for denosumab compared with no treatment was £29,200 per QALY gained in the manufacturer's base-case analysis, and this increased to £40,600 per QALY gained in the ERG's additional analyses. It concluded that the ICER for the base-case population (women 70\xa0years and over with a T-score of −2.5\xa0SD or below) for denosumab compared with no treatment was likely to lie within this range. The Committee explored the results for subgroups of women at higher risk by age and T-score, for whom oral bisphosphonates are unsuitable and in circumstances in which none of the treatments appraised by NICE are recommended. The ICERs for denosumab compared with no treatment from the manufacturers model varied between £19,300 and £71,300 per QALY gained. The Committee agreed that the most plausible ICERs were likely to be higher, based on the ERG's amended assumptions. Taking into account the uncertainties around the long-term effects of fractures on mortality and nursing home care, and the setting where denosumab is likely to be given, the Committee concluded that denosumab was not a cost-effective use of NHS resources for women for whom oral bisphosphonates are unsuitable and the treatments appraised by NICE are not recommended.\n\nFor the secondary prevention of osteoporotic fragility fractures, the Committee noted that the ICER for denosumab compared with no treatment in women for whom oral bisphosphonates are unsuitable was £12,400 per QALY gained in the manufacturer's base-case analysis, which increased to £17,900 per QALY gained in the ERG's additional analyses. Denosumab dominated raloxifene or had an ICER of £2000 per QALY gained in the manufacturer's base-case analysis, which increased to £12,200 per QALY gained in the ERG's additional analyses. The cost-effectiveness results for denosumab compared with strontium ranelate ranged from strontium ranelate being dominated by denosumab in the manufacturer's base-case analysis to an ICER of £6600 per QALY gained in the ERG's exploratory analyses. The Committee also noted the results of the subgroup analysis by age and T-score for women for whom oral bisphosphonates are unsuitable and in circumstances in which the treatments appraised by NICE are not recommended, in which the ICER for denosumab compared with no treatment varied between £12,289 and £22,957 per QALY gained. The Committee noted that teriparatide is recommended in NICE technology appraisal guidance 161 as a treatment option for the secondary prevention of osteoporotic fragility fractures in women with severe osteoporosis for whom oral bisphosphonates and strontium ranelate are unsuitable. The Committee noted that in the manufacturer's base-case analysis, denosumab was slightly less effective and much less costly than teriparatide.\n\nThe Committee concluded that treatment with denosumab was a cost-effective use of NHS resources and may be an option for the secondary prevention of osteoporotic fragility fractures in women for whom oral bisphosphonates are unsuitable (that is, in women who are unable to comply with the special instructions for administering alendronate and either risedronate or etidronate, or have an intolerance of, or a contraindication to, those treatments). The Committee also concluded that denosumab may provide an alternative treatment option that would be a cost-effective use of NHS resources for women who are eligible for treatment with teriparatide as defined in NICE technology appraisal guidance 161.\n\nThe Committee considered whether its recommendations were associated with any potential issues related to equality. Following consultation on the appraisal consultation document, the Committee was aware that one area of potential discrimination was the primary prevention of osteoporotic fractures in postmenopausal women with swallowing problems as a result of disabling stroke disease, who would otherwise be eligible for treatment with oral bisphosphonates, but do not fulfil the criteria for denosumab or other treatments. The Committee concluded that its considerations were based on the population of postmenopausal women for whom oral bisphosphonates are unsuitable which included women with and without a disability.\n\n# Summary of Appraisal Committee's key conclusions\n\nTA204 STA\n\n\n\nAppraisal Title: Denosumab for the prevention of osteoporotic fractures in postmenopausal women\n\nFAD section\n\nKey conclusion\n\nDenosumab is recommended as a treatment option for the primary prevention of osteoporotic fragility fractures only in postmenopausal women at increased risk of fractures:\n\nwho are unable to comply with the special instructions for administering alendronate and either risedronate or etidronate, or have an intolerance of or a contraindication to those treatments and\n\nwho have a combination of T-score[a], age and number of independent clinical risk factors for fracture (see section 1.3) as indicated in the following table.\n\nT-scores (SD) at (or below) which denosumab is recommended when alendronate and either risedronate or etidronate are unsuitable\n\nAge (years)\n\nNumber of independent clinical risk factors for fracture\n\n\n\n\n\n\n\n–69\n\n–[a]\n\n−4.5\n\n−4.0\n\n–74\n\n−4.5\n\n−4.0\n\n−3.5\n\nor older\n\n−4.0\n\n−4.0\n\n−3.0\n\n\n\n[a] Treatment with denosumab is not recommended.\n\n\n\nDenosumab is recommended as a treatment option for the secondary prevention of osteoporotic fragility fractures only in postmenopausal women at increased risk of fractures who are unable to comply with the special instructions for administering alendronate and either risedronate or etidronate, or have an intolerance or contraindication to those treatments.\n\nFor the purposes of this guidance, independent clinical risk factors for fracture are parental history of hip fracture, alcohol intake of 4 or more units per day, and rheumatoid arthritis.\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\nThe Committee accepted that there was good quality evidence to support the clinical effectiveness of denosumab compared with placebo and that denosumab would be a clinically effective alternative to existing treatment options for the prevention of osteoporotic fragility fractures in postmenopausal women.\n\n\n\n, 4.8\n\n\n\nThe Committee concluded that treatment with denosumab was a cost-effective use of NHS resources for the primary prevention of osteoporotic fragility fractures only in postmenopausal women at increased risk of fractures for whom oral bisphosphonates are unsuitable, and who have the same level of fracture risk as described in the recommendations of NICE technology appraisal 160 for strontium ranelate.\n\n, 4.23\n\n\n\nThe Committee concluded that treatment with denosumab was a cost-effective use of NHS resources for the secondary prevention of osteoporotic fragility fractures in postmenopausal women at increased risk of fractures for whom oral bisphosphonates are unsuitable.\n\n\n\nCurrent practice\n\nClinical need of patients including the availability of alternative treatments\n\nThe main aim of primary prevention is the opportunistic identification of postmenopausal women who are at risk of osteoporotic fragility fractures, and the aim of secondary prevention is to provide the most effective treatment for women who have already had an osteoporotic fragility fracture and are at risk of further fractures.\n\n\n\n\n\n\n\nThe Committee accepted that current UK clinical practice is to start treatment with oral bisphosphonates (first with alendronate and then either risedronate or etidronate if alendronate is unsuitable), but that these are not suitable for all women. Reasons for unsuitability are that the woman is unable to comply with the special instructions for the administration of oral bisphosphonates, or has a contraindication to or is intolerant of oral bisphosphonates. Women for whom oral bisphosphonates are unsuitable receive either no treatment or strontium ranelate for primary prevention (as set out in NICE technology appraisal guidance 160), or strontium ranelate or raloxifene for secondary prevention (as set out in NICE technology appraisal guidance 161). Treatment usually takes place in primary care (both strontium ranelate and raloxifene are given in primary care). Women who have severe osteoporosis may receive more potent agents such as zoledronate or intravenous ibandronate.\n\n\n\n\n\nThe Committee also noted that zoledronate is sometimes used in secondary care for the prevention of fractures, and that teriparatide is also used for secondary prevention when women are unable to take other therapies.\n\n\n\n\n\nThe technology\n\nProposed benefits of the technology\n\n\n\nHow innovative is the technology in its potential to make a significant and substantial impact on health-related benefits?\n\n\n\nThe Committee considered that a treatment that is administered by subcutaneous injection once every 6\xa0months, such as denosumab, offers an advantage because it may improve adherence with therapy, particularly for women who have problems swallowing or standing to take oral bisphosphonates.\n\nThe Committee noted that denosumab is a monoclonal antibody that reduces osteoclast activity and hence reduces bone breakdown. It also heard from the clinical specialists that it is the first drug in its class, and that its targeted biological mechanism of action results in fewer adverse events than other treatments.\n\n\n\n\n\n\n\n\n\n\n\n\n\nWhat is the position of the treatment in the pathway of care for the condition?\n\n\n\nThe Committee noted that the manufacturer's decision problem focused on postmenopausal women diagnosed with osteoporosis for whom oral bisphosphonates are unsuitable, and that the manufacturer stated that denosumab was not expected to compete with oral bisphosphonates in clinical practice, given the wide availability of generic oral bisphosphonates in the UK. The Committee also noted that the manufacturer did provide an analysis of denosumab compared with oral bisphosphonates for completeness. It accepted that it was reasonable to base its considerations on women for whom oral bisphosphonates are unsuitable and the subsequent discussion focused on this population only.\n\n\n\nAdverse effects\n\n\n\nThe Committee heard that there may be a risk of infection associated with denosumab treatment, however it accepted evidence from the clinical specialists that this risk was low and that if substantial evidence became available, it may be necessary to assess women with severe infections before considering the use of denosumab.\n\nThe Committee concluded that the available clinical evidence on the adverse effects associated with denosumab indicated that it was a well tolerated treatment for the prevention of osteoporotic fragility fractures in postmenopausal women.\n\n\n\nEvidence for clinical effectiveness\n\nAvailability, nature and quality of evidence\n\n\n\nThe Committee considered that the clinical effectiveness evidence presented in the manufacturer's submission was derived from a large, high-quality trial of adequate duration (FREEDOM). Because the FREEDOM study did not provide a head-to-head comparison of denosumab against all relevant comparators, the manufacturer carried out a random-effects meta-analysis to obtain direct estimates for each treatment compared with placebo.\n\n\n\nRelevance to general clinical practice in the NHS\n\n\n\nThe Committee accepted that denosumab is not expected to compete with oral bisphosphonates in clinical practice, given the wide availability of generic oral bisphosphonates in the UK as stated by the manufacturer.\n\n\n\nUncertainties generated by the evidence\n\n\n\nThere was no head-to-head clinical trial evidence comparing denosumab with active relevant comparators (the comparator in the FREEDOM trial was placebo). The manufacturer carried out a random-effects meta-analysis to obtain direct estimates for each treatment compared with placebo. However, the Committee noted the lack of a direct comparison of denosumab with active comparators. It was, therefore, unable to make a conclusion about the relative clinical effectiveness of denosumab, but was satisfied with the evidence on the direct estimates for each treatment compared with placebo and concluded that the methods used in the meta-analysis were sufficiently robust for use in the economic analysis.\n\n\n\n\n\n& 4.8\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\nThe Committee heard that there may be a risk of infection associated with denosumab treatment; however, it accepted evidence from the clinical specialists that this risk was low and that if substantial evidence became available, it may be necessary to assess women with severe infections before considering the use of denosumab.\n\n\n\nAre there any clinically relevant subgroups for which there is evidence of differential effectiveness\n\n\n\nSubgroups by T-score, age and clinical risk factors were explored in the economic model and considered by the Appraisal Committee (see below).\n\n& 4.25\n\nEstimate of the size of the clinical effectiveness including strength of supporting evidence\n\n\n\nThe Committee concluded that the evidence from the FREEDOM trial demonstrated that denosumab was effective in reducing the risk of fracture in postmenopausal women compared with placebo.\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\nThe Committee discussed the meta-analysis that was undertaken by the manufacturer to obtain direct estimates for each treatment compared with placebo. However, the Committee noted the lack of a direct comparison of denosumab with active comparators. It was therefore unable to make a conclusion about the relative clinical effectiveness of denosumab, but was satisfied with the evidence on the direct estimates for each treatment compared with placebo and concluded that the methods used in the meta-analysis were sufficiently robust for use in the economic analysis.\n\nThe Committee accepted that there was good evidence to support the clinical effectiveness of denosumab compared with placebo and that denosumab it would be a clinically effective alternative to existing treatment options for the prevention of osteoporotic fragility fractures in postmenopausal women.\n\nFor details of treatment effect size see relative risks reported in sections 3.3, 3.6 and 4.7.\n\n\n\nEvidence for cost effectiveness\n\nAvailability and nature of evidence\n\n\n\nThe Committee accepted that the manufacturer used a Markov economic model to evaluate the cost effectiveness of denosumab compared with a range of comparators (split into primary and secondary comparators). The clinical data were derived from the manufacturer's direct comparison of each comparator with placebo from their random-effects meta-analysis.\n\n\n\nUncertainties around and plausibility of assumptions and inputs in the economic model\n\nThe Committee was mindful of the ERG's concerns around a number of aspects of the economic model, such as the long term effects of fractures on mortality, the setting where denosumab is likely to be given, and the associated administration and monitoring costs modelled. The Committee also discussed issues raised from consultation on the appraisal consultation document: the use of the FRAX tool to estimate fracture risk, the cost and setting of care for women receiving denosumab, the cost of zoledronate, the relative risk for hip fracture with strontium ranelate.\n\n\n\n\n\n\n\nThe Committee concluded that the long term effects of fractures on mortality and nursing home care did not have a substantial impact on the cost effectiveness estimates for denosumab.\n\n\n\n\n\nThe Committee noted that the manufacturer's model assumed treatment duration of 5 years, and that the FREEDOM study was of 3 years' duration. The Committee accepted that the 5-year treatment duration assumption was appropriate and reflected clinical practice. The Committee heard from the ERG that the duration of benefit in terms of fracture risk (as opposed to bone mineral density) is unknown after cessation of osteoporosis treatments. The Committee concluded that there was little evidence on the duration of effect on fracture risk for osteoporosis treatments and that this was an area of uncertainty.\n\n\n\nThe Committee considered that the manufacturer's model allowed sensitivity analyses to be carried out using the FRAX tool and accepted that it is potentially useful in clinical practice. However, it was not persuaded that recommendations about treatment should be based on absolute risk as calculated using FRAX and that the stepped approach of assessing fracture risk is needed to ensure the effective allocation of NHS resources. Therefore, the Committee concluded that using a combination of T-score, age and a number of independent clinical risk factors for fracture remained more appropriate for defining treatment recommendations in this appraisal.\n\n\n\nThe Committee concluded that with the exception of administration costs for denosumab, alterations to most key parameters had limited impact on comparisons between denosumab and the primary and secondary comparators.\n\n\n\n\n\nThe Committee considered the change in cost of zoledronate and that an alternative relative risk could be used for the effect of zoledronate on wrist fracture. The Committee concluded that although treatment with denosumab may be started in secondary care, it will be subsequently delivered almost exclusively in primary care, unlike the administration of zoledronate, use of which will remain in a secondary care setting. As the Committee regarded the main comparators for denosumab to be those treatments delivered in primary care when oral bisphosphonates were unsuitable, it did not regard these issues to be central to the decision problem.\n\n\n\n\n\n\n\nThe Committee considered the relative risks for hip fracture that were used in the manufacturer's meta-analysis. The Committee was aware that NICE recommendations on strontium ranelate are due to be reconsidered following a court of appeal judgement related to assumptions about relative risk of hip fracture. It noted that the figure that the manufacturer used as the 5-year relative risk of hip fracture for strontium ranelate was 0.89 compared with placebo and this was derived from the published TROPOS study, but that alternative relative risk figures of 0.64 (obtained over 3 years) or 0.57 (obtained over 5 years) for the effect of strontium ranelate on hip fracture were suggested during consultation.\n\n\n\nThe Committee noted that when using a relative risk of hip fracture of 0.89 for strontium ranelate in the manufacturer's base case, denosumab was dominant compared with strontium ranelate for both primary and secondary prevention. The Committee heard from the ERG that exploratory analyses applying the relative risk estimate of 0.64 over the modelled 5-year treatment period in the manufacturer's model resulted in a base-case ICER of £10,200 per QALY gained for denosumab compared with strontium ranelate for primary prevention and an ICER of £5100 per QALY gained for secondary prevention. When the relative risk estimate of 0.57 for strontium ranelate was applied over the modelled 5-year treatment period in the manufacturer's model, this resulted in an ICER of £16,300 per QALY gained for denosumab compared with strontium ranelate for primary prevention and an ICER of £8600 per QALY gained for denosumab compared with strontium ranelate for secondary prevention. The Committee considered these exploratory analyses and concluded that it did not need to make a decision on which relative risk for strontium ranelate was the most appropriate one to apply, because for any of the suggested relative risk values for hip fracture for strontium ranelate, the ICERs for denosumab compared with strontium ranelate fell within a range that was still considered to be a cost effective use of NHS resources.\n\n, 4.21\n\nIncorporation of health-related quality of life benefits and utility values\n\n\n\nHave any potential significant and substantial health-related benefits been identified that were not included in the economic model, and how have they been considered?\n\n\n\nThe Committee noted that no significant differences were seen in health-related quality of life between the denosumab and placebo arms of FREEDOM.\n\n\n\nThe ERG stated that the omission of the FREEDOM trial EQ-5D data from the economic analysis was justified given the quality and depth of the manufacturer's systematic review of health-related quality of life data. The Committee concluded that the manufacturer's approach to modelling health-related quality of life was acceptable.\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\nAre there specific groups of people for whom the technology is particularly cost-effective?\n\nThe Committee noted that for the primary prevention of osteoporotic fragility fractures, denosumab dominated strontium ranelate in the manufacturer's base case, and the ICER was £15,900 per QALY gained for denosumab compared with strontium ranelate in the ERG's additional analyses (assuming denosumab is always given in secondary care). The Committee noted that in NICE technology appraisal guidance 160, strontium ranelate is recommended for postmenopausal women:\n\n• who are unable to comply with the special instructions for the administration of alendronate and either risedronate or etidronate, or have a contraindication to or are intolerant of alendronate and either risedronate or etidronate and\n\n• who also have a combination of T-score, age and number of independent clinical risk factors for fracture is as indicated in the following table.\n\n\n\nT-scores (SD) at (or below) which strontium ranelate is recommended when alendronate and either risedronate or etidronate cannot be taken\n\nAge (years)\n\nNumber of independent clinical risk factors for fracture\n\n\n\n\n\n\n\n–69\n\n–[a]\n\n−4.5\n\n−4.0\n\n–74\n\n−4.5\n\n−4.0\n\n−3.5\n\nor older\n\n−4.0\n\n−4.0\n\n−3.0\n\n\n\n[a] Treatment with strontium ranelate is not recommended.\n\n• For the purposes of technology appraisal guidance 160, independent clinical risk factors for fracture are parental history of hip fracture, alcohol intake of 4 or more units per day, and rheumatoid arthritis.\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\nThe Committee accepted that the above were appropriate when making recommendations on treatment with denosumab for the prevention of primary and secondary osteoporotic fractures. The Committee was mindful that the clinical effectiveness evidence was based on a meta-analysis of each treatment compared with placebo rather than with active comparators. However, it was satisfied that the robustness of the clinical evidence and, when taken together with the low ICERs presented, the Committee concluded that for the primary prevention of osteoporotic fragility fractures, denosumab was a cost-effective use of NHS resources as a treatment option only for postmenopausal women at increased risk of fractures for whom oral bisphosphonates are unsuitable, and who have the same level of fracture risk as described in the recommendations of NICE technology appraisal 160 for strontium ranelate.\n\n\n\nFor the secondary prevention of osteoporotic fragility fractures, the Committee also noted the results of the subgroup analysis by age and T-score, for women for whom oral bisphosphonates are unsuitable and in circumstances in which the treatments appraised by NICE are not recommended, in which the ICER for denosumab compared with no treatment varied between £12,289 and £22,957 per QALY gained. The Committee concluded that treatment with denosumab was considered to be a cost-effective use of NHS resources for the secondary prevention of osteoporotic fragility fractures in women for whom oral bisphosphonates are unsuitable.\n\n, 4.26\n\nWhat are the key drivers of cost effectiveness?\n\n\n\nThe Committee concluded that with the exception of administration costs for denosumab, alterations to most key parameters had limited impact on comparisons between denosumab and the primary and secondary comparators.\n\n\n\nMost likely cost-effectiveness estimate (given as an ICER)\n\n\n\nThe Committee accepted that the most likely cost-effectiveness estimates would lie between the manufacturer's base case (using primary care assumptions) and the ERG's additional analyses (using secondary care assumptions), and that the most plausible ICERs were likely to be closer to the manufacturer's base case estimates, given that care would mostly be in the primary setting.\n\n\n\n\n\n\n\n\n\n\n\n\n\nThe Committee noted that for the primary prevention of osteoporotic fragility fractures, denosumab dominated strontium ranelate in the manufacturer's base case, and the ICER was £15,900 per QALY gained for denosumab compared with strontium ranelate in the ERG's additional analyses (assuming denosumab is always given in secondary care). The Committee concluded that for the primary prevention of osteoporotic fragility fractures, denosumab was a cost-effective use of NHS resources as a treatment option only for postmenopausal women at increased risk of fractures for whom oral bisphosphonates are unsuitable, and who have the same level of fracture risk as described in the recommendations of NICE technology appraisal 160 for strontium ranelate.\n\n\n\n\n\nThe Committee was aware that for women for whom oral bisphosphonates are unsuitable and who do not currently fulfil the criteria for treatment with strontium ranelate, no treatment is currently recommended by NICE for the primary prevention of osteoporotic fragility fractures. The Committee noted that the ICER for denosumab compared with no treatment was £29,200 per QALY gained in the manufacturer's base-case analysis, and this increased to £40,600 per QALY gained in the ERG's additional analyses. It concluded that the ICER for the base-case population (women 70 years and over with T-score of −2.5 SD or below) for denosumab compared with no treatment was likely to lie within this range.\n\n\n\n\n\nFor the secondary prevention of osteoporotic fragility fractures, the Committee noted that the ICER for denosumab compared with no treatment in women for whom oral bisphosphonates are unsuitable was £12,400 per QALY gained in the manufacturer's base-case analysis, which increased to £17,900 per QALY gained in the ERG's additional analyses. Denosumab dominated raloxifene or had an ICER of £2000 per QALY gained (age 70, T-score −2.5) in the manufacturer's base-case analysis, which increased to £12,200 per QALY gained in the ERG's additional analyses. The ICER for denosumab compared with strontium ranelate ranged from strontium ranelate being dominated by denosumab in the manufacturer's base-case analysis to £6600 per QALY gained in the ERG's additional analyses.\n\n\n\n\n\nThe Committee concluded that treatment with denosumab was considered to be a cost-effective use of NHS resources for the secondary prevention of osteoporotic fragility fractures in women for whom oral bisphosphonates are unsuitable. The Committee noted that in the manufacturer's base-case analysis, denosumab was slightly less effective and much less costly than teriparatide. Therefore the Committee concluded that denosumab may provide an alternative treatment option that would be a cost-effective use of NHS resources for women who are eligible for treatment with teriparatide as defined in NICE technology appraisal guidance 161.\n\n\n\nAdditional factors taken into account\n\nPatient access schemes (PPRS)\n\nNot applicable. No patient access scheme was submitted.\n\n\n\nEnd of life considerations\n\nNot applicable to this disease area.\n\n\n\nEqualities considerations\n\nFollowing consultation on the appraisal consultation document, the Committee was aware that one area of potential discrimination was the primary prevention of osteoporotic fractures in postmenopausal women with swallowing problems as a result of disabling stroke disease, who would otherwise be eligible for treatment with oral bisphosphonates, but do not fulfil the criteria for denosumab or other treatments. The Committee concluded that its considerations were based on the population of postmenopausal women for whom oral bisphosphonates are unsuitable which included women with and without a disability.\n\n\n\n[a] T-score relates to the measurement of bone mineral density using central (hip and/or spine) DXA scanning, and is expressed as the number of standard deviations (SD) below peak bone mineral density.\n\n[a] Treatment with denosumab is not recommended.\n\n[a] Treatment with strontium ranelate is not recommended.", 'Related NICE guidance': 'Alendronate, etidronate, risedronate, raloxifene and strontium ranelate for the primary prevention of osteoporotic fragility fractures in postmenopausal women (amended).NICE technology appraisal guidance 160 (2008; amended 2010).\n\nAlendronate, etidronate, risedronate, raloxifene, strontium ranelate and teriparatide for the secondary prevention of osteoporotic fragility fractures in postmenopausal women (amended).NICE technology appraisal guidance 161 (2008; amended 2010).', 'Review of guidance': 'The guidance on this technology will be considered for review at the same time that NICE technology appraisal guidance 160 and 161 (2008; amended 2010) are considered for review. The Guidance Executive will decide whether the technology should be reviewed based on information gathered by NICE, and in consultation with consultees and commentators.\n\nAndrew DillonChief ExecutiveOctober 2010', 'Changes after publication': 'February 2014: implementation section updated to clarify that denosumab is recommended as an option for preventing osteoporotic fractures in postmenopausal women. Additional minor maintenance update also carried out.\n\nMarch 2012: minor maintenance', 'About this guidance': 'NICE technology appraisal guidance is about the use of new and existing medicines and treatments in the NHS in England and Wales.\n\nThis guidance was developed using the NICE single technology appraisal process.\n\nWe have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available.\n\nYour responsibility\n\nThis guidance represents the views of NICE and was arrived at after careful consideration of the evidence available. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. However, the guidance does not override the individual responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.\n\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.\n\nCopyright\n\n© National Institute for Health and Clinical Excellence 2010. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.'}	https://www.nice.org.uk/guidance/ta204	Evidence-based recommendations on denosumab (Prolia) for preventing osteoporotic fragility fractures in postmenopausal women.
38489b8a019678f5c730f5682768375dc140a8b2	nice	Bendamustine for the treatment of indolent (low grade) non-Hodgkin's lymphoma that is refractory to rituximab (terminated appraisal)	Bendamustine for the treatment of indolent (low grade) non-Hodgkin's lymphoma that is refractory to rituximab (terminated appraisal) # Background The manufacturer of bendamustine (Napp Pharmaceuticals) was invited to submit evidence for this single technology appraisal (STA) in May 2010. In June 2010, the manufacturer informed NICE that it would not be making an evidence submission because it was unable to identify relevant sources of clinical evidence suitable for a NICE appraisal in people with rituximab-refractory disease. The manufacturer indicated that further research was ongoing but data would not be available in a time frame that would allow NICE to produce timely guidance. NICE has therefore terminated this single technology appraisal.# Information NHS organisations should take into account the reasons why the manufacturer did not make an evidence submission when considering whether or not to recommend local use bendamustine for the treatment of indolent (low grade) non-Hodgkin's lymphoma that is refractory to rituximab or a rituximab-containing regimen. If, after doing this, organisations still wish to consider the use of bendamustine for the treatment of indolent (low grade) non-Hodgkin's lymphoma that is refractory to rituximab or a rituximab-containing regimen, they should follow the advice set out in 'Good practice guidance on managing the introduction of new healthcare interventions and links to NICE technology appraisal guidance' which outlines the approach that should be adopted in circumstances where NICE guidance is unavailable. NICE will review the position at any point if the manufacturer indicates that it wishes to make a full submission. # Related NICE guidance For information about NICE guidance that has been issued or is in development, see the website. ## Published Rituximab for the treatment of relapsed or refractory stage III or IV follicular non-Hodgkin's lymphoma (review of technology appraisal guidance 37). NICE technology appraisal guidance 137 (2008). Rituximab for the first-line maintenance treatment of follicular non-Hodgkin's lymphoma. NICE technology appraisal guidance 226 (2011). Rituximab for the first-line treatment of stage III-IV follicular lymphoma: (review of NICE technology appraisal guidance 110). NICE technology appraisal guidance 243 (2012).	{'Background': 'The manufacturer of bendamustine (Napp Pharmaceuticals) was invited to submit evidence for this single technology appraisal (STA) in May 2010.\n\nIn June 2010, the manufacturer informed NICE that it would not be making an evidence submission because it was unable to identify relevant sources of clinical evidence suitable for a NICE appraisal in people with rituximab-refractory disease. The manufacturer indicated that further research was ongoing but data would not be available in a time frame that would allow NICE to produce timely guidance.\n\nNICE has therefore terminated this single technology appraisal.', 'Information': "NHS organisations should take into account the reasons why the manufacturer did not make an evidence submission when considering whether or not to recommend local use bendamustine for the treatment of indolent (low grade) non-Hodgkin's lymphoma that is refractory to rituximab or a rituximab-containing regimen. If, after doing this, organisations still wish to consider the use of bendamustine for the treatment of indolent (low grade) non-Hodgkin's lymphoma that is refractory to rituximab or a rituximab-containing regimen, they should follow the advice set out in 'Good practice guidance on managing the introduction of new healthcare interventions and links to NICE technology appraisal guidance' which outlines the approach that should be adopted in circumstances where NICE guidance is unavailable.\n\nNICE will review the position at any point if the manufacturer indicates that it wishes to make a full submission.\n\n# Related NICE guidance\n\nFor information about NICE guidance that has been issued or is in development, see the website.\n\n## Published\n\nRituximab for the treatment of relapsed or refractory stage III or IV follicular non-Hodgkin's lymphoma (review of technology appraisal guidance 37). NICE technology appraisal guidance 137 (2008).\n\nRituximab for the first-line maintenance treatment of follicular non-Hodgkin's lymphoma. NICE technology appraisal guidance 226 (2011).\n\nRituximab for the first-line treatment of stage III-IV follicular lymphoma: (review of NICE technology appraisal guidance 110). NICE technology appraisal guidance 243 (2012)."}	https://www.nice.org.uk/guidance/ta206
37057aa6b6c6719f77d6c3f579208b1b90b1c880	nice	Temsirolimus for the treatment of relapsed or refractory mantle cell lymphoma (terminated appraisal)	Temsirolimus for the treatment of relapsed or refractory mantle cell lymphoma (terminated appraisal) # Background The manufacturer of temsirolimus (Wyeth) was invited to submit evidence for this single technology appraisal (STA) in November 2009. In January 2010, the manufacturer informed NICE that it would not be making an evidence submission. The manufacturer subsequently confirmed this in August 2010. Given the rarity of the condition, the complex clinical management of mantle cell lymphoma and the large number of comparator regimens used in the single randomised clinical trial, the manufacturer did not believe that an adequate assessment of the clinical and cost effectiveness of temsirolimus would be possible. NICE has therefore terminated this single technology appraisal.# Information NHS organisations should take into account the reasons why the manufacturer did not make an evidence submission when considering whether or not to recommend local use of temsirolimus for the treatment of relapsed or refractory mantle cell lymphoma. If, after doing this, organisations still wish to consider the use of temsirolimus for the treatment of relapsed or refractory mantle cell lymphoma, they should follow the advice set out in 'Good practice guidance on managing the introduction of new healthcare interventions and links to NICE technology appraisal guidance' which outlines the approach that should be adopted in circumstances where NICE guidance is unavailable. NICE will review the position at any point if the manufacturer indicates that it wishes to make a full submission. # Related NICE guidance There is no related NICE guidance.	{'Background': 'The manufacturer of temsirolimus (Wyeth) was invited to submit evidence for this single technology appraisal (STA) in November 2009.\n\nIn January 2010, the manufacturer informed NICE that it would not be making an evidence submission. The manufacturer subsequently confirmed this in August 2010. Given the rarity of the condition, the complex clinical management of mantle cell lymphoma and the large number of comparator regimens used in the single randomised clinical trial, the manufacturer did not believe that an adequate assessment of the clinical and cost effectiveness of temsirolimus would be possible.\n\nNICE has therefore terminated this single technology appraisal.', 'Information': "NHS organisations should take into account the reasons why the manufacturer did not make an evidence submission when considering whether or not to recommend local use of temsirolimus for the treatment of relapsed or refractory mantle cell lymphoma. If, after doing this, organisations still wish to consider the use of temsirolimus for the treatment of relapsed or refractory mantle cell lymphoma, they should follow the advice set out in 'Good practice guidance on managing the introduction of new healthcare interventions and links to NICE technology appraisal guidance' which outlines the approach that should be adopted in circumstances where NICE guidance is unavailable.\n\nNICE will review the position at any point if the manufacturer indicates that it wishes to make a full submission.\n\n# Related NICE guidance\n\nThere is no related NICE guidance."}	https://www.nice.org.uk/guidance/ta207
720d1165f6f3d96313b5042685e45560c2cce36b	nice	Bedwetting in under 19s	Bedwetting in under 19s This guideline covers assessing and treating bedwetting in people aged under 19. It aims to reduce bedwetting and the distress this causes by explaining what to ask in an assessment, what advice to provide, and which treatments are effective. # Introduction Bedwetting is a widespread and distressing condition that can have a deep impact on a child or young person's behaviour, emotional wellbeing and social life. It is also very stressful for the parents or carers. The prevalence of bedwetting decreases with age. Bedwetting less than 2 nights a week has a prevalence of 21% at about 4 and a half years and 8% at 9 and a half years. More frequent bedwetting is less common and has a prevalence of 8% at 4 and a half years and 1.5% at 9 and a half years. The causes of bedwetting are not fully understood. Bedwetting can be considered to be a symptom that may result from a combination of different predisposing factors. There are a number of different disturbances of physiology that may be associated with bedwetting. These disturbances may be categorised as sleep arousal difficulties, polyuria and bladder dysfunction. Bedwetting also often runs in families. Experts and expert bodies differ in their definitions of 'nocturnal enuresis' (see the full guideline for a discussion). The term 'bedwetting' is used in this guideline to describe the symptom of involuntary wetting during sleep without any inherent suggestion of frequency of bedwetting or pathophysiology. This guideline makes recommendations on the assessment and management of bedwetting in children and young people. The guidance applies to children and young people up to 19 years with the symptom of bedwetting. Children are generally expected to be dry by a developmental age of 5 years, and historically it has been common practice to consider children for treatment only when they reach 7 years. The guideline scope did not specify a minimum age limit to allow consideration of whether there are interventions of benefit to younger children previously excluded from advice and services due to their age. We have included specific advice for children under 5 years, and indicated treatment options for children between 5 and 7 years. Children and young people with bedwetting may also have symptoms related to the urinary tract during the day. A history of daytime urinary symptoms may be important in determining the approach to management of bedwetting and so the assessment sections include questions about daytime urinary symptoms and how the answers to these may influence the approach to managing bedwetting. However, the management of daytime urinary symptoms is outside the scope of this guideline. The treatment of bedwetting has a positive effect on the self‑esteem of children and young people. Healthcare professionals should persist in offering different treatments and treatment combinations if the first‑choice treatment is not successful. Children and young people with bedwetting are cared for by a number of different healthcare professionals in a variety of settings. All healthcare professionals should be aware of and work within legal and professional codes and competency frameworks. The guideline will assume that prescribers will use a drug's summary of product characteristics to inform decisions made with individual patients. Butler RJ, Heron J (2008) The prevalence of infrequent bedwetting and nocturnal enuresis in childhood: A large British cohort. Scandinavian Journal of Urology and Nephrology 42: 257–64# Patient‑centred care This guideline offers best practice advice on the care of children and young people with bedwetting. Treatment and care should take into account patients' needs and preferences. Children and young people with bedwetting and their parents and/or carers should have the opportunity to make informed decisions about their care and treatment, in partnership with their healthcare professionals. If a child or young person is not old enough or does not have the capacity to make decisions, healthcare professionals should follow the Department of Health's advice on consent and the code of practice that accompanies the Mental Capacity Act. In Wales, healthcare professionals should follow advice on consent from the Welsh Government. If the patient is under 16, healthcare professionals should follow the guidelines in the Department of Health's Seeking consent: working with children. Good communication between healthcare professionals and patients is essential. It should be supported by evidence‑based written information tailored to the patient's needs. Treatment and care, and the information patients are given about it, should be culturally appropriate. It should also be accessible to people with additional needs such as physical, sensory or learning disabilities, and to people who do not speak or read English. Families and carers should have the opportunity to be involved in decisions about treatment and care. Where appropriate, for example for older children, this should be with the child's agreement. Families and carers should also be given the information and support they need. Care of young people in transition between paediatric and adult services should be planned and managed according to the best practice guidance described in Transition: getting it right for young people. Adult and paediatric healthcare teams should work jointly to provide assessment and services to young people with bedwetting. Diagnosis and management should be reviewed throughout the transition process, and there should be clarity about who is the lead clinician to ensure continuity of care.# Guidance The following guidance is based on the best available evidence. The full guideline gives details of the methods and the evidence used to develop the guidance. These recommendations apply to all healthcare professionals who are involved in the management of bedwetting in children and young people. Healthcare professionals are reminded of their duty under the Disability Discrimination Act (2005) to make reasonable adjustments to ensure that all people have the same opportunity for health. For the purposes of this guideline we have used the terms 'bedwetting' and 'daytime symptoms' to describe those symptoms that may be experienced by the population who present for treatment of 'bedwetting'. The following definitions were used for this guideline: Bedwetting: involuntary wetting during sleep without any inherent suggestion of frequency of bedwetting or pathophysiology. Daytime symptoms: daytime urinary symptoms such as wetting, urinary frequency or urgency. Response to an intervention: the child has achieved 14 consecutive dry nights or a 90% improvement in the number of wet nights per week. Partial response: the child's bedwetting has improved but 14 consecutive dry nights or a 90% improvement in the number of wet nights per week has not been achieved. # Principles of care Inform children and young people with bedwetting and their parents or carers that bedwetting is not the child or young person's fault and that punitive measures should not be used in the management of bedwetting. Offer support, assessment and treatment tailored to the circumstances and needs of the child or young person and parents or carers. Do not exclude younger children (for example, those under 7 years) from the management of bedwetting on the basis of age alone. Perform regular medication reviews for children and young people on repeated courses of drug treatment for bedwetting. # Information for the child or young person and family Offer information tailored to the needs of children and young people being treated for bedwetting and their parents and carers. Offer information and details of support groups to children and young people being treated for bedwetting and their parents or carers. Offer information about practical ways to reduce the impact of bedwetting before and during treatment (for example, using bed protection and washable and disposable products). # Assessment and investigation Ask whether the bedwetting started in the last few days or weeks. If so, consider whether this is a presentation of a systemic illness. Ask if the child or young person had previously been dry at night without assistance for 6 months. If so, enquire about any possible medical, emotional or physical triggers, and consider whether assessment and treatment is needed for any identified triggers. Ask about the pattern of bedwetting, including questions such as: How many nights a week does bedwetting occur? How many times a night does bedwetting occur? Does there seem to be a large amount of urine? At what times of night does the bedwetting occur? Does the child or young person wake up after bedwetting? Ask about the presence of daytime symptoms in a child or young person with bedwetting, including: daytime frequency (that is, passing urine more than seven times a day) daytime urgency daytime wetting passing urine infrequently (fewer than four times a day) abdominal straining or poor urinary stream pain passing urine. Ask about daytime toileting patterns in a child or young person with bedwetting, including: whether daytime symptoms occur only in some situations avoidance of toilets at school or other settings whether the child or young person goes to the toilet more or less frequently than his or her peers. Ask about the child or young person's fluid intake throughout the day. In particular, ask whether the child or young person, or the parents or carers are restricting fluids. Consider whether a record of the child or young person's fluid intake, daytime symptoms, bedwetting and toileting patterns would be useful in the assessment and management of bedwetting. If so, consider asking the child or young person and parents or carers to record this information. Do not perform urinalysis routinely in children and young people with bedwetting, unless any of the following apply: bedwetting started in the last few days or weeks there are daytime symptoms there are any signs of ill health there is a history, symptoms or signs suggestive of urinary tract infection there is a history, symptoms or signs suggestive of diabetes mellitus. Assess whether the child or young person has any comorbidities or there are other factors to consider, in particular: constipation and/or soiling developmental, attention or learning difficulties diabetes mellitus behavioural or emotional problems family problems or a vulnerable child or young person or family. Consider assessment, investigation and/or referral when bedwetting is associated with: severe daytime symptoms a history of recurrent urinary infections known or suspected physical or neurological problems comorbidities or other factors (for example, those listed in recommendation 1.3.9). Investigate and treat children and young people with suspected urinary tract infection in line with urinary tract infection (NICE guideline CG54). Investigate and treat children and young people with soiling or constipation in line with constipation in children and young people (NICE guideline CG99). Refer children and young people with suspected type 1 diabetes immediately (on the same day) to a multidisciplinary paediatric diabetes team with the competencies needed to confirm diagnosis and to provide immediate care. Consider investigating and treating daytime symptoms before bedwetting if daytime symptoms predominate. Consider involving a professional with psychological expertise for children and young people with bedwetting and emotional or behavioural problems. Discuss factors that might affect treatment and support needs, such as: sleeping arrangements (for example, does the child or young person have his or her own bed or bedroom) the impact of bedwetting on the child or young person and family whether the child or young person and parents or carers have the necessary level of commitment, including time available, to engage in a treatment programme. Discuss with the parents or carers whether they need support, particularly if they are having difficulty coping with the burden of bedwetting, or if they are expressing anger, negativity or blame towards the child or young person. Consider maltreatment if: a child or young person is reported to be deliberately bedwetting parents or carers are seen or reported to punish a child or young person for bedwetting despite professional advice that the symptom is involuntary a child or young person has secondary daytime wetting or secondary bedwetting that persists despite adequate assessment and management unless there is a medical explanation (for example, urinary tract infection) or clearly identified stressful situation that is not part of maltreatment (for example, bereavement, parental separation). Use the findings of the history to inform the diagnosis (according to table 1) and management of bedwetting. Table 1 Findings from the history and their possible interpretation Findings from history Possible interpretation Large volume of urine in the first few hours of night Typical pattern for bedwetting only. Variable volume of urine, often more than once a night Typical pattern for children and young people who have bedwetting and daytime symptoms with possible underlying overactive bladder. Bedwetting every night Severe bedwetting, which is less likely to resolve spontaneously than infrequent bedwetting. Previously dry for more than 6 months Bedwetting is defined as secondary. Daytime frequency Daytime urgency Daytime wetting Abdominal straining or poor urinary stream Pain passing urine Any of these may indicate the presence of a bladder disorder such as overactive bladder or more rarely (when symptoms are very severe and persistent) an underlying urological disease. Constipation A common comorbidity that can cause bedwetting and requires treatment (see constipation in children and young people ). Soiling Frequent soiling is usually secondary to underlying faecal impaction and constipation which may have been unrecognised. Inadequate fluid intake May mask an underlying bladder problem, such as overactive bladder disorder, and may impede the development of an adequate bladder capacity. Behavioural and emotional problems These may be a cause or a consequence of bedwetting. Treatment may need to be tailored to the specific requirements of each child or young person and family. Family problems A difficult or 'stressful' environment may be a trigger for bedwetting. These factors should be addressed alongside the management of bedwetting. Practical issues Easy access to a toilet at night, sharing a bedroom or bed and proximity of parents to provide support are all important issues to consider and address when considering treatment, especially with an alarm. # Planning management Explain the condition, the effect and aims of treatment, and the advantages and disadvantages of the possible treatments to the child or young person and parents or carers (see recommendations 1.8.13 and 1.10.9). Clarify what the child or young person and parents or carers hope the treatment will achieve. Ask whether short‑term dryness is a priority for family or recreational reasons (for example, for a sleep‑over). Explore the child or young person's views about their bedwetting, including: what they think the main problem is whether they think the problem needs treatment. Explore and assess the ability of the family to cope with using an alarm for the treatment of bedwetting. Consider whether or not it is appropriate to offer alarm or drug treatment, depending on the age of the child or young person, the frequency of bedwetting and the motivation and needs of the child or young person and their family. # Advice on fluid intake, diet and toileting patterns Advise children and young people with bedwetting and their parents or carers that: adequate daily fluid intake is important in the management of bedwetting daily fluid intake varies according to ambient temperature, dietary intake and physical activity. A suggested intake of drinks is given in table 2: Table 2 Suggested daily intake of drinks for children and young people Age Sex Total drinks per day –8 years Female Male –1400 ml –1400 ml –13 years Female Male –2100 ml –2300 ml –18 years Female Male –2500 ml –3200 ml Advise the child or young person and parents or carers that the consumption of caffeine‑based drinks should be avoided in children and young people with bedwetting. Advise the child or young person and parents or carers to eat a healthy diet and not to restrict diet as a form of treatment for bedwetting. Advise the child or young person of the importance of using the toilet at regular intervals throughout the day. Advise parents or carers to encourage the child or young person to use the toilet to pass urine at regular intervals during the day and before sleep (typically between four and seven times in total). This should be continued alongside the chosen treatment for bedwetting. Address excessive or insufficient fluid intake or abnormal toileting patterns before starting other treatment for bedwetting in children and young people. Suggest a trial without nappies or pull‑ups for a child or young person with bedwetting who is toilet trained by day and is wearing nappies or pull‑ups at night. Offer advice on alternative bed protection to parents and carers. # Lifting and waking Offer advice on waking and lifting during the night as follows: Neither waking nor lifting children and young people with bedwetting, at regular times or randomly, will promote long‑term dryness. Waking of children and young people by parents or carers, either at regular times or randomly, should be used only as a practical measure in the short‑term management of bedwetting. Young people with bedwetting that has not responded to treatment may find self‑instigated waking (for example, using a mobile phone alarm or alarm clock) a useful management strategy. # Reward systems Explain that reward systems with positive rewards for agreed behaviour rather than dry nights should be used either alone or in conjunction with other treatments for bedwetting. For example, rewards may be given for: drinking recommended levels of fluid during the day using the toilet to pass urine before sleep engaging in management (for example, taking medication or helping to change sheets). Inform parents or carers that they should not use systems that penalise or remove previously gained rewards. Advise parents or carers to try a reward system alone (as described in recommendation 1.7.1) for the initial treatment of bedwetting in young children who have some dry nights. # Initial treatment – alarms Offer an alarm as the first‑line treatment to children and young people whose bedwetting has not responded to advice on fluids, toileting or an appropriate reward system, unless: an alarm is considered undesirable to the child or young person or their parents or carers or an alarm is considered inappropriate, particularly if: bedwetting is very infrequent (that is, less than 1–2 wet beds per week) the parents or carers are having emotional difficulty coping with the burden of bedwetting the parents or carers are expressing anger, negativity or blame towards the child or young person. Assess the response to an alarm by 4 weeks and continue with treatment if the child or young person is showing early signs of response. Stop treatment only if there are no early signs of response. Continue alarm treatment in children and young people with bedwetting who are showing signs of response until a minimum of 2 weeks' uninterrupted dry nights has been achieved. Assess whether it is appropriate to continue with alarm treatment if complete dryness is not achieved after 3 months. Only continue with alarm treatment if the bedwetting is still improving and the child or young person and parents or carers are motivated to continue. Do not exclude alarm treatment as an option for bedwetting in children and young people with: daytime symptoms as well as bedwetting secondary bedwetting. Consider an alternative type of alarm (for example, a vibrating alarm) for the treatment of bedwetting in children and young people who have a hearing impairment. Consider an alarm for the treatment of bedwetting in children and young people with learning difficulties and/or physical disabilities. Tailor the type of alarm to each individual's needs and abilities. Consider an alarm for the treatment of bedwetting in children under 7 years, depending on their ability, maturity, motivation and understanding of the alarm. ## Using an alarm Inform children and young people and parents or carers about the benefits of alarms combined with reward systems. Advise on the use of positive rewards for desired behaviour, such as waking up when the alarm goes off, going to the toilet after the alarm has gone off, returning to bed and resetting the alarm. Encourage children and young people with bedwetting and their parents or carers to discuss and agree on their roles and responsibilities for using the alarm and the use of rewards. Ensure that advice and support are available to children and young people and their parents or carers who are given an alarm, and agree how these should be obtained. Be aware that they may need a considerable amount of help in learning how to use an alarm. Inform the child or young person and their parents or carers that the aims of alarm treatment for bedwetting are to train the child or young person to: recognise the need to pass urine wake to go to the toilet or hold on learn over time to hold on or to wake spontaneously and stop wetting the bed. Inform the child or young person and their parents or carers that: alarms have a high long‑term success rate using an alarm can disrupt sleep that parents or carers may need to help the child or young person to wake to the alarm using an alarm requires sustained commitment, involvement and effort from the child or young person and their parents or carers they will need to record their progress (for example, if and when the child or young person wakes and how wet they and the bed are) alarms are not suitable for all children and young people and their families. If offering an alarm for bedwetting, inform the child and young person and their parents or carers how to: set and use the alarm respond to the alarm when it goes off maintain the alarm deal with problems with the alarm, including who to contact when there is a problem return the alarm when they no longer need it. Inform the child and young person and their parents or carers that it may take a few weeks for the early signs of a response to the alarm to occur and that these may include: smaller wet patches waking to the alarm the alarm going off later and fewer times per night fewer wet nights. Inform the child or young person and their parents or carers that dry nights may be a late sign of response to the alarm and may take weeks to achieve. Inform the parents or carers that they can restart using the alarm immediately, without consulting a healthcare professional, if the child or young person starts bedwetting again following a response to alarm treatment. # Lack of response to alarm treatment If bedwetting does not respond to initial alarm treatment, offer: combination treatment with an alarm and desmopressin or desmopressin alone if continued use of an alarm is no longer acceptable to the child or young person or their parents and carers. Offer desmopressin alone to children and young people with bedwetting if there has been a partial response to a combination of an alarm and desmopressin following initial treatment with an alarm. # Initial treatment – desmopressin Offer desmopressin to children and young people over 7 years, if: rapid‑onset and/or short‑term improvement in bedwetting is the priority of treatment or an alarm is inappropriate or undesirable (see recommendation 1.8.1). Consider desmopressin for children aged 5–7 years if treatment is required and: rapid‑onset and/or short‑term improvement in bedwetting is the priority of treatment or an alarm is inappropriate or undesirable (see recommendation 1.8.1). Do not exclude desmopressin as an option for the management of bedwetting in children and young people who also have daytime symptoms. However, do not use desmopressin in the treatment of children and young people who only have daytime wetting. In children and young people who are not completely dry after 1 to 2 weeks of the initial dose of desmopressin (200 micrograms for Desmotabs or 120 micrograms for DesmoMelt), consider increasing the dose (to 400 micrograms for Desmotabs or 240 micrograms for DesmoMelt). Assess the response to desmopressin at 4 weeks and continue treatment for 3 months if there are signs of a response. Consider stopping if there are no signs of response. Signs of response include: smaller wet patches fewer wetting episodes per night fewer wet nights. Do not exclude desmopressin as an option for the treatment of bedwetting in children and young people with sickle cell disease if an alarm is inappropriate or undesirable and they can comply with night‑time fluid restriction. Provide advice about withdrawal of desmopressin at times of sickle cell crisis. Do not exclude desmopressin as an option for the treatment of bedwetting in children and young people with emotional, attention or behavioural problems or developmental and learning difficulties if an alarm is inappropriate or undesirable and they can comply with night‑time fluid restriction. Do not routinely measure weight, serum electrolytes, blood pressure and urine osmolality in children and young people being treated with desmopressin for bedwetting. If offering desmopressin for bedwetting, inform the child or young person and their parents or carers: that many children and young people, but not all, will experience a reduction in wetness that many children and young people, but not all, will relapse when treatment is withdrawn how desmopressin works -f the importance of fluid restriction from 1 hour before until 8 hours after taking desmopressin that it should be taken at bedtime if appropriate, how to increase the dose if there is an inadequate response to the starting dose to continue treatment with desmopressin for 3 months that repeated courses of desmopressin can be used. Consider advising that desmopressin should be taken 1–2 hours before bedtime in children and young people with bedwetting that has either partially responded or not responded to desmopressin taken at bedtime. Ensure that the child or young person can comply with fluid restriction starting from 1 hour before the drug is taken. Consider continuing treatment with desmopressin for children and young people with bedwetting that has partially responded, as bedwetting may improve for up to 6 months after starting treatment. # Children and young people experiencing recurrence of bedwetting Consider alarm treatment again if a child or young person who was previously dry with an alarm has started regularly bedwetting again. Offer combination treatment with an alarm and desmopressin to children and young people who have more than one recurrence of bedwetting following successful treatment with an alarm. Consider using repeated courses of desmopressin for children and young people with bedwetting that has responded to desmopressin treatment but who experience repeated recurrences. Withdraw desmopressin treatment at regular intervals (for 1 week every 3 months) to check if dryness has been achieved when using it for the long‑term treatment of bedwetting. Gradually withdraw desmopressin rather than suddenly stopping it if a child or young person has had a recurrence of bedwetting following response to previous desmopressin treatment courses. Consider alarm treatment as an alternative to continuing drug treatment for children and young people who have recurrences of bedwetting, if an alarm is now considered appropriate and desirable. # Lack of response to initial treatment options Refer children and young people with bedwetting that has not responded to courses of treatment with an alarm and/or desmopressin for further review and assessment of factors that may be associated with a poor response, such as an overactive bladder, an underlying disease or social and emotional factors. # Anticholinergics The use of anticholinergics for bedwetting in children and young people is discussed in the recommendations in this section. Not all anticholinergics have a UK marketing authorisation for treating bedwetting in children and young people. If a drug without a marketing authorisation for this indication is prescribed, informed consent should be obtained and documented. Do not use an anticholinergic alone for the management of bedwetting in children and young people without daytime symptoms. Consider an anticholinergic combined with desmopressin for bedwetting in children and young people who also have daytime symptoms and have been assessed by a healthcare professional with expertise in prescribing the combination of an anticholinergic and desmopressin. Consider an anticholinergic combined with desmopressin for children and young people who have been assessed by a healthcare professional with expertise in the management of bedwetting that has not responded to an alarm and/or desmopressin and have any of the following: bedwetting that has partially responded to desmopressin alone bedwetting that has not responded to desmopressin alone bedwetting that has not responded to a combination of alarm and desmopressin. Consider continuing treatment for children and young people with bedwetting that has partially responded to desmopressin combined with an anticholinergic, as bedwetting may continue to improve for up to 6 months after starting treatment. Consider using repeated courses of desmopressin combined with an anticholinergic in children and young people who have responded to this combination but experience repeated recurrences of bedwetting following previous response to treatment. If offering an anticholinergic combined with desmopressin for bedwetting, inform the child or young person and their parents or carers: that success rates are difficult to predict, but more children and young people are drier with this combination than with desmopressin alone that desmopressin and an anticholinergic can be taken together at bedtime to continue treatment for 3 months that repeated courses can be used. Do not offer an anticholinergic combined with imipramine for the treatment of bedwetting in children and young people. # Tricyclics Do not use tricyclics as the first‑line treatment for bedwetting in children and young people. If offering a tricyclic, imipramine should be used for the treatment of bedwetting in children and young people. Consider imipramine for children and young people with bedwetting who: have not responded to all other treatments and have been assessed by a healthcare professional with expertise in the management of bedwetting that has not responded to an alarm and/or desmopressin. If offering imipramine for bedwetting, inform the child or young person and their parents or carers: that many children and young people, but not all, will experience a reduction in wetness how imipramine works that it should be taken at bedtime that the dose should be increased gradually about relapse rates (for example, more than two out of three children and young people will relapse after a 3‑month course of imipramine) that the initial treatment course is for 3 months and further courses may be considered about the particular dangers of imipramine overdose, and the importance of taking only the prescribed amount and storing it safely. Perform a medical review every 3 months in children and young people who are using repeated courses of imipramine for the management of bedwetting. Withdraw imipramine gradually when stopping treatment for bedwetting in children and young people. # Training programmes for the management of bedwetting Do not use strategies that recommend the interruption of urinary stream or encourage infrequent passing of urine during the day. Do not use dry‑bed training with or without an alarm for the treatment of bedwetting in children and young people. # Children under 5 years with bedwetting Children are generally expected to be dry at night by a developmental age of 5 years, and historically it has been common practice not to offer advice to families of children who are younger than 5 years and are bedwetting. This section provides recommendations specific to the under 5 age group indicating situations where healthcare professionals can offer useful advice and interventions. Reassure parents or carers that many children under 5 years wet the bed, for example, approximately one in five children of 4 and a half years wets the bed at least once a week. Ask whether toilet training has been attempted, and if not, ask about the reasons for this and offer support and advice. If there are no reasons why toilet training should not be attempted, advise parents or carers to toilet train their child. Suggest a trial of at least 2 nights in a row without nappies or pull‑ups for a child with bedwetting who is under 5 years and has been toilet trained by day for longer than 6 months. Offer advice on alternative bed protection to parents and carers. Consider a longer trial in children: who are older who achieve a reduction in wetness whose family circumstances allow the trial to continue. Advise the parents or carers of a child under 5 years with bedwetting that if the child wakes at night, they should take him or her to the toilet. Consider further assessment and investigation to exclude a specific medical problem for children over 2 years who, despite awareness of toileting needs and showing appropriate toileting behaviour, are struggling to not wet themselves during the day as well as the night. Assess children under 5 years with bedwetting for constipation, in line with constipation in children and young people (NICE guideline CG99), as undiagnosed chronic constipation is a common cause of wetting and soiling in younger children. For the purposes of the child mistreatment guideline, to consider maltreatment means that maltreatment is one possible explanation for the alerting feature or is included in the differential diagnosis. Lifting is carrying or walking a child to toilet. Lifting without waking means that effort is not made to ensure the child is fully woken. Waking means waking a child from sleep to take them to the toilet. Early signs of a response may include smaller wet patches, waking to the alarm, the alarm going off later and fewer times per night and fewer wet nights. Dry‑bed training is a training programme that may include combinations of a number of different behavioural interventions, and that may include rewards, punishment, training routines and waking routines, and may be undertaken with or without an alarm.# Notes on the scope of the guidance NICE guidelines are developed in accordance with a scope that defines what the guideline will and will not cover. How this guideline was developed NICE commissioned the National Collaborating Centre for Primary Care (now the National Clinical Guideline Centre) to develop this guideline. The Centre established a Guideline Development Group (see appendix A), which reviewed the evidence and developed the recommendations. An independent Guideline Review Panel oversaw the development of the guideline (see appendix B). There is more information about how NICE guidelines are developed on the NICE website.# Research recommendations The Guideline Development Group has made the following recommendations for research, based on its review of evidence, to improve NICE guidance and patient care in the future. The Guideline Development Group's full set of research recommendations is detailed in the full guideline (see section 5). # Multicomponent treatments What elements of multicomponent treatments (for example dry‑bed training and retention control training) are clinically effective and cost effective for treating bedwetting in children and young people under 19 years old? Why this is important It is not known which of the elements of multicomponent treatments (for example dry‑bed training and retention‑control training) are clinically effective and cost effective for treating bedwetting in children and young people under 19 years old. Data from randomised controlled trials of dry‑bed training and retention‑control training suggest that the treatments may be clinically effective. However, certain elements of the multicomponent treatments studied are not acceptable as a form of treatment due to their punitive nature. Further research is needed to establish which elements could be used effectively to treat bedwetting. Research should: Use randomised controlled trials to test the effect of the different elements of dry‑bed training alone and in different combinations for the treatment of bedwetting. Use randomised controlled trials to test the effect of the different elements of retention control training alone and in different combinations for the treatment of bedwetting. Consider different age groups of children being treated, such as younger children (under 7 years) and older children (over 10 years), as the ability of children to take responsibility for their behaviour may be important. Clearly describe the techniques used, including who gave the instructions, the timing of the treatments and the setting. Outcomes of interest include: the number of children who achieved 14 consecutive dry nights, the number of children who remain dry at 6 months and 2 years after treatment, the mean number of wet nights after treatment, the change in the number of wet nights, the psychological effect of treatment, psychological effects (self‑esteem, self‑concept, PinQ), quality of life measures and drop outs. # Standard interventions What is the clinical and cost effectiveness of standard interventions, for example alarm and desmopressin, for treating bedwetting in children and young people under 19 years old? Why this is important The evidence base for management of bedwetting is poor. Studies are inadequately powered, symptoms are poorly defined and study populations are commonly children seen in secondary and tertiary centres. Follow‑up periods are often inadequate. Research should provide: More subgroup data (for example, young children, children with daytime symptoms as well as bedwetting, children who were previously successful with subsequent relapse, children with sickle cell disease, children with severe wetting and children with special needs). More robust statistical data in trials of standard interventions for treating bedwetting (for example, adequately powered to detect differences). Data on longer term follow‑up. Data from populations at a primary care/community care level. # Psychological functioning and quality of life What is the impact of bedwetting upon the psychological functioning and quality of life of children and young people and their families? How do these change with treatment? Why is this important? There are relatively few studies that focus upon the psychological impact and health‑related quality of life of children who experience bedwetting. In addition, studies of effectiveness have focused on the achievement of dryness as the primary outcome rather than how treatment might affect social and psychological aspects as well as the quality of life of children and young people and their families. Research should: Examine the psychological impact and quality of life of children and young people and their families as well as the effectiveness of treatment upon these aspects. Use standardised measures to assess the psychological impact of bedwetting on children and young people as well as the quality of life of the child or young person and family. Use standardised measures to assess change associated with treatment for bedwetting. Quality‑of‑life research of children and young people with bedwetting pre‑ and post‑treatment would also be very useful to inform further economic evaluation work. # Complementary therapies What is the effectiveness of complementary therapies (acupuncture and hypnotherapy) for reducing the number of wet beds and improving self‑esteem in children and young people who wet the bed, when they are used independently or in conjunction with conventional treatments? Why this is important Many families consider the use of complementary and/or alternative medicine (CAM) as a treatment option when conventional treatment 'fails' or in order to avoid drug or other treatments. There is very little evidence about the efficacy of many CAM treatments, but the use of CAM is widespread and increasing across the developed world. There is a clear need for more effective guidance for health professionals, so that they can give evidence‑based advice to patients about what does and does not work and what is and is not safe, and for the public. Research should: Use randomised controlled trials to test the effect of using CAM therapies in addition to or instead of other treatments for bedwetting. Clearly describe the CAM therapies tested, including the provision of the treatment for both the treatment and the control group. Priority should be given to research on acupuncture and hypnotherapy but other CAM therapies should not be excluded. If possible, the comparative effectiveness and cost effectiveness of different CAM therapies should be tested. Outcomes of interest include: self‑esteem, number of dry nights, permanent or temporary nature of increased number of dry nights, quality of life, costs and social engagement. # Bedwetting in adolescents What is the prevalence of wetting and/or soiling in adolescence and what are the long‑term consequences for adolescents with these problems? Why this is important There is evidence that, for an important minority of children, wetting and soiling problems persist into late childhood and sometimes beyond puberty, but their prevalence is not clearly known. It has also recently been reported that in children who experience more frequent bedwetting (more than three times a week) it is more likely to persist into late childhood and adolescence. These studies suggest that, contrary to popular belief, wetting and soiling problems do not always resolve with increasing age. If wetting and soiling problems remain unresolved or untreated they can become socially and psychologically debilitating. There are no longitudinal cohort studies examining the impact of wetting and soiling on a wide range of outcomes in adolescence relating to mental health, education/school attainment, relationships with parents and peers, social activities and goals/aspirations for the future. Persistence of wetting and soiling problems into adolescence is likely to be accompanied by ridicule and bullying by peers and increasing intolerance from parents, especially if they believe that their child is to blame for the problem. Such reactions can only serve to exacerbate the young person's distress and may lead to delays in seeking help. In particular, teenagers who are unsuccessfully treated in childhood are often reluctant to seek help for wetting or soiling due to the severe embarrassment associated with the problem, and others may simply believe that no help is available. Research should: Use adolescents own self‑reports of frequency of bedwetting, daytime wetting and soiling. Adapt existing trajectory models to incorporate information on the frequency of wetting and soiling to examine whether children with more frequent problems are more likely to experience continuing wetting and soiling into adolescence. Outcomes of interest include: the examination of mental health, psychosocial and educational outcomes and whether adolescents who have combined wetting and soiling are at increased risk of negative outcomes compared to those with wetting or soiling alone. A continence‑specific paediatric quality‑of‑life measurement tool.# Other versions of this guideline # Full guideline The full guideline nocturnal enuresis: the management of bedwetting in children and young people contains details of the methods and evidence used to develop the guideline. It is published by the National Clinical Guideline Centre. # Information for the public NICE has produced information for the public explaining this guideline. We encourage NHS and voluntary sector organisations to use text from this information in their own matierlas about bedwetting in children and young people.# Updating the guideline NICE guidelines are updated so that recommendations take into account important new information. New evidence is checked 3 years after publication, and healthcare professionals and patients are asked for their views; we use this information to decide whether all or part of a guideline needs updating. If important new evidence is published at other times, we may decide to do a more rapid update of some recommendations. Please see our website for information about updating the guideline.# Appendix B: The Guideline Review Panel The Guideline Review Panel is an independent panel that oversees the development of the guideline and takes responsibility for monitoring adherence to NICE guideline development processes. In particular, the panel ensures that stakeholder comments have been adequately considered and responded to. The panel includes members from the following perspectives: primary care, lay, public health and industry. Dr Robert Walker (Chair)General Practitioner, Workington Dr Mark HillHead of Medical Affairs, Novartis Pharmaceuticals UK Ltd Dr John HarleyClinical Governance and Prescribing Lead and General Practitioner, North Tees PCT Mrs Ailsa DonnellyLay member Mrs Sarah FishburnLay member Mr Robin BealConsultant in Accident and Emergency Medicine, Isle of Wight# Appendix C: The algorithms Care pathways can be found in the bedwetting (nocturnal enuresis) in children and young people pathway.# About this guideline NICE guidelines are recommendations about the treatment and care of people with specific diseases and conditions in the NHS in England and Wales. The guideline was developed by the National Clinical Guideline Centre. The Centre worked with a group of healthcare professionals (including consultants, GPs and nurses), patients and carers, and technical staff, who reviewed the evidence and drafted the recommendations. The recommendations were finalised after public consultation. The methods and processes for developing NICE guidelines are described in the guidelines manual. We have produced information for the public explaining this guideline. Tools to help you put the guideline into practice and information about the evidence it is based on are also available. ISBN: 978-1-4731-2855-2	{'Introduction ': "Bedwetting is a widespread and distressing condition that can have a deep impact on a child or young person's behaviour, emotional wellbeing and social life. It is also very stressful for the parents or carers. The prevalence of bedwetting decreases with age. Bedwetting less than 2 nights a week has a prevalence of 21% at about 4 and a half years and 8% at 9 and a half years. More frequent bedwetting is less common and has a prevalence of 8% at 4 and a half years and 1.5% at 9 and a half years.\n\nThe causes of bedwetting are not fully understood. Bedwetting can be considered to be a symptom that may result from a combination of different predisposing factors. There are a number of different disturbances of physiology that may be associated with bedwetting. These disturbances may be categorised as sleep arousal difficulties, polyuria and bladder dysfunction. Bedwetting also often runs in families.\n\nExperts and expert bodies differ in their definitions of 'nocturnal enuresis' (see the full guideline for a discussion). The term 'bedwetting' is used in this guideline to describe the symptom of involuntary wetting during sleep without any inherent suggestion of frequency of bedwetting or pathophysiology.\n\nThis guideline makes recommendations on the assessment and management of bedwetting in children and young people. The guidance applies to children and young people up to 19 years with the symptom of bedwetting. Children are generally expected to be dry by a developmental age of 5 years, and historically it has been common practice to consider children for treatment only when they reach 7\xa0years. The guideline scope did not specify a minimum age limit to allow consideration of whether there are interventions of benefit to younger children previously excluded from advice and services due to their age. We have included specific advice for children under 5 years, and indicated treatment options for children between 5 and 7 years.\n\nChildren and young people with bedwetting may also have symptoms related to the urinary tract during the day. A history of daytime urinary symptoms may be important in determining the approach to management of bedwetting and so the assessment sections include questions about daytime urinary symptoms and how the answers to these may influence the approach to managing bedwetting. However, the management of daytime urinary symptoms is outside the scope of this guideline.\n\nThe treatment of bedwetting has a positive effect on the self‑esteem of children and young people. Healthcare professionals should persist in offering different treatments and treatment combinations if the first‑choice treatment is not successful. Children and young people with bedwetting are cared for by a number of different healthcare professionals in a variety of settings. All healthcare professionals should be aware of and work within legal and professional codes and competency frameworks.\n\nThe guideline will assume that prescribers will use a drug's summary of product characteristics to inform decisions made with individual patients.\n\n Butler RJ, Heron J (2008) The prevalence of infrequent bedwetting and nocturnal enuresis in childhood: A large British cohort. Scandinavian Journal of Urology and Nephrology 42: 257–64", 'Patient‑centred care': "This guideline offers best practice advice on the care of children and young people with bedwetting.\n\nTreatment and care should take into account patients' needs and preferences. Children and young people with bedwetting and their parents and/or carers should have the opportunity to make informed decisions about their care and treatment, in partnership with their healthcare professionals. If a child or young person is not old enough or does not have the capacity to make decisions, healthcare professionals should follow the Department of Health's advice on consent and the code of practice that accompanies the Mental Capacity Act. In Wales, healthcare professionals should follow advice on consent from the Welsh Government.\n\nIf the patient is under 16, healthcare professionals should follow the guidelines in the Department of Health's Seeking consent: working with children.\n\nGood communication between healthcare professionals and patients is essential. It should be supported by evidence‑based written information tailored to the patient's needs. Treatment and care, and the information patients are given about it, should be culturally appropriate. It should also be accessible to people with additional needs such as physical, sensory or learning disabilities, and to people who do not speak or read English.\n\nFamilies and carers should have the opportunity to be involved in decisions about treatment and care. Where appropriate, for example for older children, this should be with the child's agreement.\n\nFamilies and carers should also be given the information and support they need.\n\nCare of young people in transition between paediatric and adult services should be planned and managed according to the best practice guidance described in Transition: getting it right for young people.\n\nAdult and paediatric healthcare teams should work jointly to provide assessment and services to young people with bedwetting. Diagnosis and management should be reviewed throughout the transition process, and there should be clarity about who is the lead clinician to ensure continuity of care.", 'Guidance': "The following guidance is based on the best available evidence. The full guideline gives details of the methods and the evidence used to develop the guidance.\n\nThese recommendations apply to all healthcare professionals who are involved in the management of bedwetting in children and young people. Healthcare professionals are reminded of their duty under the Disability Discrimination Act (2005) to make reasonable adjustments to ensure that all people have the same opportunity for health.\n\nFor the purposes of this guideline we have used the terms 'bedwetting' and 'daytime symptoms' to describe those symptoms that may be experienced by the population who present for treatment of 'bedwetting'.\n\nThe following definitions were used for this guideline:\n\nBedwetting: involuntary wetting during sleep without any inherent suggestion of frequency of bedwetting or pathophysiology.\n\nDaytime symptoms: daytime urinary symptoms such as wetting, urinary frequency or urgency.\n\nResponse to an intervention: the child has achieved 14\xa0consecutive dry nights or a 90% improvement in the number of wet nights per week.\n\nPartial response: the child's bedwetting has improved but 14 consecutive dry nights or a 90% improvement in the number of wet nights per week has not been achieved.\n\n# Principles of care\n\nInform children and young people with bedwetting and their parents or carers that bedwetting is not the child or young person's fault and that punitive measures should not be used in the management of bedwetting.\n\nOffer support, assessment and treatment tailored to the circumstances and needs of the child or young person and parents or carers.\n\nDo not exclude younger children (for example, those under 7 years) from the management of bedwetting on the basis of age alone.\n\nPerform regular medication reviews for children and young people on repeated courses of drug treatment for bedwetting.\n\n# Information for the child or young person and family\n\nOffer information tailored to the needs of children and young people being treated for bedwetting and their parents and carers.\n\nOffer information and details of support groups to children and young people being treated for bedwetting and their parents or carers.\n\nOffer information about practical ways to reduce the impact of bedwetting before and during treatment (for example, using bed protection and washable and disposable products).\n\n# Assessment and investigation\n\nAsk whether the bedwetting started in the last few days or weeks. If so, consider whether this is a presentation of a systemic illness.\n\nAsk if the child or young person had previously been dry at night without assistance for 6 months. If so, enquire about any possible medical, emotional or physical triggers, and consider whether assessment and treatment is needed for any identified triggers.\n\nAsk about the pattern of bedwetting, including questions such as:\n\nHow many nights a week does bedwetting occur?\n\nHow many times a night does bedwetting occur?\n\nDoes there seem to be a large amount of urine?\n\nAt what times of night does the bedwetting occur?\n\nDoes the child or young person wake up after bedwetting?\n\nAsk about the presence of daytime symptoms in a child or young person with bedwetting, including:\n\ndaytime frequency (that is, passing urine more than seven times a day)\n\ndaytime urgency\n\ndaytime wetting\n\npassing urine infrequently (fewer than four times a day)\n\nabdominal straining or poor urinary stream\n\npain passing urine.\n\nAsk about daytime toileting patterns in a child or young person with bedwetting, including:\n\nwhether daytime symptoms occur only in some situations\n\navoidance of toilets at school or other settings\n\nwhether the child or young person goes to the toilet more or less frequently than his or her peers.\n\nAsk about the child or young person's fluid intake throughout the day. In particular, ask whether the child or young person, or the parents or carers are restricting fluids.\n\nConsider whether a record of the child or young person's fluid intake, daytime symptoms, bedwetting and toileting patterns would be useful in the assessment and management of bedwetting. If so, consider asking the child or young person and parents or carers to record this information.\n\nDo not perform urinalysis routinely in children and young people with bedwetting, unless any of the following apply:\n\nbedwetting started in the last few days or weeks\n\nthere are daytime symptoms\n\nthere are any signs of ill health\n\nthere is a history, symptoms or signs suggestive of urinary tract infection\n\nthere is a history, symptoms or signs suggestive of diabetes mellitus.\n\nAssess whether the child or young person has any comorbidities or there are other factors to consider, in particular:\n\nconstipation and/or soiling\n\ndevelopmental, attention or learning difficulties\n\ndiabetes mellitus\n\nbehavioural or emotional problems\n\nfamily problems or a vulnerable child or young person or family.\n\nConsider assessment, investigation and/or referral when bedwetting is associated with:\n\nsevere daytime symptoms\n\na history of recurrent urinary infections\n\nknown or suspected physical or neurological problems\n\ncomorbidities or other factors (for example, those listed in recommendation 1.3.9).\n\nInvestigate and treat children and young people with suspected urinary tract infection in line with urinary tract infection (NICE guideline CG54).\n\nInvestigate and treat children and young people with soiling or constipation in line with constipation in children and young people (NICE guideline CG99).\n\nRefer children and young people with suspected type 1 diabetes immediately (on the same day) to a multidisciplinary paediatric diabetes team with the competencies needed to confirm diagnosis and to provide immediate care. [This recommendation is from the NICE guideline on diabetes (type 1 and type 2) in children and young people]\n\nConsider investigating and treating daytime symptoms before bedwetting if daytime symptoms predominate.\n\nConsider involving a professional with psychological expertise for children and young people with bedwetting and emotional or behavioural problems.\n\nDiscuss factors that might affect treatment and support needs, such as:\n\nsleeping arrangements (for example, does the child or young person have his or her own bed or bedroom)\n\nthe impact of bedwetting on the child or young person and family\n\nwhether the child or young person and parents or carers have the necessary level of commitment, including time available, to engage in a treatment programme.\n\nDiscuss with the parents or carers whether they need support, particularly if they are having difficulty coping with the burden of bedwetting, or if they are expressing anger, negativity or blame towards the child or young person.\n\nConsider maltreatment if:\n\na child or young person is reported to be deliberately bedwetting\n\nparents or carers are seen or reported to punish a child or young person for bedwetting despite professional advice that the symptom is involuntary\n\na child or young person has secondary daytime wetting or secondary bedwetting that persists despite adequate assessment and management unless there is a medical explanation (for example, urinary tract infection) or clearly identified stressful situation that is not part of maltreatment (for example, bereavement, parental separation).[This recommendation is adapted from when to suspect child maltreatment (NICE guideline CG89)]\n\nUse the findings of the history to inform the diagnosis (according to table 1) and management of bedwetting.\n\nTable 1 Findings from the history and their possible interpretation\n\nFindings from history\n\nPossible interpretation\n\nLarge volume of urine in the first few hours of night\n\nTypical pattern for bedwetting only.\n\nVariable volume of urine, often more than once a night\n\nTypical pattern for children and young people who have bedwetting and daytime symptoms with possible underlying overactive bladder.\n\nBedwetting every night\n\nSevere bedwetting, which is less likely to resolve spontaneously than infrequent bedwetting.\n\nPreviously dry for more than 6 months\n\nBedwetting is defined as secondary.\n\nDaytime frequency\n\nDaytime urgency\n\nDaytime wetting\n\nAbdominal straining or poor urinary stream\n\nPain passing urine\n\nAny of these may indicate the presence of a bladder disorder such as overactive bladder or more rarely (when symptoms are very severe and persistent) an underlying urological disease.\n\nConstipation\n\nA common comorbidity that can cause bedwetting and requires treatment (see constipation in children and young people [NICE guideline CG99]).\n\nSoiling\n\nFrequent soiling is usually secondary to underlying faecal impaction and constipation which may have been unrecognised.\n\nInadequate fluid intake\n\nMay mask an underlying bladder problem, such as overactive bladder disorder, and may impede the development of an adequate bladder capacity.\n\nBehavioural and emotional problems\n\nThese may be a cause or a consequence of bedwetting. Treatment may need to be tailored to the specific requirements of each child or young person and family.\n\nFamily problems\n\nA difficult or 'stressful' environment may be a trigger for bedwetting. These factors should be addressed alongside the management of bedwetting.\n\nPractical issues\n\nEasy access to a toilet at night, sharing a bedroom or bed and proximity of parents to provide support are all important issues to consider and address when considering treatment, especially with an alarm.\n\n\n\n# Planning management\n\nExplain the condition, the effect and aims of treatment, and the advantages and disadvantages of the possible treatments to the child or young person and parents or carers (see recommendations 1.8.13 and 1.10.9).\n\nClarify what the child or young person and parents or carers hope the treatment will achieve. Ask whether short‑term dryness is a priority for family or recreational reasons (for example, for a sleep‑over).\n\nExplore the child or young person's views about their bedwetting, including:\n\nwhat they think the main problem is\n\nwhether they think the problem needs treatment.\n\nExplore and assess the ability of the family to cope with using an alarm for the treatment of bedwetting.\n\nConsider whether or not it is appropriate to offer alarm or drug treatment, depending on the age of the child or young person, the frequency of bedwetting and the motivation and needs of the child or young person and their family.\n\n# Advice on fluid intake, diet and toileting patterns\n\nAdvise children and young people with bedwetting and their parents or carers that:\n\nadequate daily fluid intake is important in the management of bedwetting\n\ndaily fluid intake varies according to ambient temperature, dietary intake and physical activity. A suggested intake of drinks is given in table 2:\n\nTable 2 Suggested daily intake of drinks for children and young people\n\nAge\n\nSex\n\nTotal drinks per day\n\n–8 years\n\nFemale\n\nMale\n\n–1400 ml\n\n–1400 ml\n\n–13 years\n\nFemale\n\nMale\n\n–2100 ml\n\n–2300 ml\n\n–18 years\n\n\n\nFemale\n\nMale\n\n–2500 ml\n\n–3200 ml\n\nAdvise the child or young person and parents or carers that the consumption of caffeine‑based drinks should be avoided in children and young people with bedwetting.\n\nAdvise the child or young person and parents or carers to eat a healthy diet and not to restrict diet as a form of treatment for bedwetting.\n\nAdvise the child or young person of the importance of using the toilet at regular intervals throughout the day.\n\nAdvise parents or carers to encourage the child or young person to use the toilet to pass urine at regular intervals during the day and before sleep (typically between four and seven times in total). This should be continued alongside the chosen treatment for bedwetting.\n\nAddress excessive or insufficient fluid intake or abnormal toileting patterns before starting other treatment for bedwetting in children and young people.\n\nSuggest a trial without nappies or pull‑ups for a child or young person with bedwetting who is toilet trained by day and is wearing nappies or pull‑ups at night. Offer advice on alternative bed protection to parents and carers.\n\n# Lifting and waking\n\nOffer advice on waking and lifting during the night as follows:\n\nNeither waking nor lifting children and young people with bedwetting, at regular times or randomly, will promote long‑term dryness.\n\nWaking of children and young people by parents or carers, either at regular times or randomly, should be used only as a practical measure in the short‑term management of bedwetting.\n\nYoung people with bedwetting that has not responded to treatment may find self‑instigated waking (for example, using a mobile phone alarm or alarm clock) a useful management strategy.\n\n# Reward systems\n\nExplain that reward systems with positive rewards for agreed behaviour rather than dry nights should be used either alone or in conjunction with other treatments for bedwetting. For example, rewards may be given for:\n\ndrinking recommended levels of fluid during the day\n\nusing the toilet to pass urine before sleep\n\nengaging in management (for example, taking medication or helping to change sheets).\n\nInform parents or carers that they should not use systems that penalise or remove previously gained rewards.\n\nAdvise parents or carers to try a reward system alone (as described in recommendation 1.7.1) for the initial treatment of bedwetting in young children who have some dry nights.\n\n# Initial treatment – alarms\n\nOffer an alarm as the first‑line treatment to children and young people whose bedwetting has not responded to advice on fluids, toileting or an appropriate reward system, unless:\n\nan alarm is considered undesirable to the child or young person or their parents or carers or\n\nan alarm is considered inappropriate, particularly if:\n\n\n\nbedwetting is very infrequent (that is, less than 1–2 wet beds per week)\n\nthe parents or carers are having emotional difficulty coping with the burden of bedwetting\n\nthe parents or carers are expressing anger, negativity or blame towards the child or young person.\n\n\n\nAssess the response to an alarm by 4 weeks and continue with treatment if the child or young person is showing early signs of response. Stop treatment only if there are no early signs of response.\n\nContinue alarm treatment in children and young people with bedwetting who are showing signs of response until a minimum of 2 weeks' uninterrupted dry nights has been achieved.\n\nAssess whether it is appropriate to continue with alarm treatment if complete dryness is not achieved after 3 months. Only continue with alarm treatment if the bedwetting is still improving and the child or young person and parents or carers are motivated to continue.\n\nDo not exclude alarm treatment as an option for bedwetting in children and young people with:\n\ndaytime symptoms as well as bedwetting\n\nsecondary bedwetting.\n\nConsider an alternative type of alarm (for example, a vibrating alarm) for the treatment of bedwetting in children and young people who have a hearing impairment.\n\nConsider an alarm for the treatment of bedwetting in children and young people with learning difficulties and/or physical disabilities. Tailor the type of alarm to each individual's needs and abilities.\n\nConsider an alarm for the treatment of bedwetting in children under 7 years, depending on their ability, maturity, motivation and understanding of the alarm.\n\n## Using an alarm\n\nInform children and young people and parents or carers about the benefits of alarms combined with reward systems. Advise on the use of positive rewards for desired behaviour, such as waking up when the alarm goes off, going to the toilet after the alarm has gone off, returning to bed and resetting the alarm.\n\nEncourage children and young people with bedwetting and their parents or carers to discuss and agree on their roles and responsibilities for using the alarm and the use of rewards.\n\nEnsure that advice and support are available to children and young people and their parents or carers who are given an alarm, and agree how these should be obtained. Be aware that they may need a considerable amount of help in learning how to use an alarm.\n\nInform the child or young person and their parents or carers that the aims of alarm treatment for bedwetting are to train the child or young person to:\n\nrecognise the need to pass urine\n\nwake to go to the toilet or hold on\n\nlearn over time to hold on or to wake spontaneously and stop wetting the bed.\n\nInform the child or young person and their parents or carers that:\n\nalarms have a high long‑term success rate\n\nusing an alarm can disrupt sleep\n\nthat parents or carers may need to help the child or young person to wake to the alarm\n\nusing an alarm requires sustained commitment, involvement and effort from the child or young person and their parents or carers\n\nthey will need to record their progress (for example, if and when the child or young person wakes and how wet they and the bed are)\n\nalarms are not suitable for all children and young people and their families.\n\nIf offering an alarm for bedwetting, inform the child and young person and their parents or carers how to:\n\nset and use the alarm\n\nrespond to the alarm when it goes off\n\nmaintain the alarm\n\ndeal with problems with the alarm, including who to contact when there is a problem\n\nreturn the alarm when they no longer need it.\n\nInform the child and young person and their parents or carers that it may take a few weeks for the early signs of a response to the alarm to occur and that these may include:\n\nsmaller wet patches\n\nwaking to the alarm\n\nthe alarm going off later and fewer times per night\n\nfewer wet nights.\n\nInform the child or young person and their parents or carers that dry nights may be a late sign of response to the alarm and may take weeks to achieve.\n\nInform the parents or carers that they can restart using the alarm immediately, without consulting a healthcare professional, if the child or young person starts bedwetting again following a response to alarm treatment.\n\n# Lack of response to alarm treatment\n\nIf bedwetting does not respond to initial alarm treatment, offer:\n\ncombination treatment with an alarm and desmopressin or\n\ndesmopressin alone if continued use of an alarm is no longer acceptable to the child or young person or their parents and carers.\n\nOffer desmopressin alone to children and young people with bedwetting if there has been a partial response to a combination of an alarm and desmopressin following initial treatment with an alarm.\n\n# Initial treatment – desmopressin\n\nOffer desmopressin to children and young people over 7 years, if:\n\nrapid‑onset and/or short‑term improvement in bedwetting is the priority of treatment or\n\nan alarm is inappropriate or undesirable (see recommendation 1.8.1).\n\nConsider desmopressin for children aged 5–7 years if treatment is required and:\n\nrapid‑onset and/or short‑term improvement in bedwetting is the priority of treatment or\n\nan alarm is inappropriate or undesirable (see recommendation 1.8.1).\n\nDo not exclude desmopressin as an option for the management of bedwetting in children and young people who also have daytime symptoms. However, do not use desmopressin in the treatment of children and young people who only have daytime wetting.\n\nIn children and young people who are not completely dry after 1 to 2\xa0weeks of the initial dose of desmopressin (200\xa0micrograms for Desmotabs or 120\xa0micrograms for DesmoMelt), consider increasing the dose (to 400 micrograms for Desmotabs or 240\xa0micrograms for DesmoMelt).\n\nAssess the response to desmopressin at 4 weeks and continue treatment for 3 months if there are signs of a response. Consider stopping if there are no signs of response. Signs of response include:\n\nsmaller wet patches\n\nfewer wetting episodes per night\n\nfewer wet nights.\n\nDo not exclude desmopressin as an option for the treatment of bedwetting in children and young people with sickle cell disease if an alarm is inappropriate or undesirable and they can comply with night‑time fluid restriction. Provide advice about withdrawal of desmopressin at times of sickle cell crisis.\n\nDo not exclude desmopressin as an option for the treatment of bedwetting in children and young people with emotional, attention or behavioural problems or developmental and learning difficulties if an alarm is inappropriate or undesirable and they can comply with night‑time fluid restriction.\n\nDo not routinely measure weight, serum electrolytes, blood pressure and urine osmolality in children and young people being treated with desmopressin for bedwetting.\n\nIf offering desmopressin for bedwetting, inform the child or young person and their parents or carers:\n\nthat many children and young people, but not all, will experience a reduction in wetness\n\nthat many children and young people, but not all, will relapse when treatment is withdrawn\n\nhow desmopressin works\n\nof the importance of fluid restriction from 1 hour before until 8\xa0hours after taking desmopressin\n\nthat it should be taken at bedtime\n\nif appropriate, how to increase the dose if there is an inadequate response to the starting dose\n\nto continue treatment with desmopressin for 3 months\n\nthat repeated courses of desmopressin can be used.\n\nConsider advising that desmopressin should be taken 1–2 hours before bedtime in children and young people with bedwetting that has either partially responded or not responded to desmopressin taken at bedtime. Ensure that the child or young person can comply with fluid restriction starting from 1\xa0hour before the drug is taken.\n\nConsider continuing treatment with desmopressin for children and young people with bedwetting that has partially responded, as bedwetting may improve for up to 6 months after starting treatment.\n\n# Children and young people experiencing recurrence of bedwetting\n\nConsider alarm treatment again if a child or young person who was previously dry with an alarm has started regularly bedwetting again.\n\nOffer combination treatment with an alarm and desmopressin to children and young people who have more than one recurrence of bedwetting following successful treatment with an alarm.\n\nConsider using repeated courses of desmopressin for children and young people with bedwetting that has responded to desmopressin treatment but who experience repeated recurrences. Withdraw desmopressin treatment at regular intervals (for 1 week every 3\xa0months) to check if dryness has been achieved when using it for the long‑term treatment of bedwetting.\n\nGradually withdraw desmopressin rather than suddenly stopping it if a child or young person has had a recurrence of bedwetting following response to previous desmopressin treatment courses.\n\nConsider alarm treatment as an alternative to continuing drug treatment for children and young people who have recurrences of bedwetting, if an alarm is now considered appropriate and desirable.\n\n# Lack of response to initial treatment options\n\nRefer children and young people with bedwetting that has not responded to courses of treatment with an alarm and/or desmopressin for further review and assessment of factors that may be associated with a poor response, such as an overactive bladder, an underlying disease or social and emotional factors.\n\n# Anticholinergics\n\nThe use of anticholinergics for bedwetting in children and young people is discussed in the recommendations in this section. Not all anticholinergics have a UK marketing authorisation for treating bedwetting in children and young people. If a drug without a marketing authorisation for this indication is prescribed, informed consent should be obtained and documented.\n\nDo not use an anticholinergic alone for the management of bedwetting in children and young people without daytime symptoms.\n\nConsider an anticholinergic combined with desmopressin for bedwetting in children and young people who also have daytime symptoms and have been assessed by a healthcare professional with expertise in prescribing the combination of an anticholinergic and desmopressin.\n\nConsider an anticholinergic combined with desmopressin for children and young people who have been assessed by a healthcare professional with expertise in the management of bedwetting that has not responded to an alarm and/or desmopressin and have any of the following:\n\nbedwetting that has partially responded to desmopressin alone\n\nbedwetting that has not responded to desmopressin alone\n\nbedwetting that has not responded to a combination of alarm and desmopressin.\n\nConsider continuing treatment for children and young people with bedwetting that has partially responded to desmopressin combined with an anticholinergic, as bedwetting may continue to improve for up to 6\xa0months after starting treatment.\n\nConsider using repeated courses of desmopressin combined with an anticholinergic in children and young people who have responded to this combination but experience repeated recurrences of bedwetting following previous response to treatment.\n\nIf offering an anticholinergic combined with desmopressin for bedwetting, inform the child or young person and their parents or carers:\n\nthat success rates are difficult to predict, but more children and young people are drier with this combination than with desmopressin alone\n\nthat desmopressin and an anticholinergic can be taken together at bedtime\n\nto continue treatment for 3 months\n\nthat repeated courses can be used.\n\nDo not offer an anticholinergic combined with imipramine for the treatment of bedwetting in children and young people.\n\n# Tricyclics\n\nDo not use tricyclics as the first‑line treatment for bedwetting in children and young people.\n\nIf offering a tricyclic, imipramine should be used for the treatment of bedwetting in children and young people.\n\nConsider imipramine for children and young people with bedwetting who:\n\nhave not responded to all other treatments and\n\nhave been assessed by a healthcare professional with expertise in the management of bedwetting that has not responded to an alarm and/or desmopressin.\n\nIf offering imipramine for bedwetting, inform the child or young person and their parents or carers:\n\nthat many children and young people, but not all, will experience a reduction in wetness\n\nhow imipramine works\n\nthat it should be taken at bedtime\n\nthat the dose should be increased gradually\n\nabout relapse rates (for example, more than two out of three children and young people will relapse after a 3‑month course of imipramine)\n\nthat the initial treatment course is for 3 months and further courses may be considered\n\nabout the particular dangers of imipramine overdose, and the importance of taking only the prescribed amount and storing it safely.\n\nPerform a medical review every 3 months in children and young people who are using repeated courses of imipramine for the management of bedwetting.\n\nWithdraw imipramine gradually when stopping treatment for bedwetting in children and young people.\n\n# Training programmes for the management of bedwetting\n\nDo not use strategies that recommend the interruption of urinary stream or encourage infrequent passing of urine during the day.\n\nDo not use dry‑bed training with or without an alarm for the treatment of bedwetting in children and young people.\n\n# Children under 5 years with bedwetting\n\nChildren are generally expected to be dry at night by a developmental age of 5 years, and historically it has been common practice not to offer advice to families of children who are younger than 5 years and are bedwetting. This section provides recommendations specific to the under 5 age group indicating situations where healthcare professionals can offer useful advice and interventions.\n\nReassure parents or carers that many children under 5 years wet the bed, for example, approximately one in five children of 4 and a half years wets the bed at least once a week.\n\nAsk whether toilet training has been attempted, and if not, ask about the reasons for this and offer support and advice. If there are no reasons why toilet training should not be attempted, advise parents or carers to toilet train their child.\n\nSuggest a trial of at least 2 nights in a row without nappies or pull‑ups for a child with bedwetting who is under 5 years and has been toilet trained by day for longer than 6 months. Offer advice on alternative bed protection to parents and carers. Consider a longer trial in children:\n\nwho are older\n\nwho achieve a reduction in wetness\n\nwhose family circumstances allow the trial to continue.\n\nAdvise the parents or carers of a child under 5 years with bedwetting that if the child wakes at night, they should take him or her to the toilet.\n\nConsider further assessment and investigation to exclude a specific medical problem for children over 2 years who, despite awareness of toileting needs and showing appropriate toileting behaviour, are struggling to not wet themselves during the day as well as the night. Assess children under 5 years with bedwetting for constipation, in line with constipation in children and young people (NICE guideline CG99), as undiagnosed chronic constipation is a common cause of wetting and soiling in younger children.\n\n For the purposes of the child mistreatment guideline, to consider maltreatment means that maltreatment is one possible explanation for the alerting feature or is included in the differential diagnosis.\n\n Lifting is carrying or walking a child to toilet. Lifting without waking means that effort is not made to ensure the child is fully woken. Waking means waking a child from sleep to take them to the toilet.\n\n Early signs of a response may include smaller wet patches, waking to the alarm, the alarm going off later and fewer times per night and fewer wet nights.\n\n Dry‑bed training is a training programme that may include combinations of a number of different behavioural interventions, and that may include rewards, punishment, training routines and waking routines, and may be undertaken with or without an alarm.", 'Notes on the scope of the guidance': 'NICE guidelines are developed in accordance with a scope that defines what the guideline will and will not cover.\n\nHow this guideline was developed\n\nNICE commissioned the National Collaborating Centre for Primary Care (now the National Clinical Guideline Centre) to develop this guideline. The Centre established a Guideline Development Group (see appendix A), which reviewed the evidence and developed the recommendations. An independent Guideline Review Panel oversaw the development of the guideline (see appendix B).\n\nThere is more information about how NICE guidelines are developed on the NICE website.', 'Research recommendations': "The Guideline Development Group has made the following recommendations for research, based on its review of evidence, to improve NICE guidance and patient care in the future. The Guideline Development Group's full set of research recommendations is detailed in the full guideline (see section 5).\n\n# Multicomponent treatments\n\nWhat elements of multicomponent treatments (for example dry‑bed training and retention control training) are clinically effective and cost effective for treating bedwetting in children and young people under 19 years old?\n\nWhy this is important\n\nIt is not known which of the elements of multicomponent treatments (for example dry‑bed training and retention‑control training) are clinically effective and cost effective for treating bedwetting in children and young people under 19 years old. Data from randomised controlled trials of dry‑bed training and retention‑control training suggest that the treatments may be clinically effective. However, certain elements of the multicomponent treatments studied are not acceptable as a form of treatment due to their punitive nature. Further research is needed to establish which elements could be used effectively to treat bedwetting.\n\nResearch should:\n\nUse randomised controlled trials to test the effect of the different elements of dry‑bed training alone and in different combinations for the treatment of bedwetting.\n\nUse randomised controlled trials to test the effect of the different elements of retention control training alone and in different combinations for the treatment of bedwetting.\n\nConsider different age groups of children being treated, such as younger children (under 7 years) and older children (over 10 years), as the ability of children to take responsibility for their behaviour may be important.\n\nClearly describe the techniques used, including who gave the instructions, the timing of the treatments and the setting.\n\nOutcomes of interest include: the number of children who achieved 14\xa0consecutive dry nights, the number of children who remain dry at 6 months and 2 years after treatment, the mean number of wet nights after treatment, the change in the number of wet nights, the psychological effect of treatment, psychological effects (self‑esteem, self‑concept, PinQ), quality of life measures and drop outs.\n\n# Standard interventions\n\nWhat is the clinical and cost effectiveness of standard interventions, for example alarm and desmopressin, for treating bedwetting in children and young people under 19 years old?\n\nWhy this is important\n\nThe evidence base for management of bedwetting is poor. Studies are inadequately powered, symptoms are poorly defined and study populations are commonly children seen in secondary and tertiary centres. Follow‑up periods are often inadequate.\n\nResearch should provide:\n\nMore subgroup data (for example, young children, children with daytime symptoms as well as bedwetting, children who were previously successful with subsequent relapse, children with sickle cell disease, children with severe wetting and children with special needs).\n\nMore robust statistical data in trials of standard interventions for treating bedwetting (for example, adequately powered to detect differences).\n\nData on longer term follow‑up.\n\nData from populations at a primary care/community care level.\n\n# Psychological functioning and quality of life\n\nWhat is the impact of bedwetting upon the psychological functioning and quality of life of children and young people and their families? How do these change with treatment?\n\nWhy is this important?\n\nThere are relatively few studies that focus upon the psychological impact and health‑related quality of life of children who experience bedwetting. In addition, studies of effectiveness have focused on the achievement of dryness as the primary outcome rather than how treatment might affect social and psychological aspects as well as the quality of life of children and young people and their families.\n\nResearch should:\n\nExamine the psychological impact and quality of life of children and young people and their families as well as the effectiveness of treatment upon these aspects.\n\nUse standardised measures to assess the psychological impact of bedwetting on children and young people as well as the quality of life of the child or young person and family.\n\nUse standardised measures to assess change associated with treatment for bedwetting.\n\nQuality‑of‑life research of children and young people with bedwetting pre‑ and post‑treatment would also be very useful to inform further economic evaluation work.\n\n# Complementary therapies\n\nWhat is the effectiveness of complementary therapies (acupuncture and hypnotherapy) for reducing the number of wet beds and improving self‑esteem in children and young people who wet the bed, when they are used independently or in conjunction with conventional treatments?\n\nWhy this is important\n\nMany families consider the use of complementary and/or alternative medicine (CAM) as a treatment option when conventional treatment 'fails' or in order to avoid drug or other treatments. There is very little evidence about the efficacy of many CAM treatments, but the use of CAM is widespread and increasing across the developed world. There is a clear need for more effective guidance for health professionals, so that they can give evidence‑based advice to patients about what does and does not work and what is and is not safe, and for the public.\n\nResearch should:\n\nUse randomised controlled trials to test the effect of using CAM therapies in addition to or instead of other treatments for bedwetting.\n\nClearly describe the CAM therapies tested, including the provision of the treatment for both the treatment and the control group.\n\nPriority should be given to research on acupuncture and hypnotherapy but other CAM therapies should not be excluded.\n\nIf possible, the comparative effectiveness and cost effectiveness of different CAM therapies should be tested.\n\nOutcomes of interest include: self‑esteem, number of dry nights, permanent or temporary nature of increased number of dry nights, quality of life, costs and social engagement.\n\n# Bedwetting in adolescents\n\nWhat is the prevalence of wetting and/or soiling in adolescence and what are the long‑term consequences for adolescents with these problems?\n\nWhy this is important\n\nThere is evidence that, for an important minority of children, wetting and soiling problems persist into late childhood and sometimes beyond puberty, but their prevalence is not clearly known. It has also recently been reported that in children who experience more frequent bedwetting (more than three times a week) it is more likely to persist into late childhood and adolescence. These studies suggest that, contrary to popular belief, wetting and soiling problems do not always resolve with increasing age. If wetting and soiling problems remain unresolved or untreated they can become socially and psychologically debilitating. There are no longitudinal cohort studies examining the impact of wetting and soiling on a wide range of outcomes in adolescence relating to mental health, education/school attainment, relationships with parents and peers, social activities and goals/aspirations for the future. Persistence of wetting and soiling problems into adolescence is likely to be accompanied by ridicule and bullying by peers and increasing intolerance from parents, especially if they believe that their child is to blame for the problem. Such reactions can only serve to exacerbate the young person's distress and may lead to delays in seeking help. In particular, teenagers who are unsuccessfully treated in childhood are often reluctant to seek help for wetting or soiling due to the severe embarrassment associated with the problem, and others may simply believe that no help is available.\n\nResearch should:\n\nUse adolescents own self‑reports of frequency of bedwetting, daytime wetting and soiling.\n\nAdapt existing trajectory models to incorporate information on the frequency of wetting and soiling to examine whether children with more frequent problems are more likely to experience continuing wetting and soiling into adolescence.\n\nOutcomes of interest include: the examination of mental health, psychosocial and educational outcomes and whether adolescents who have combined wetting and soiling are at increased risk of negative outcomes compared to those with wetting or soiling alone.\n\n A continence‑specific paediatric quality‑of‑life measurement tool.", 'Other versions of this guideline': '# Full guideline\n\nThe full guideline nocturnal enuresis: the management of bedwetting in children and young people contains details of the methods and evidence used to develop the guideline. It is published by the National Clinical Guideline Centre.\n\n# Information for the public\n\nNICE has produced information for the public explaining this guideline.\n\nWe encourage NHS and voluntary sector organisations to use text from this information in their own matierlas about bedwetting in children and young people.', 'Updating the guideline': 'NICE guidelines are updated so that recommendations take into account important new information. New evidence is checked 3 years after publication, and healthcare professionals and patients are asked for their views; we use this information to decide whether all or part of a guideline needs updating. If important new evidence is published at other times, we may decide to do a more rapid update of some recommendations. Please see our website for information about updating the guideline.', 'Appendix B: The Guideline Review Panel': 'The Guideline Review Panel is an independent panel that oversees the development of the guideline and takes responsibility for monitoring adherence to NICE guideline development processes. In particular, the panel ensures that stakeholder comments have been adequately considered and responded to. The panel includes members from the following perspectives: primary care, lay, public health and industry.\n\nDr Robert Walker (Chair)General Practitioner, Workington\n\nDr Mark HillHead of Medical Affairs, Novartis Pharmaceuticals UK Ltd\n\nDr John HarleyClinical Governance and Prescribing Lead and General Practitioner, North Tees PCT\n\nMrs Ailsa DonnellyLay member\n\nMrs Sarah FishburnLay member\n\nMr Robin BealConsultant in Accident and Emergency Medicine, Isle of Wight', 'Appendix C: The algorithms': 'Care pathways can be found in the bedwetting (nocturnal enuresis) in children and young people pathway.', 'About this guideline': 'NICE guidelines are recommendations about the treatment and care of people with specific diseases and conditions in the NHS in England and Wales.\n\nThe guideline was developed by the National Clinical Guideline Centre. The Centre worked with a group of healthcare professionals (including consultants, GPs and nurses), patients and carers, and technical staff, who reviewed the evidence and drafted the recommendations. The recommendations were finalised after public consultation.\n\nThe methods and processes for developing NICE guidelines are described in the guidelines manual.\n\nWe have produced information for the public explaining this guideline. Tools to help you put the guideline into practice and information about the evidence it is based on are also available.\n\nISBN: 978-1-4731-2855-2'}	https://www.nice.org.uk/guidance/cg111	This guideline covers assessing and treating bedwetting in people aged under 19. It aims to reduce bedwetting and the distress this causes by explaining what to ask in an assessment, what advice to provide, and which treatments are effective.
04768dd2093f0e9dba64a4aa327b59ed25890f11	nice	Endoscopic submucosal dissection of gastric lesions	Endoscopic submucosal dissection of gastric lesions # Guidance Current evidence on the safety and efficacy of endoscopic submucosal dissection (ESD) of gastric lesions shows that it is efficacious in achieving complete resection in a high proportion of cases, but evidence of long-term survival following treatment of malignant lesions is limited in quantity. There are safety concerns regarding the risks of perforation and bleeding. Therefore this procedure should only be used with special arrangements for clinical governance, consent and audit or research. Clinicians wishing to undertake ESD of gastric lesions should take the following actions. Inform the clinical governance leads in their Trusts. Ensure that patients understand the uncertainty about the procedure's efficacy in relation to treating malignant lesions; and the risks of perforation, bleeding, and possible conversion to open surgery. Patients should be provided with clear written information. In addition, the use of NICE's information for patients ('Understanding NICE guidance') is recommended. Audit and review clinical outcomes of all patients having ESD of gastric lesions (see section 3.1). Patient selection should be carried out by an upper gastrointestinal cancer multidisciplinary team. This is a technically challenging procedure and should only be carried out by clinicians with specific training in the technique. The Joint Advisory Group on Gastrointestinal Endoscopy intends to prepare training standards for this procedure. NICE encourages further research into ESD of gastric lesions. There should be clear documentation of the incidence of complications, including perforation, bleeding and the need for open surgery (with the reasons for this), rates of complete resection, and long-term outcomes, including local recurrence and survival following treatment of malignant lesions.# The procedure # Indications and current treatments Gastric lesions include benign, dysplastic, and malignant tumours. Patients may be asymptomatic or experience loss of appetite and weight, anaemia and abdominal discomfort or pain. Current treatment options for small gastric lesions are snare polypectomy (for protruding lesions) or endoscopic mucosal resection (EMR) (for 'flat' lesions). EMR usually removes lesions piecemeal; in contrast, ESD aims to remove lesions intact and with a margin of healthy tissue. # Outline of the procedure Endoscopic submucosal dissection aims to remove lesions without the need for open abdominal surgery. It is usually preceded by diagnostic endoscopy, biopsy and imaging investigations. The procedure is carried out with the patient under sedation or general anaesthesia. Using endoscopic visualisation, the submucosa is injected with saline to help lift the lesion. This fluid may contain a pigment to help define the lesion, and adrenaline to reduce bleeding. A circumferential mucosal incision is made with an electrocautery knife around the lesion. Submucosal dissection is then carried out, parallel to the muscle layer, aiming to remove the lesion intact and with a healthy margin of tissue. A transparent hood may be used to retract the already dissected part of the lesion out of the visual field. Haemostasis is achieved by electrocautery. Endoscopic clips may be used for larger vessels or to manage perforation. Sections 2.3 and 2.4 describe efficacy and safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview. # Efficacy A non-randomised comparative study of 900 malignant lesions (patient numbers not stated) reported significantly greater complete resection rates of 95% (544/572) for ESD vs 64% (210/328) for EMR, and curative (with tumour-free margins) resection rates of 83% (473/572) vs 59% (195/328) respectively; p < 0.05 for both comparisons. A non-randomised comparative study of 896 patients (1020 malignant lesions) reported significantly greater complete en-bloc resection rates for non-ulcerated lesions of 93% (157/169) for ESD compared with 43% (343/790) for EMR, and histologically clear margin resection rates of 93% (157/169) vs 25% (194/790) respectively (p < 0.01). A case series of 59 premalignant or malignant lesions (patient numbers not stated) reported en-bloc resection by ESD in 86% (44/51) and free-margin complete resection in 73% (37/51) of lesions. The non-randomised comparative study of 900 lesions reported no recurrence among ESD-treated lesions and recurrence in 4% (13/328) of EMR-treated lesions (p < 0.05). The non-randomised comparative study of 896 patients reported no recurrence in ESD-treated patients at a mean 19.4-month follow-up, and recurrence rates of 3% (10/347) in ESD-treated patients and 4% (21/478) in EMR-treated patients during 83.2-month follow-up. The case series of 59 lesions reported local recurrence in 5 patients treated by piecemeal ESD at up to 8-month follow-up. The Specialist Advisers listed key efficacy outcomes as en-bloc and curative resection rates, recurrence rate and survival. # Safety Two non-randomised studies – 1 of 900 lesions and the other of 346 patients – reported perforation in 4% (20/572) and 5% (11/243) of ESD-treated lesions or patients, and 2% (5/328) and 2% (2/103) of EMR-treated lesions or patients respectively (differences reported as not significant). In the study of 346 patients, 3 perforations in ESD-treated patients and 1 in an EMR-treated patient were detected intraprocedurally but the others were recognised post-procedurally (timing not stated). All perforations following ESD were managed non-surgically with a combination of endoscopic clipping, fasting, nasogastric tube drainage and antibiotics. A non-randomised study of 655 patients (714 lesions) reported that perforations were significantly more frequent in ESD-treated patients than in EMR-treated patients (4% vs 1% of lesions) (p < 0.05). All patients were managed endoscopically (not otherwise described). The Specialist Advisers listed bleeding as an anecdotal adverse event and considered the theoretical risk of perforation leading to tumour seeding. # Other comments The Committee considered that ESD could be suitable for a national register.# Further information This guidance requires that clinicians undertaking the procedure make special arrangements for audit. NICE has identified relevant audit criteria and has developed an audit tool (which is for use at local discretion). For related NICE guidance see our website. # Information for patients NICE has produced information on this procedure for patients and carers ('Understanding NICE guidance'). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind. A large print version is also available.# About this guidance NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland. This guidance was developed using the NICE interventional procedure guidance process. We have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available. Changes since publication January 2012: minor maintenance. Your responsibility This guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer. Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties. Copyright © National Institute for Health and Clinical Excellence 2010. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE. Contact NICE National Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT www.nice.org.uk nice@nice.org.uk	{'Guidance': "Current evidence on the safety and efficacy of endoscopic submucosal dissection (ESD) of gastric lesions shows that it is efficacious in achieving complete resection in a high proportion of cases, but evidence of long-term survival following treatment of malignant lesions is limited in quantity. There are safety concerns regarding the risks of perforation and bleeding. Therefore this procedure should only be used with special arrangements for clinical governance, consent and audit or research.\n\nClinicians wishing to undertake ESD of gastric lesions should take the following actions.\n\nInform the clinical governance leads in their Trusts.\n\nEnsure that patients understand the uncertainty about the procedure's efficacy in relation to treating malignant lesions; and the risks of perforation, bleeding, and possible conversion to open surgery. Patients should be provided with clear written information. In addition, the use of NICE's information for patients ('Understanding NICE guidance') is recommended.\n\nAudit and review clinical outcomes of all patients having ESD of gastric lesions (see section 3.1).\n\nPatient selection should be carried out by an upper gastrointestinal cancer multidisciplinary team.\n\nThis is a technically challenging procedure and should only be carried out by clinicians with specific training in the technique. The Joint Advisory Group on Gastrointestinal Endoscopy intends to prepare training standards for this procedure.\n\nNICE encourages further research into ESD of gastric lesions. There should be clear documentation of the incidence of complications, including perforation, bleeding and the need for open surgery (with the reasons for this), rates of complete resection, and long-term outcomes, including local recurrence and survival following treatment of malignant lesions.", 'The procedure': "# Indications and current treatments\n\nGastric lesions include benign, dysplastic, and malignant tumours. Patients may be asymptomatic or experience loss of appetite and weight, anaemia and abdominal discomfort or pain.\n\nCurrent treatment options for small gastric lesions are snare polypectomy (for protruding lesions) or endoscopic mucosal resection (EMR) (for 'flat' lesions). EMR usually removes lesions piecemeal; in contrast, ESD aims to remove lesions intact and with a margin of healthy tissue.\n\n# Outline of the procedure\n\nEndoscopic submucosal dissection aims to remove lesions without the need for open abdominal surgery. It is usually preceded by diagnostic endoscopy, biopsy and imaging investigations.\n\nThe procedure is carried out with the patient under sedation or general anaesthesia. Using endoscopic visualisation, the submucosa is injected with saline to help lift the lesion. This fluid may contain a pigment to help define the lesion, and adrenaline to reduce bleeding. A circumferential mucosal incision is made with an electrocautery knife around the lesion. Submucosal dissection is then carried out, parallel to the muscle layer, aiming to remove the lesion intact and with a healthy margin of tissue. A transparent hood may be used to retract the already dissected part of the lesion out of the visual field. Haemostasis is achieved by electrocautery. Endoscopic clips may be used for larger vessels or to manage perforation.\n\nSections 2.3 and 2.4 describe efficacy and safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview.\n\n# Efficacy\n\nA non-randomised comparative study of 900 malignant lesions (patient numbers not stated) reported significantly greater complete resection rates of 95% (544/572) for ESD vs 64% (210/328) for EMR, and curative (with tumour-free margins) resection rates of 83% (473/572) vs 59% (195/328) respectively; p < 0.05 for both comparisons.\n\nA non-randomised comparative study of 896 patients (1020 malignant lesions) reported significantly greater complete en-bloc resection rates for non-ulcerated lesions of 93% (157/169) for ESD compared with 43% (343/790) for EMR, and histologically clear margin resection rates of 93% (157/169) vs 25% (194/790) respectively (p < 0.01).\n\nA case series of 59 premalignant or malignant lesions (patient numbers not stated) reported en-bloc resection by ESD in 86% (44/51) and free-margin complete resection in 73% (37/51) of lesions.\n\nThe non-randomised comparative study of 900 lesions reported no recurrence among ESD-treated lesions and recurrence in 4% (13/328) of EMR-treated lesions (p < 0.05).\n\nThe non-randomised comparative study of 896 patients reported no recurrence in ESD-treated patients at a mean 19.4-month follow-up, and recurrence rates of 3% (10/347) in ESD-treated patients and 4% (21/478) in EMR-treated patients during 83.2-month follow-up.\n\nThe case series of 59 lesions reported local recurrence in 5 patients treated by piecemeal ESD at up to 8-month follow-up.\n\nThe Specialist Advisers listed key efficacy outcomes as en-bloc and curative resection rates, recurrence rate and survival.\n\n# Safety\n\nTwo non-randomised studies – 1 of 900 lesions and the other of 346 patients – reported perforation in 4% (20/572) and 5% (11/243) of ESD-treated lesions or patients, and 2% (5/328) and 2% (2/103) of EMR-treated lesions or patients respectively (differences reported as not significant). In the study of 346 patients, 3 perforations in ESD-treated patients and 1 in an EMR-treated patient were detected intraprocedurally but the others were recognised post-procedurally (timing not stated). All perforations following ESD were managed non-surgically with a combination of endoscopic clipping, fasting, nasogastric tube drainage and antibiotics.\n\nA non-randomised study of 655 patients (714 lesions) reported that perforations were significantly more frequent in ESD-treated patients than in EMR-treated patients (4% [11/303] vs 1% [5/411] of lesions) (p < 0.05). All patients were managed endoscopically (not otherwise described).\n\nThe Specialist Advisers listed bleeding as an anecdotal adverse event and considered the theoretical risk of perforation leading to tumour seeding.\n\n# Other comments\n\nThe Committee considered that ESD could be suitable for a national register.", 'Further information': "This guidance requires that clinicians undertaking the procedure make special arrangements for audit. NICE has identified relevant audit criteria and has developed an audit tool (which is for use at local discretion).\n\nFor related NICE guidance see our website.\n\n# Information for patients\n\nNICE has produced information on this procedure for patients and carers ('Understanding NICE guidance'). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind. A large print version is also available.", 'About this guidance': 'NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland.\n\nThis guidance was developed using the NICE interventional procedure guidance process.\n\nWe have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available.\n\nChanges since publication\n\nJanuary 2012: minor maintenance.\n\nYour responsibility\n\nThis guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.\n\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.\n\nCopyright\n\n© National Institute for Health and Clinical Excellence 2010. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.\n\nContact NICE\n\nNational Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT\n\nwww.nice.org.uk\n \n nice@nice.org.uk\n 0845 033 7780'}	https://www.nice.org.uk/guidance/ipg360
78c9f4dcc04e4f9bc1e2915880012a9c6cdc5e05	nice	Insertion of metal rib reinforcements to stabilise a flail chest wall	Insertion of metal rib reinforcements to stabilise a flail chest wall # Guidance Current evidence on insertion of metal rib reinforcements to stabilise a flail chest wall is limited in quantity but consistently shows efficacy. In addition, there are no major safety concerns in the context of patients who have had severe trauma with impaired pulmonary function. Therefore the procedure may be used provided that normal arrangements are in place for clinical governance, consent and audit. Patient selection should be carried out by critical care specialists, chest physicians and thoracic surgeons with appropriate training and experience.# The procedure # Indications and current treatments Chest wall injury is common as a result of major blunt trauma (for example, motor vehicle accidents). It varies in severity from minor bruising or an isolated rib fracture, to severe crush injuries leading to respiratory compromise. A flail chest occurs when a segment of the thoracic cage moves independently from the rest of the chest wall. A flail chest causes paradoxical movement of this segment of the chest wall – in-drawing on inspiration and moving outwards on expiration – and this segment of chest wall fails to contribute to lung expansion. Flail chest has been defined in a variety of ways, but at least 2 fractures per rib in at least 2 ribs are needed to produce a flail segment. Large flail segments may extend bilaterally or involve the sternum, and may compromise respiration sufficiently to require mechanical ventilation. Management of chest wall injury is directed towards protecting the underlying lung, achieving adequate ventilation and oxygenation, and preventing infection. Analgesia sufficient to allow normal respiration and coughing may be adequate for mild cases. More severe cases require ventilatory support, and suction to remove mucus or secretions from the airways to prevent atelectasis. # Outline of the procedure Surgical stabilisation with metal rib reinforcements aims to allow earlier weaning from ventilator support, reduce acute complications, and avoid chronic pain sometimes associated with permanent deformity of the chest wall. With the patient under general anaesthesia, an incision is made over the rib fractures to be treated, and the fractured ribs are reduced. The affected ribs are stabilised using struts or metal plates, fixed with screws or intramedullary wires. These metal plates and screws are usually left in place in the long term. There are many variations in the materials and techniques used to stabilise flail chest with metal rib reinforcements. It should be noted that Kirschner wires, used alone, are not covered by this guidance. Sections 2.3 and 2.4 describe efficacy and safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview. # Efficacy A randomised controlled trial (RCT) of 37 patients treated by surgical stabilisation (n = 18) or mechanical ventilation (n = 19) reported a significantly lower proportion of patients with pneumonia at day 21 in the surgical stabilisation group compared with the mechanical ventilation group (22% vs 89% ) (p < 0.05). The RCT of 37 patients reported a mean critical care stay of 16.5 days in the surgical stabilisation group and 26.8 days in the mechanical ventilation group (p < 0.05). The RCT of 37 patients treated by surgical stabilisation (n = 18) or mechanical ventilation (n = 19) reported a mean percentage of forced vital capacity at 12 months of 96% and 80% respectively (p < 0.05). A case series of 66 patients reported that 52% (26/50) of patients had normal pulmonary function at 6-month follow-up. The RCT of 37 patients reported that a significantly higher percentage of patients had returned to full-time employment at 6 months in the surgical group compared with the mechanical ventilation group (61% vs 5% [1/19) (p < 0.01). The Specialist Advisers listed additional key efficacy outcomes as survival, duration of ventilation, long-term stabilisation of chest wall, reduced pain and patient satisfaction. # Safety Death was reported in 30% (3/10) of patients with pulmonary contusion treated by surgical stabilisation in a non-randomised comparative study of 42 patients. Of these deaths, 2 were from massive haemorrhage and 1 was from sepsis with multi-organ failure. No deaths were reported in patients without pulmonary contusion who were treated by surgical stabilisation. Persistent pain at the operative site was reported in 11% (6/57) and 24% (5/21) of patients in a case series of 66 patients at 6-month follow-up and a case series of 23 patients at 3-month follow-up respectively. This improved in 3 and 2 patients respectively after stabilisation plates and screws were removed at 6 months. The Specialist Advisers considered theoretical adverse events to include migration of metalwork, fracture of stabilisers, lung injury from stabilisers, screw loosening or separation, infection and allergy.# Further information For related NICE guidance see our website. # Information for patients NICE has produced information on this procedure for patients and carers ('Understanding NICE guidance'). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind. A large print version is also available.# About this guidance NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland. This guidance was developed using the NICE interventional procedure guidance process. We have produced a summary of this guidance for patients and carers. Information about the evidence it is based on is also available. Changes since publication January 2012: minor maintenance. Your responsibility This guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer. Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties. Copyright © National Institute for Health and Clinical Excellence 2010. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE. Contact NICE National Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT www.nice.org.uk nice@nice.org.uk	{'Guidance': 'Current evidence on insertion of metal rib reinforcements to stabilise a flail chest wall is limited in quantity but consistently shows efficacy. In addition, there are no major safety concerns in the context of patients who have had severe trauma with impaired pulmonary function. Therefore the procedure may be used provided that normal arrangements are in place for clinical governance, consent and audit.\n\nPatient selection should be carried out by critical care specialists, chest physicians and thoracic surgeons with appropriate training and experience.', 'The procedure': '# Indications and current treatments\n\nChest wall injury is common as a result of major blunt trauma (for example, motor vehicle accidents). It varies in severity from minor bruising or an isolated rib fracture, to severe crush injuries leading to respiratory compromise.\n\nA flail chest occurs when a segment of the thoracic cage moves independently from the rest of the chest wall. A flail chest causes paradoxical movement of this segment of the chest wall – in-drawing on inspiration and moving outwards on expiration – and this segment of chest wall fails to contribute to lung expansion. Flail chest has been defined in a variety of ways, but at least 2 fractures per rib in at least 2 ribs are needed to produce a flail segment. Large flail segments may extend bilaterally or involve the sternum, and may compromise respiration sufficiently to require mechanical ventilation.\n\nManagement of chest wall injury is directed towards protecting the underlying lung, achieving adequate ventilation and oxygenation, and preventing infection. Analgesia sufficient to allow normal respiration and coughing may be adequate for mild cases. More severe cases require ventilatory support, and suction to remove mucus or secretions from the airways to prevent atelectasis.\n\n# Outline of the procedure\n\nSurgical stabilisation with metal rib reinforcements aims to allow earlier weaning from ventilator support, reduce acute complications, and avoid chronic pain sometimes associated with permanent deformity of the chest wall.\n\nWith the patient under general anaesthesia, an incision is made over the rib fractures to be treated, and the fractured ribs are reduced. The affected ribs are stabilised using struts or metal plates, fixed with screws or intramedullary wires. These metal plates and screws are usually left in place in the long term.\n\nThere are many variations in the materials and techniques used to stabilise flail chest with metal rib reinforcements. It should be noted that Kirschner wires, used alone, are not covered by this guidance.\n\nSections 2.3 and 2.4 describe efficacy and safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview.\n\n# Efficacy\n\nA randomised controlled trial (RCT) of 37 patients treated by surgical stabilisation (n = 18) or mechanical ventilation (n = 19) reported a significantly lower proportion of patients with pneumonia at day 21 in the surgical stabilisation group compared with the mechanical ventilation group (22% [4/18] vs 89% [17/19]) (p < 0.05).\n\nThe RCT of 37 patients reported a mean critical care stay of 16.5 days in the surgical stabilisation group and 26.8 days in the mechanical ventilation group (p < 0.05).\n\nThe RCT of 37 patients treated by surgical stabilisation (n = 18) or mechanical ventilation (n = 19) reported a mean percentage of forced vital capacity at 12 months of 96% and 80% respectively (p < 0.05). A case series of 66 patients reported that 52% (26/50) of patients had normal pulmonary function at 6-month follow-up.\n\nThe RCT of 37 patients reported that a significantly higher percentage of patients had returned to full-time employment at 6 months in the surgical group compared with the mechanical ventilation group (61% [11/18] vs 5% [1/19) (p < 0.01).\n\nThe Specialist Advisers listed additional key efficacy outcomes as survival, duration of ventilation, long-term stabilisation of chest wall, reduced pain and patient satisfaction.\n\n# Safety\n\nDeath was reported in 30% (3/10) of patients with pulmonary contusion treated by surgical stabilisation in a non-randomised comparative study of 42 patients. Of these deaths, 2 were from massive haemorrhage and 1 was from sepsis with multi-organ failure. No deaths were reported in patients without pulmonary contusion who were treated by surgical stabilisation.\n\nPersistent pain at the operative site was reported in 11% (6/57) and 24% (5/21) of patients in a case series of 66 patients at 6-month follow-up and a case series of 23 patients at 3-month follow-up respectively. This improved in 3 and 2 patients respectively after stabilisation plates and screws were removed at 6 months.\n\nThe Specialist Advisers considered theoretical adverse events to include migration of metalwork, fracture of stabilisers, lung injury from stabilisers, screw loosening or separation, infection and allergy.', 'Further information': "For related NICE guidance see our website.\n\n# Information for patients\n\nNICE has produced information on this procedure for patients and carers ('Understanding NICE guidance'). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind. A large print version is also available.", 'About this guidance': 'NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland.\n\nThis guidance was developed using the NICE interventional procedure guidance process.\n\nWe have produced a summary of this guidance for patients and carers. Information about the evidence it is based on is also available.\n\nChanges since publication\n\nJanuary 2012: minor maintenance.\n\nYour responsibility\n\nThis guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.\n\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.\n\nCopyright\n\n© National Institute for Health and Clinical Excellence 2010. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.\n\nContact NICE\n\nNational Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT\n\nwww.nice.org.uk\n \n nice@nice.org.uk\n 0845 033 7780'}	https://www.nice.org.uk/guidance/ipg361
75d54c08ddd329874bdb82c7d3df9840ac8908c0	nice	Percutaneous posterior tibial nerve stimulation for overactive bladder syndrome	Percutaneous posterior tibial nerve stimulation for overactive bladder syndrome # Guidance Current evidence on percutaneous posterior tibial nerve stimulation (PTNS) for overactive bladder (OAB) syndrome shows that it is efficacious in reducing symptoms in the short and medium term. There are no major safety concerns. Therefore the procedure may be used provided that normal arrangements are in place for clinical governance, consent and audit.# The procedure # Indications and current treatments Overactive bladder syndrome is defined as urinary urgency, with or without urge incontinence, usually with frequency and nocturia. In most cases, the cause of the overactive bladder is unknown. In some cases, it is associated with neurological conditions such as multiple sclerosis or Parkinson's disease. First-line treatments for OAB include bladder training, pelvic floor muscle training and anticholinergic drugs. Botulinum toxin injection and sacral nerve stimulation may be used in patients for whom conservative treatments have been unsuccessful. More extensive surgical options for treating OAB include bladder reconstruction (such as augmentation cystoplasty) and urinary diversion. # Outline of the procedure The exact mechanism of action of PTNS on the bladder is unclear, but it is thought to be mediated by retrograde stimulation of the sacral nerve plexus (neuromodulation). The posterior tibial nerve contains mixed sensory motor nerve fibres that originate from the same spinal segments as the nerves to the bladder and pelvic floor. A fine-gauge needle is inserted percutaneously just above the ankle, next to the tibial nerve, and a surface electrode is placed on the foot. The needle and electrode are connected to a low-voltage stimulator. Stimulation of the posterior tibial nerve produces a typical motor (plantar flexion or fanning of the toes) and sensory (tingling in the ankle, foot or toes) response. Initial treatment usually consists of 12 outpatient sessions lasting 30 minutes each, typically a week apart. Further sessions are generally needed for longer-term relief. Sections 2.3 and 2.4 describe efficacy and safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview # Efficacy A randomised controlled trial (RCT) of 220 patients treated by PTNS or sham reported a moderate or marked improvement in overall bladder symptoms in 55% (60/110) and 21% (23/110) of patients respectively at 13-week follow-up (p < 0.001). An RCT of 100 patients treated by PTNS or medication reported that 80% (35/44) and 55% (23/42) of patients respectively considered themselves to be cured or improved after 12 weeks of therapy (p = 0.01). A case series of 90 patients reported a subjective response of 64% (58/90) (defined as a patient request for continuous chronic treatment to maintain the response) and an objective response of 57% (34/60) (defined as a reduction of 50% or more in urinary leakage episodes per 24 hours) at 12-week follow-up. The RCT of 100 patients treated by PTNS or medication reported a significant improvement in quality of life scores in both groups, 12 weeks after treatment. In a case series of 35 patients, the proportion of patients who were symptom-free decreased from 54% (19/35) immediately after treatment to 23% (8/35) at 1-year follow-up. In a case series of 33 patients who responded to an initial 12 sessions of PTNS and were offered additional treatment sessions at varying intervals for a further 9 months, 94% (30/32) of patients considered themselves to be cured or improved at 6 months and 96% (24/25) at 12-month follow-up. The Specialist Advisers commented that long-term efficacy has not been established and listed key efficacy outcomes as reduced episodes of urgency and urge incontinence, reduced daily pad usage, and improvements in quality of life and bladder capacity. # Safety In the RCT of 100 patients treated by PTNS or medication, at least 1 'moderate adverse event' considered to be related to the treatment was reported in 16% (8/49) and 14% (7/49) of patients respectively at 12-week follow-up. In the PTNS group, there was 1 report each of generalised swelling (not otherwise described), worsening of incontinence, headache, haematuria, inability to tolerate stimulation, leg cramps, intermittent foot or toe pain and vasovagal response to needle placement within the 12-week follow-up period. The RCT of 220 patients treated by PTNS or sham reported 7 treatment-related adverse events among the 110 patients treated by PTNS. These were bleeding or discomfort at the needle site (4% ), and 1 case each of ankle bruising and tingling in the leg. The Specialist Advisers listed adverse events reported in the literature as minor bleeding, pain and infection at the needle site.# Further information For related NICE guidance see our website. # Information for patients NICE has produced information on this procedure for patients and carers ('Understanding NICE guidance'). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind. A large print version is also available.# About this guidance NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland. This guidance was developed using the NICE interventional procedure guidance process. We have produced a summary of this guidance for patients and carers. Information about the evidence it is based on is also available. Changes since publication January 2012: minor maintenance. Your responsibility This guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer. Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties. Copyright © National Institute for Health and Clinical Excellence 2010. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE. Contact NICE National Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT www.nice.org.uk nice@nice.org.uk	{'Guidance': 'Current evidence on percutaneous posterior tibial nerve stimulation (PTNS) for overactive bladder (OAB) syndrome shows that it is efficacious in reducing symptoms in the short and medium term. There are no major safety concerns. Therefore the procedure may be used provided that normal arrangements are in place for clinical governance, consent and audit.', 'The procedure': "# Indications and current treatments\n\nOveractive bladder syndrome is defined as urinary urgency, with or without urge incontinence, usually with frequency and nocturia. In most cases, the cause of the overactive bladder is unknown. In some cases, it is associated with neurological conditions such as multiple sclerosis or Parkinson's disease.\n\nFirst-line treatments for OAB include bladder training, pelvic floor muscle training and anticholinergic drugs. Botulinum toxin injection and sacral nerve stimulation may be used in patients for whom conservative treatments have been unsuccessful. More extensive surgical options for treating OAB include bladder reconstruction (such as augmentation cystoplasty) and urinary diversion.\n\n# Outline of the procedure\n\nThe exact mechanism of action of PTNS on the bladder is unclear, but it is thought to be mediated by retrograde stimulation of the sacral nerve plexus (neuromodulation). The posterior tibial nerve contains mixed sensory motor nerve fibres that originate from the same spinal segments as the nerves to the bladder and pelvic floor.\n\nA fine-gauge needle is inserted percutaneously just above the ankle, next to the tibial nerve, and a surface electrode is placed on the foot. The needle and electrode are connected to a low-voltage stimulator. Stimulation of the posterior tibial nerve produces a typical motor (plantar flexion or fanning of the toes) and sensory (tingling in the ankle, foot or toes) response. Initial treatment usually consists of 12 outpatient sessions lasting 30 minutes each, typically a week apart. Further sessions are generally needed for longer-term relief.\n\nSections 2.3 and 2.4 describe efficacy and safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the \n overview\n .\n\n# Efficacy\n\nA randomised controlled trial (RCT) of 220 patients treated by PTNS or sham reported a moderate or marked improvement in overall bladder symptoms in 55% (60/110) and 21% (23/110) of patients respectively at 13-week follow-up (p < 0.001).\n\nAn RCT of 100 patients treated by PTNS or medication reported that 80% (35/44) and 55% (23/42) of patients respectively considered themselves to be cured or improved after 12 weeks of therapy (p = 0.01).\n\nA case series of 90 patients reported a subjective response of 64% (58/90) (defined as a patient request for continuous chronic treatment to maintain the response) and an objective response of 57% (34/60) (defined as a reduction of 50% or more in urinary leakage episodes per 24 hours) at 12-week follow-up.\n\nThe RCT of 100 patients treated by PTNS or medication reported a significant improvement in quality of life scores in both groups, 12 weeks after treatment.\n\nIn a case series of 35 patients, the proportion of patients who were symptom-free decreased from 54% (19/35) immediately after treatment to 23% (8/35) at 1-year follow-up. In a case series of 33 patients who responded to an initial 12 sessions of PTNS and were offered additional treatment sessions at varying intervals for a further 9 months, 94% (30/32) of patients considered themselves to be cured or improved at 6 months and 96% (24/25) at 12-month follow-up.\n\nThe Specialist Advisers commented that long-term efficacy has not been established and listed key efficacy outcomes as reduced episodes of urgency and urge incontinence, reduced daily pad usage, and improvements in quality of life and bladder capacity.\n\n# Safety\n\nIn the RCT of 100 patients treated by PTNS or medication, at least 1 'moderate adverse event' considered to be related to the treatment was reported in 16% (8/49) and 14% (7/49) of patients respectively at 12-week follow-up. In the PTNS group, there was 1 report each of generalised swelling (not otherwise described), worsening of incontinence, headache, haematuria, inability to tolerate stimulation, leg cramps, intermittent foot or toe pain and vasovagal response to needle placement within the 12-week follow-up period.\n\nThe RCT of 220 patients treated by PTNS or sham reported 7 treatment-related adverse events among the 110 patients treated by PTNS. These were bleeding or discomfort at the needle site (4% [5/110]), and 1 case each of ankle bruising and tingling in the leg.\n\nThe Specialist Advisers listed adverse events reported in the literature as minor bleeding, pain and infection at the needle site.", 'Further information': "For related NICE guidance see our website.\n\n# Information for patients\n\nNICE has produced information on this procedure for patients and carers ('Understanding NICE guidance'). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind. A large print version is also available.", 'About this guidance': 'NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland.\n\nThis guidance was developed using the NICE interventional procedure guidance process.\n\nWe have produced a summary of this guidance for patients and carers. Information about the evidence it is based on is also available.\n\nChanges since publication\n\nJanuary 2012: minor maintenance.\n\nYour responsibility\n\nThis guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.\n\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.\n\nCopyright\n\n© National Institute for Health and Clinical Excellence 2010. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.\n\nContact NICE\n\nNational Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT\n\nwww.nice.org.uk\n \n nice@nice.org.uk\n 0845 033 7780'}	https://www.nice.org.uk/guidance/ipg362
b3d307d982e38d3ee4f248ff5d8b5811942b0ada	nice	Minimally invasive total hip replacement	Minimally invasive total hip replacement # Guidance This document replaces previous guidance on single mini-incision hip replacement (interventional procedure guidance 152) and minimally invasive two-incision surgery for total hip replacement (interventional procedure guidance 112). Current evidence on the safety and efficacy of minimally invasive total hip replacement appears adequate to support the use of this procedure provided that normal arrangements are in place for clinical governance, consent and audit. Surgeons undertaking this procedure should have specific training in the minimally invasive technique they are using, and in use of the instrumentation it requires. Patient selection should be done by surgeons and their teams who can offer both conventional and minimally invasive total hip replacement. Clinicians should submit data on all patients treated using this procedure to the National Joint Registry.# The procedure # Indications and current treatments Disability arising from hip pain is common and is usually caused by osteoarthritis. Conservative treatments include medication (antiinflammatories and analgesics) and physiotherapy. If conservative treatments fail, hip resurfacing or a hip replacement may be necessary. A traditional hip replacement involves accessing the joint through a large incision (approximately 20–30 cm in length) with division of muscles, ligaments and tendons. Several different approaches may be used. # Outline of the procedure Minimally invasive total hip replacement is carried out with the patient under general or epidural anaesthesia, using an approach that aims to avoid damage to the muscles and tendons around the hip joint. A single incision of 10 cm or less in length is made. Alternatively, incisions are made at the front and back of the hip. Division of muscles may be necessary but is less extensive than in standard approaches. Specially designed retractors and customised instruments are typically used to expose the hip joint, prepare the acetabular socket and the femur, and insert the prosthesis. A specialised operating table may also be used. Fluoroscopic guidance and computer-assisted navigation tools may be used to aid positioning of the implant. A range of different prostheses are available for this procedure, which may be cemented or uncemented. Sections 2.3 and 2.4 describe efficacy and safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview # Efficacy A systematic review of 1205 patients reported that there was no significant difference in the mean change of Harris hip score (which assesses functional ability and hip dynamics, scored from0 to 100, higher scores better) from baseline in patients treated by mini-incision total hip replacement (n = 597) compared with those treated by the standard-incision approach (weighted mean difference 3.99) (95% confidence interval –0.18 to 8.16) (p = 0.06) (follow-up not stated). A case series of 759 patients (1000 hips) reported that the mean Harris hip score improved from 34 points at baseline to 92 points at a mean 37-month follow-up (significance not stated). A randomised controlled trial of 219 patients treated by mini-incision or standard-incision hip replacement reported that 85% (88/103) and 91% (96/105) of patients respectively were able to 'mobilise' the day after the operation (p = 0.54). The systematic review of 1205 patients reported that mean length of hospital stay was significantly shorter after minimally invasive procedures than after standard-incision procedures: WMD –3.59 (95% CI –5.69 to –1.50) (p = 0.0008). The Specialist Advisers listed key efficacy outcomes as long-term functional result, length of hospital stay, requirement for analgesics, and blood loss. # Safety Revision surgery was required in 1 patient in a case series of 400 hips at 18-month follow-up, in 2% (21/1000) of hips in the case series of 759 patients at a mean 37-month follow-up, and in 9% (8/90) of hips in the case series of 70 patients at a mean 11-year follow-up. The systematic review of 1205 patients reported that the overall rate of complications was not significantly different between patients treated by minimally invasive surgery and those who had standard-incision procedures: odds ratio 1.08 (95% CI –0.59 to 1.97) (p = 0.81) (follow-up not stated). Deep vein thrombosis or pulmonary embolism was reported in 1% (12/1000) of the hip procedures in the case series of 759 patients at a mean follow-up of 37 months. The UK National Joint Registry reported rates of calcar crack (femoral crack around the insertion of the prosthesis) of less than 1% (95/19,041) in patients treated by the procedure and less than 1% (1185/306,625) in patients treated by surgery using a standard approach. The rates of femoral shaft fracture were less than 1% (10/19,041 and 192/306,625 respectively) at follow-up of 0.1 to 6.5 years. Trochanteric fracture occurred in less than 1% (29/19,041) and less than 1% (622/306,625) of patients respectively. The case series of 759 patients (1000 hips) reported heterotopic ossification in 20% (198/1000) of hips at a mean follow-up of 37-months, but none of these were high grade (grade IV) or required further treatment. The case series of 70 patients (90 hips) reported osteolysis in 11% (8/70) of hips that underwent radiographic assessment at a mean follow-up of 11 years. The Specialist Advisers commented that malposition of components leading to dislocation, and femoral fracture are reported as adverse events. They considered theoretical adverse events to include neurovascular damage resulting from poor operative view. # Other comments Most of the evidence presented to the Committee was on single-incision minimally invasive hip replacement. The Committee saw some evidence on minimally invasive 2-incision total hip replacement (much of it mixed with evidence on single-incision surgery). They noted that the 2-incision technique is seldom used in UK practice at present. NICE has asked the National Joint Registry to collect data on 1-incision and 2-incision minimally invasive hip replacement separately, to inform any future review of these different approaches.# Further information For related NICE guidance see our website. # Information for patients NICE has produced information on this procedure for patients and carers ('Understanding NICE guidance'). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind. A large print version is also available.# About this guidance NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland. This guidance was developed using the NICE interventional procedure guidance process. It updates and replaces NICE interventional procedure guidance 152 and 112. We have produced a summary of this guidance for patients and carers. Information about the evidence it is based on is also available. Changes since publication January 2012: minor maintenance. Your responsibility This guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer. Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties. Copyright © National Institute for Health and Clinical Excellence 2010. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE. Contact NICE National Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT www.nice.org.uk nice@nice.org.uk	{'Guidance': 'This document replaces previous guidance on single mini-incision hip replacement (interventional procedure guidance 152) and minimally invasive two-incision surgery for total hip replacement (interventional procedure guidance 112).\n\nCurrent evidence on the safety and efficacy of minimally invasive total hip replacement appears adequate to support the use of this procedure provided that normal arrangements are in place for clinical governance, consent and audit.\n\nSurgeons undertaking this procedure should have specific training in the minimally invasive technique they are using, and in use of the instrumentation it requires.\n\nPatient selection should be done by surgeons and their teams who can offer both conventional and minimally invasive total hip replacement.\n\nClinicians should submit data on all patients treated using this procedure to the National Joint Registry.', 'The procedure': "# Indications and current treatments\n\nDisability arising from hip pain is common and is usually caused by osteoarthritis. Conservative treatments include medication (antiinflammatories and analgesics) and physiotherapy. If conservative treatments fail, hip resurfacing or a hip replacement may be necessary.\n\nA traditional hip replacement involves accessing the joint through a large incision (approximately 20–30 cm in length) with division of muscles, ligaments and tendons. Several different approaches may be used.\n\n# Outline of the procedure\n\nMinimally invasive total hip replacement is carried out with the patient under general or epidural anaesthesia, using an approach that aims to avoid damage to the muscles and tendons around the hip joint. A single incision of 10 cm or less in length is made. Alternatively, incisions are made at the front and back of the hip. Division of muscles may be necessary but is less extensive than in standard approaches. Specially designed retractors and customised instruments are typically used to expose the hip joint, prepare the acetabular socket and the femur, and insert the prosthesis. A specialised operating table may also be used. Fluoroscopic guidance and computer-assisted navigation tools may be used to aid positioning of the implant.\n\nA range of different prostheses are available for this procedure, which may be cemented or uncemented.\n\nSections 2.3 and 2.4 describe efficacy and safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the \n overview\n .\n\n# Efficacy\n\nA systematic review of 1205 patients reported that there was no significant difference in the mean change of Harris hip score (which assesses functional ability and hip dynamics, scored from0 to 100, higher scores better) from baseline in patients treated by mini-incision total hip replacement (n = 597) compared with those treated by the standard-incision approach (weighted mean difference [WMD] 3.99) (95% confidence interval [CI] –0.18 to 8.16) (p = 0.06) (follow-up not stated). A case series of 759 patients (1000 hips) reported that the mean Harris hip score improved from 34 points at baseline to 92 points at a mean 37-month follow-up (significance not stated).\n\nA randomised controlled trial of 219 patients treated by mini-incision or standard-incision hip replacement reported that 85% (88/103) and 91% (96/105) of patients respectively were able to 'mobilise' the day after the operation (p = 0.54).\n\nThe systematic review of 1205 patients reported that mean length of hospital stay was significantly shorter after minimally invasive procedures than after standard-incision procedures: WMD –3.59 (95% CI –5.69 to –1.50) (p = 0.0008).\n\nThe Specialist Advisers listed key efficacy outcomes as long-term functional result, length of hospital stay, requirement for analgesics, and blood loss.\n\n# Safety\n\nRevision surgery was required in 1 patient in a case series of 400 hips at 18-month follow-up, in 2% (21/1000) of hips in the case series of 759 patients at a mean 37-month follow-up, and in 9% (8/90) of hips in the case series of 70 patients at a mean 11-year follow-up.\n\nThe systematic review of 1205 patients reported that the overall rate of complications was not significantly different between patients treated by minimally invasive surgery and those who had standard-incision procedures: odds ratio 1.08 (95% CI –0.59 to 1.97) (p = 0.81) (follow-up not stated).\n\nDeep vein thrombosis or pulmonary embolism was reported in 1% (12/1000) of the hip procedures in the case series of 759 patients at a mean follow-up of 37 months.\n\nThe UK National Joint Registry reported rates of calcar crack (femoral crack around the insertion of the prosthesis) of less than 1% (95/19,041) in patients treated by the procedure and less than 1% (1185/306,625) in patients treated by surgery using a standard approach. The rates of femoral shaft fracture were less than 1% (10/19,041 and 192/306,625 respectively) at follow-up of 0.1 to 6.5 years. Trochanteric fracture occurred in less than 1% (29/19,041) and less than 1% (622/306,625) of patients respectively.\n\nThe case series of 759 patients (1000 hips) reported heterotopic ossification in 20% (198/1000) of hips at a mean follow-up of 37-months, but none of these were high grade (grade IV) or required further treatment. The case series of 70 patients (90 hips) reported osteolysis in 11% (8/70) of hips that underwent radiographic assessment at a mean follow-up of 11 years.\n\nThe Specialist Advisers commented that malposition of components leading to dislocation, and femoral fracture are reported as adverse events. They considered theoretical adverse events to include neurovascular damage resulting from poor operative view.\n\n# Other comments\n\nMost of the evidence presented to the Committee was on single-incision minimally invasive hip replacement. The Committee saw some evidence on minimally invasive 2-incision total hip replacement (much of it mixed with evidence on single-incision surgery). They noted that the 2-incision technique is seldom used in UK practice at present. NICE has asked the National Joint Registry to collect data on 1-incision and 2-incision minimally invasive hip replacement separately, to inform any future review of these different approaches.", 'Further information': "For related NICE guidance see our website.\n\n# Information for patients\n\nNICE has produced information on this procedure for patients and carers ('Understanding NICE guidance'). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind. A large print version is also available.", 'About this guidance': 'NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland.\n\nThis guidance was developed using the NICE interventional procedure guidance process.\n\nIt updates and replaces NICE interventional procedure guidance 152 and 112.\n\nWe have produced a summary of this guidance for patients and carers. Information about the evidence it is based on is also available.\n\nChanges since publication\n\nJanuary 2012: minor maintenance.\n\nYour responsibility\n\nThis guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.\n\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.\n\nCopyright\n\n© National Institute for Health and Clinical Excellence 2010. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.\n\nContact NICE\n\nNational Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT\n\nwww.nice.org.uk\n \n nice@nice.org.uk\n 0845 033 7780'}	https://www.nice.org.uk/guidance/ipg363
8995185ce4d02e04d537e3e2751eccca3ac2275d	nice	Transperineal template biopsy and mapping of the prostate	Transperineal template biopsy and mapping of the prostate # Guidance Current evidence on the efficacy of transperineal template biopsy of the prostate shows an increase in diagnostic yield in patients with suspected prostate cancer who have had negative or equivocal results from other biopsy methods. There are no major safety concerns. Therefore this procedure may be used for this indication provided that normal arrangements are in place for clinical governance, consent and audit. Evidence was not found to support the use of transperineal template biopsy of the prostate as a mapping technique to determine the exact location and extent of prostate cancer in order to guide focal therapy, nor as part of an active surveillance regime. Therefore the procedure should be used with these intentions only with special arrangements for clinical governance, consent and audit or research. Clinicians wishing to undertake transperineal template biopsy of the prostate as part of an active surveillance regime or as a mapping technique to guide focal therapy of prostate cancer should take the following actions. Inform the clinical governance leads in their Trusts. Ensure that patients and their carers understand the uncertainty about the use of the procedure for active surveillance and/or mapping, and provide them with clear written information. In addition, the use of NICE's information for patients ('Understanding NICE guidance') is recommended. Audit and review clinical outcomes of all patients having transperineal template biopsy of the prostate (see section 3.1). NICE encourages further research on the use of transperineal template biopsy of the prostate for both mapping and active surveillance. Comparing the results with specimens obtained at prostatectomy will help to define the accuracy of the procedure in determining the location and extent of prostate cancer.# The procedure # Indications and current treatments Prostate biopsy in patients with suspected prostate cancer is usually carried out by a transrectal needle biopsy. Amongst other uses, transperineal template biopsy may be used for patients with suspected prostate cancer who have had a negative or inconclusive transrectal biopsy. The use of transperineal template biopsy of the prostate has also been proposed for other indications including mapping to determine the location and extent of prostate cancer as a guide to focal treatment (such as ablation); as part of active surveillance of low-risk localised prostate cancer with the aim of reducing the number of biopsies; and as a reference test for evaluation of new methods of imaging the prostate. # Outline of the procedure This procedure is carried out with the patient under local or general anaesthesia, with intravenous prophylactic antibiotic coverage and a temporary urinary catheter. A grid template with multiple holes approximately 5 mm apart is placed on the perineum. Under transrectal ultrasound guidance a biopsy needle is introduced through different holes in the template, to obtain biopsies from defined parts of the prostate. Template biopsy allows a large number of tissue samples to be obtained from different parts of the prostate. This may improve detection of small cancers compared with other biopsy methods. An aim of the transperineal approach is to reduce the risk of infection compared with transrectal biopsy. Sections 2.3 and 2.4 describe efficacy and safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview # Efficacy A randomised controlled trial (RCT) of 246 patients investigated by 12-core transperineal biopsy or transrectal biopsy reported cancer detection rates of 42% (53/126) and 48% (58/120) respectively (p = 0.323). A case series of 373 patients reported that cancer was detected in 76% (60/79) of patients at first biopsy and in 34% (22/64) of patients with 3 or more previous negative biopsies. A non-randomised controlled study of 135 patients reported greater Gleason score agreement between biopsy and final pathology for 12-core transperineal biopsy (70% ) compared with 6-core transrectal biopsy (49% ) (p = 0.013). A case series of 747 patients reported adenocarcinoma detection in 39% (291/747) of patients; more frequently in apical compared with basal regions of the prostate (p < 0.001), and anterior rather than posterior regions (p = 0.036) (absolute figures not stated). No evidence was found to support the efficacy of the procedure in active surveillance or for mapping as a guide to focal prostate cancer therapy. The Specialist Advisers listed key efficacy outcomes as prostate cancer detection rate (particularly apical tumours) and better tumour localisation. # Safety The RCT of 246 patients biopsied by either a transperineal or transrectal approach reported fever greater than 38.5°C in 0% (0/126) and 2% (2/120) of patients respectively (p = 0.136). Infection (not otherwise described) was reported in 1 patient in the case series of 747 patients (follow-up not stated). The RCT of 246 patients investigated by transperineal or transrectal prostate biopsy reported haematospermia in 2% (2/126) and 0% (0/120) of patients respectively (p = 0.166) (duration and follow-up not stated). Urinary retention was reported in 10% (77/747) (all required a catheter when discharged from hospital), 2% (6/371) (all required overnight catheterisation), 2% (7/303) (not otherwise described) and 11% (24/210) (not otherwise described) of patients in case series of 747, 371, 303 and 210 patients. The Specialist Advisers considered theoretical adverse events to include septicaemia, bleeding, urinary tract infection and haematuria. # Other comments The Committee noted that there is considerable variation in the number of biopsy samples taken during the procedure.# Further information This guidance requires that clinicians undertaking the procedure as part of an active surveillance regime or as a mapping technique to guide focal prostate cancer therapy make special arrangements for audit. NICE has identified relevant audit criteria and has developed an audit tool (which is for use at local discretion). For related NICE guidance see our website. # Information for patients NICE has produced information on this procedure for patients and carers ('Understanding NICE guidance'). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind. A large print version is also available.# About this guidance NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland. This guidance was developed using the NICE interventional procedure guidance process. We have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available. Changes since publication January 2012: minor maintenance. Your responsibility This guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer. Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties. Copyright © National Institute for Health and Clinical Excellence 2010. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE. Contact NICE National Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT www.nice.org.uk nice@nice.org.uk	{'Guidance': "Current evidence on the efficacy of transperineal template biopsy of the prostate shows an increase in diagnostic yield in patients with suspected prostate cancer who have had negative or equivocal results from other biopsy methods. There are no major safety concerns. Therefore this procedure may be used for this indication provided that normal arrangements are in place for clinical governance, consent and audit.\n\nEvidence was not found to support the use of transperineal template biopsy of the prostate as a mapping technique to determine the exact location and extent of prostate cancer in order to guide focal therapy, nor as part of an active surveillance regime. Therefore the procedure should be used with these intentions only with special arrangements for clinical governance, consent and audit or research.\n\nClinicians wishing to undertake transperineal template biopsy of the prostate as part of an active surveillance regime or as a mapping technique to guide focal therapy of prostate cancer should take the following actions.\n\nInform the clinical governance leads in their Trusts.\n\nEnsure that patients and their carers understand the uncertainty about the use of the procedure for active surveillance and/or mapping, and provide them with clear written information. In addition, the use of NICE's information for patients ('Understanding NICE guidance') is recommended.\n\nAudit and review clinical outcomes of all patients having transperineal template biopsy of the prostate (see section 3.1).\n\nNICE encourages further research on the use of transperineal template biopsy of the prostate for both mapping and active surveillance. Comparing the results with specimens obtained at prostatectomy will help to define the accuracy of the procedure in determining the location and extent of prostate cancer.", 'The procedure': '# Indications and current treatments\n\nProstate biopsy in patients with suspected prostate cancer is usually carried out by a transrectal needle biopsy. Amongst other uses, transperineal template biopsy may be used for patients with suspected prostate cancer who have had a negative or inconclusive transrectal biopsy.\n\nThe use of transperineal template biopsy of the prostate has also been proposed for other indications including mapping to determine the location and extent of prostate cancer as a guide to focal treatment (such as ablation); as part of active surveillance of low-risk localised prostate cancer with the aim of reducing the number of biopsies; and as a reference test for evaluation of new methods of imaging the prostate.\n\n# Outline of the procedure\n\nThis procedure is carried out with the patient under local or general anaesthesia, with intravenous prophylactic antibiotic coverage and a temporary urinary catheter. A grid template with multiple holes approximately 5 mm apart is placed on the perineum. Under transrectal ultrasound guidance a biopsy needle is introduced through different holes in the template, to obtain biopsies from defined parts of the prostate.\n\nTemplate biopsy allows a large number of tissue samples to be obtained from different parts of the prostate. This may improve detection of small cancers compared with other biopsy methods. An aim of the transperineal approach is to reduce the risk of infection compared with transrectal biopsy.\n\nSections 2.3 and 2.4 describe efficacy and safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the \n overview\n .\n\n# Efficacy\n\nA randomised controlled trial (RCT) of 246 patients investigated by 12-core transperineal biopsy or transrectal biopsy reported cancer detection rates of 42% (53/126) and 48% (58/120) respectively (p = 0.323). A case series of 373 patients reported that cancer was detected in 76% (60/79) of patients at first biopsy and in 34% (22/64) of patients with 3 or more previous negative biopsies.\n\nA non-randomised controlled study of 135 patients reported greater Gleason score agreement between biopsy and final pathology for 12-core transperineal biopsy (70% [32/46]) compared with 6-core transrectal biopsy (49% [44/89]) (p = 0.013).\n\nA case series of 747 patients reported adenocarcinoma detection in 39% (291/747) of patients; more frequently in apical compared with basal regions of the prostate (p < 0.001), and anterior rather than posterior regions (p = 0.036) (absolute figures not stated).\n\nNo evidence was found to support the efficacy of the procedure in active surveillance or for mapping as a guide to focal prostate cancer therapy.\n\nThe Specialist Advisers listed key efficacy outcomes as prostate cancer detection rate (particularly apical tumours) and better tumour localisation.\n\n# Safety\n\nThe RCT of 246 patients biopsied by either a transperineal or transrectal approach reported fever greater than 38.5°C in 0% (0/126) and 2% (2/120) of patients respectively (p = 0.136). Infection (not otherwise described) was reported in 1 patient in the case series of 747 patients (follow-up not stated).\n\nThe RCT of 246 patients investigated by transperineal or transrectal prostate biopsy reported haematospermia in 2% (2/126) and 0% (0/120) of patients respectively (p = 0.166) (duration and follow-up not stated).\n\nUrinary retention was reported in 10% (77/747) (all required a catheter when discharged from hospital), 2% (6/371) (all required overnight catheterisation), 2% (7/303) (not otherwise described) and 11% (24/210) (not otherwise described) of patients in case series of 747, 371, 303 and 210 patients.\n\nThe Specialist Advisers considered theoretical adverse events to include septicaemia, bleeding, urinary tract infection and haematuria.\n\n# Other comments\n\nThe Committee noted that there is considerable variation in the number of biopsy samples taken during the procedure.', 'Further information': "This guidance requires that clinicians undertaking the procedure as part of an active surveillance regime or as a mapping technique to guide focal prostate cancer therapy make special arrangements for audit. NICE has identified relevant audit criteria and has developed an audit tool (which is for use at local discretion).\n\nFor related NICE guidance see our website.\n\n# Information for patients\n\nNICE has produced information on this procedure for patients and carers ('Understanding NICE guidance'). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind. A large print version is also available.", 'About this guidance': 'NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland.\n\nThis guidance was developed using the NICE interventional procedure guidance process.\n\nWe have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available.\n\nChanges since publication\n\nJanuary 2012: minor maintenance.\n\nYour responsibility\n\nThis guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.\n\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.\n\nCopyright\n\n© National Institute for Health and Clinical Excellence 2010. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.\n\nContact NICE\n\nNational Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT\n\nwww.nice.org.uk\n \n nice@nice.org.uk\n 0845 033 7780'}	https://www.nice.org.uk/guidance/ipg364
3c91dfbe4e0f517f294406c7e75aeb2916bc5a40	nice	Endoscopic mucosal resection and endoscopic submucosal dissection of non-ampullary duodenal lesions	Endoscopic mucosal resection and endoscopic submucosal dissection of non-ampullary duodenal lesions # Guidance The evidence on efficacy of endoscopic mucosal resection (EMR) and endoscopic submucosal dissection (ESD) of non-ampullary duodenal lesions is limited in quantity and there are safety concerns regarding the risks of perforation and bleeding. Therefore these procedures should only be used with special arrangements for clinical governance, consent and audit or research. Clinicians wishing to undertake EMR and ESD of non-ampullary duodenal lesions should take the following actions. Inform the clinical governance leads in their Trusts. Ensure that patients understand the uncertainty about these procedures' safety and efficacy in relation to the risks of perforation and bleeding, and that conversion to open surgery may be necessary. Patients should be provided with clear written information. In addition, the use of NICE's information for patients ('Understanding NICE guidance') is recommended. Audit and review clinical outcomes of all patients having EMR and ESD of non-ampullary duodenal lesions (see section 3.1). Patient selection should be carried out by an upper gastrointestinal cancer multidisciplinary team. Both EMR and ESD of non-ampullary duodenal lesions are technically challenging procedures and should be carried out only by clinicians with specific training and expertise in the use of EMR and ESD in other parts of the gastrointestinal tract (where lesions are more common). The Joint Advisory Group on Gastrointestinal Endoscopy intends to prepare training standards on these procedures. NICE encourages further research into EMR and ESD of non-ampullary duodenal lesions. There should be clear documentation of the incidence of complications, including perforation, bleeding and the need for open surgery (with the reasons for this), rates of complete resection, and long-term outcomes, including local recurrence and survival following treatment of malignant lesions.# The procedure # Indications and current treatments Duodenal lesions (benign, dysplastic or neoplastic) are rare. Symptoms include nausea and vomiting, loss of appetite and weight, anaemia and abdominal pain. Lesions in people who have inherited polyposis syndromes may be identified through regular surveillance examinations. Current treatment of malignant lesions may require major surgery (Whipple procedure). Endoscopic treatments such as snare polypectomy and argon plasma coagulation (APC) have been used for smaller lesions. # Outline of the procedure Both procedures aim to remove lesions without the need for open abdominal surgery. They are usually preceded by diagnostic endoscopy, biopsy and imaging investigations. Both EMR and ESD are carried out with the patient under sedation or general anaesthesia. Using endoscopic visualisation, the submucosa is injected with saline to help lift the lesion. This fluid may contain pigment to help define the lesion, and adrenaline to reduce bleeding. In EMR, lesions are usually removed piecemeal with a snare. In ESD, submucosal dissection is performed with an electrocautery knife, parallel to the muscle layer, aiming to remove the lesion intact and with clear margins. A transparent hood may be used to retract the already dissected part of the lesion out of the visual field. Haemostasis is achieved by electrocautery. Endoscopic clips may be used for larger vessels or to manage perforation. Sections 2.3 and 2.4 describe efficacy and safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview. # Efficacy Case series of 27 and 23 patients reported complete resection in 85% (23/27) and 86% (18/21) of EMR-treated patients respectively. A case series of 14 patients reported that all 9 ESD-treated lesions were resected en bloc and 5 of the 6 EMR-treated lesions were resected en bloc. The case series of 23 patients (21 EMR-treated patients) reported no local recurrences among 8 lesions removed en bloc at a median 13-month follow-up. Among 13 lesions removed piecemeal, 38% (5/13) of lesions had remnant adenoma at a median follow-up of 10 months; all were treated successfully with snare resection and/or APC. Case series of 13 EMR-treated patients, 4 ESD-treated patients and 3 EMR-treated patients reported no deaths or recurrences at mean follow-up of between 18 and 51.7 months. The Specialist Advisers listed key efficacy outcomes as complete removal and recurrence rates, recovery period and mortality. # Safety Perforation was reported in 2 ESD-treated patients and another 2 ESD-treated patients (successfully managed conservatively) in case series of 14 and 4 patients respectively. Bleeding was reported in 33% (9/27) of patients in the case series of 27 EMR-treated patients (within a larger series of 92 patients treated with EMR of different gastrointestinal organs). Among the 92 patients, 22 developed bleeding, 73% (16/22) of whom developed it early (within 24 hours of EMR treatment). Among those who bled early, 88% (14/16) were treated with endoscopic clip placement, snare ligation, electrocoagulation and/or injection therapy; 2 of the 6 patients who bled later than 24 hours required endoscopic management. Blood transfusion was required in 14% (3/22) of patients. Post-procedural bleeding was reported in 2 of 9 ESD-treated patients and 1 of 5 EMR-treated patients in the case series of 14 patients; all were successfully treated using endoscopic clips. The case series of 23 and 13 patients reported that 1 patient in each series developed bleeding after EMR (1 occurred up to 48 hours after EMR); both were successfully treated using endoscopic clips. The Specialist Advisers considered theoretical adverse events to include delayed haemorrhage, perforation, bleeding and pain. They stated that the risks of perforation and bleeding are higher when these procedures are used in the duodenum than in other parts of the gastrointestinal tract. # Other comments The Committee considered that ESD could be suitable for a national register.# Further information This guidance requires that clinicians undertaking the procedure make special arrangements for audit. NICE has identified relevant audit criteria and has developed an audit tool (which is for use at local discretion). For related NICE guidance see our website. # Information for patients NICE has produced information on this procedure for patients and carers ('Understanding NICE guidance'). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind. A large print version is also available.# About this guidance NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland. This guidance was developed using the NICE interventional procedure guidance process. We have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available. Changes since publication January 2012: minor maintenance. Your responsibility This guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer. Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties. Copyright © National Institute for Health and Clinical Excellence 2010. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE. Contact NICE National Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT www.nice.org.uk nice@nice.org.uk	{'Guidance': "The evidence on efficacy of endoscopic mucosal resection (EMR) and endoscopic submucosal dissection (ESD) of non-ampullary duodenal lesions is limited in quantity and there are safety concerns regarding the risks of perforation and bleeding. Therefore these procedures should only be used with special arrangements for clinical governance, consent and audit or research.\n\nClinicians wishing to undertake EMR and ESD of non-ampullary duodenal lesions should take the following actions.\n\nInform the clinical governance leads in their Trusts.\n\nEnsure that patients understand the uncertainty about these procedures' safety and efficacy in relation to the risks of perforation and bleeding, and that conversion to open surgery may be necessary. Patients should be provided with clear written information. In addition, the use of NICE's information for patients ('Understanding NICE guidance') is recommended.\n\nAudit and review clinical outcomes of all patients having EMR and ESD of non-ampullary duodenal lesions (see section 3.1).\n\nPatient selection should be carried out by an upper gastrointestinal cancer multidisciplinary team.\n\nBoth EMR and ESD of non-ampullary duodenal lesions are technically challenging procedures and should be carried out only by clinicians with specific training and expertise in the use of EMR and ESD in other parts of the gastrointestinal tract (where lesions are more common). The Joint Advisory Group on Gastrointestinal Endoscopy intends to prepare training standards on these procedures.\n\nNICE encourages further research into EMR and ESD of non-ampullary duodenal lesions. There should be clear documentation of the incidence of complications, including perforation, bleeding and the need for open surgery (with the reasons for this), rates of complete resection, and long-term outcomes, including local recurrence and survival following treatment of malignant lesions.", 'The procedure': '# Indications and current treatments\n\nDuodenal lesions (benign, dysplastic or neoplastic) are rare. Symptoms include nausea and vomiting, loss of appetite and weight, anaemia and abdominal pain. Lesions in people who have inherited polyposis syndromes may be identified through regular surveillance examinations.\n\nCurrent treatment of malignant lesions may require major surgery (Whipple procedure). Endoscopic treatments such as snare polypectomy and argon plasma coagulation (APC) have been used for smaller lesions.\n\n# Outline of the procedure\n\nBoth procedures aim to remove lesions without the need for open abdominal surgery. They are usually preceded by diagnostic endoscopy, biopsy and imaging investigations.\n\nBoth EMR and ESD are carried out with the patient under sedation or general anaesthesia. Using endoscopic visualisation, the submucosa is injected with saline to help lift the lesion. This fluid may contain pigment to help define the lesion, and adrenaline to reduce bleeding. In EMR, lesions are usually removed piecemeal with a snare. In ESD, submucosal dissection is performed with an electrocautery knife, parallel to the muscle layer, aiming to remove the lesion intact and with clear margins. A transparent hood may be used to retract the already dissected part of the lesion out of the visual field. Haemostasis is achieved by electrocautery. Endoscopic clips may be used for larger vessels or to manage perforation.\n\nSections 2.3 and 2.4 describe efficacy and safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview.\n\n# Efficacy\n\nCase series of 27 and 23 patients reported complete resection in 85% (23/27) and 86% (18/21) of EMR-treated patients respectively. A case series of 14 patients reported that all 9 ESD-treated lesions were resected en bloc and 5 of the 6 EMR-treated lesions were resected en bloc.\n\nThe case series of 23 patients (21 EMR-treated patients) reported no local recurrences among 8 lesions removed en bloc at a median 13-month follow-up. Among 13 lesions removed piecemeal, 38% (5/13) of lesions had remnant adenoma at a median follow-up of 10 months; all were treated successfully with snare resection and/or APC.\n\nCase series of 13 EMR-treated patients, 4 ESD-treated patients and 3 EMR-treated patients reported no deaths or recurrences at mean follow-up of between 18 and 51.7 months.\n\nThe Specialist Advisers listed key efficacy outcomes as complete removal and recurrence rates, recovery period and mortality.\n\n# Safety\n\nPerforation was reported in 2 ESD-treated patients and another 2 ESD-treated patients (successfully managed conservatively) in case series of 14 and 4 patients respectively.\n\nBleeding was reported in 33% (9/27) of patients in the case series of 27 EMR-treated patients (within a larger series of 92 patients treated with EMR of different gastrointestinal organs). Among the 92 patients, 22 developed bleeding, 73% (16/22) of whom developed it early (within 24 hours of EMR treatment). Among those who bled early, 88% (14/16) were treated with endoscopic clip placement, snare ligation, electrocoagulation and/or injection therapy; 2 of the 6 patients who bled later than 24 hours required endoscopic management. Blood transfusion was required in 14% (3/22) of patients.\n\nPost-procedural bleeding was reported in 2 of 9 ESD-treated patients and 1 of 5 EMR-treated patients in the case series of 14 patients; all were successfully treated using endoscopic clips. The case series of 23 and 13 patients reported that 1 patient in each series developed bleeding after EMR (1 occurred up to 48 hours after EMR); both were successfully treated using endoscopic clips.\n\nThe Specialist Advisers considered theoretical adverse events to include delayed haemorrhage, perforation, bleeding and pain. They stated that the risks of perforation and bleeding are higher when these procedures are used in the duodenum than in other parts of the gastrointestinal tract.\n\n# Other comments\n\nThe Committee considered that ESD could be suitable for a national register.', 'Further information': "This guidance requires that clinicians undertaking the procedure make special arrangements for audit. NICE has identified relevant audit criteria and has developed an audit tool (which is for use at local discretion).\n\nFor related NICE guidance see our website.\n\n# Information for patients\n\nNICE has produced information on this procedure for patients and carers ('Understanding NICE guidance'). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind. A large print version is also available.", 'About this guidance': 'NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland.\n\nThis guidance was developed using the NICE interventional procedure guidance process.\n\nWe have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available.\n\nChanges since publication\n\nJanuary 2012: minor maintenance.\n\nYour responsibility\n\nThis guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.\n\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.\n\nCopyright\n\n© National Institute for Health and Clinical Excellence 2010. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.\n\nContact NICE\n\nNational Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT\n\nwww.nice.org.uk\n \n nice@nice.org.uk\n 0845 033 7780'}	https://www.nice.org.uk/guidance/ipg359
c0e031329ef9d5b170d556f79b3c278e29ef2174	nice	Peginterferon alfa and ribavirin for the treatment of chronic hepatitis C	Peginterferon alfa and ribavirin for the treatment of chronic hepatitis C Evidence-based recommendations on peginterferon alfa (Pegasys; ViraferonPeg) and ribavirin for treating chronic hepatitis C in adults. # Guidance This guidance should be read in conjunction with the following NICE guidance: NICE technology appraisal guidance 75 (TA75) 'Interferon alfa (pegylated and non-pegylated) and ribavirin for the treatment of chronic hepatitis C' (which covers moderate to severe hepatitis C) NICE technology appraisal guidance 106 (TA106) 'Peginterferon alfa and ribavirin for the treatment of mild chronic hepatitis C'. This appraisal addresses extensions to the marketing authorisations for peginterferon alfa-2a and peginterferon alfa-2b. This guidance updates and replaces: section 1.2, bullet 3 only, of TA75 section 1.4 of TA75 for adults who are eligible for shortened courses of combination therapy (as described in section 1.2 of the current guidance) section 1.7, bullet 1 only, of TA75 sections 1.4 and 1.5 of TA106. All other recommendations in TA75 and TA106 still stand. Combination therapy with peginterferon alfa (2a or 2b) and ribavirin is recommended as a treatment option for adults with chronic hepatitis C: who have been treated previously with peginterferon alfa (2a or 2b) and ribavirin in combination, or with peginterferon alfa monotherapy, and whose condition either did not respond to treatment or responded initially to treatment but subsequently relapsed or who are co-infected with HIV. Shortened courses of combination therapy with peginterferon alfa (2a or 2b) and ribavirin are recommended for the treatment of adults with chronic hepatitis C who: have a rapid virological response to treatment at week 4 that is identified by a highly sensitive test and are considered suitable for a shortened course of treatment. When deciding on the duration of combination therapy, clinicians should take into account the licensed indication of the chosen drug (peginterferon alfa-2a or peginterferon alfa-2b), the genotype of the hepatitis C virus, the viral load at the start of treatment and the response to treatment (as indicated by the viral load).# Clinical need and practice Hepatitis C is an infectious disease of the liver caused by the hepatitis C virus (HCV). The virus is acquired primarily through percutaneous exposure to contaminated blood. People infected with HCV are often asymptomatic, but about 20% develop acute hepatitis. In approximately 80% of people who are infected, the virus is not cleared and they go on to develop chronic hepatitis C. Chronic hepatitis C is categorised as mild, moderate or severe depending on the extent of liver damage. The rate of progression from mild to severe disease is slow but variable, taking about 20 to 50 years from the time of infection. About 30% of infected people develop cirrhosis within 20 to 30 years, and some of these develop hepatocellular carcinoma. Some people with end-stage liver disease or hepatocellular carcinoma may require liver transplantation. Estimates from the Health Protection Agency suggest that approximately 142,000 people between the ages of 15 and 59 years had chronic HCV infection in England and Wales in 2003, a prevalence of 0.44% in this age group. The prevalence of chronic HCV infection varies by sex and age, and it is most common in men and in people aged 25 to 44 years. In 2007, the number of confirmed new HCV infections in England and Wales was 7540. Six genetic types of HCV, known as genotypes, have been found. Genotype 1 is the most common in the UK, accounting for about 40% to 50% of those infected with HCV. Genotypes 2 and 3 together contribute another 40% to 50%, while genotypes 4, 5 and 6 account for the remaining infections. In England and Wales, genotypes 1 and 3 represent more than 90% of all diagnosed HCV infections. The primary aim of treatment is to clear the virus from the blood. Successful treatment is usually indicated by a sustained virological response, which is defined as undetectable serum HCV RNA 6 months after the end of treatment. A sustained virological response is considered to indicate permanent resolution of infection, although relapse may occur in approximately 5% of people after 5 years. Previous NICE guidance (TA106 and TA75) recommends combination therapy with ribavirin and either peginterferon alfa-2a or peginterferon alfa-2b for adults with chronic hepatitis C. The previous guidance also recommends that monotherapy with peginterferon alfa-2a or peginterferon alfa-2b should be used only by people who are unable to tolerate ribavirin or for whom ribavirin is contraindicated. The recommended duration of treatment is 24 or 48 weeks depending on a combination of factors, including the HCV genotype, the viral load at the start of treatment and whether a person has a rapid virological response to treatment. For people with mild HCV infection, the person and their clinician should decide whether to treat immediately or adopt an approach of 'watchful waiting' (see TA106). The use of peginterferon alfa and ribavirin combination therapy is also considered suitable for people who are co-infected with HCV and HIV, unless it is contraindicated. Approximately 75% to 85% of people with moderate or severe infection with HCV genotype 2 or 3 have a sustained virological response 6 months after finishing a course of treatment with peginterferon alfa plus ribavirin. The proportion of people with HCV genotype 1 who show a sustained virological response after the end of treatment is about 40% to 50%, while for the other genotypes (4, 5 and 6) the proportion is generally reported to be between 50% and 75%. Clinical advice indicates that a substantial proportion of people treated in specialist clinics in England and Wales have had previous treatment, but their condition has not responded or has relapsed.# The technologies # Peginterferon alfa-2a Peginterferon alfa-2a (Pegasys, Roche Products) has a UK marketing authorisation for 'the treatment of chronic hepatitis C in adult patients who are positive for serum HCV-RNA, including patients with compensated cirrhosis and/or who are co-infected with clinically stable HIV'. The preferred treatment regimen is in combination with ribavirin, but monotherapy is indicated in cases of intolerance or contraindication to ribavirin. Patients may not have been previously treated or their condition may have not responded to previous treatment with interferon alfa (pegylated or non-pegylated) alone or in combination with ribavirin. The recommended dose is 180 micrograms once a week, administered subcutaneously, for 16, 24 or 48 weeks depending on HCV genotype, baseline viral load and response to treatment. The recommended duration of peginterferon alfa-2a monotherapy is 48 weeks. When peginterferon alfa-2a is given in combination with ribavirin, people with HCV genotype 1 or 4 infections who have detectable HCV RNA at week 4 (that is, there is not a rapid virological response) should receive 48 weeks of treatment. People with genotype 2 or 3 infections and undetectable HCV RNA at week 4 (that is, a rapid virological response) should receive 24 weeks of treatment. An extension to the licence for peginterferon alfa-2a now means that some people with hepatitis C are eligible for shortened courses of treatment. People with HCV genotype 1 and a low viral load (equal to or less than 800,000 IU/ml) at the start of treatment, a rapid virological response at week 4 and undetectable HCV RNA at week 24 may complete treatment at week 24 rather than receiving the standard 48 weeks of therapy. The licence extension also allows people with HCV genotype 2 or 3 who have a low viral load (equal to or less than 800,000 IU/ml), undetectable HCV RNA by week 4 (that is, a rapid virological response) and undetectable HCV RNA at week 16 to stop treatment at week 16 rather than receiving the standard 24 weeks of therapy. People with HCV genotype 4 may be treated in line with the regimen for people with genotype 1, but without requiring a low viral load. People with genotype 5 or 6 should be treated for 48 weeks. People co-infected with HIV should also be treated for 48 weeks, regardless of genotype. Re-treatment with peginterferon alfa-2a plus ribavirin may be offered to people whose hepatitis C has not shown an adequate response to treatment (non-response) or has responded but subsequently relapsed. Re-treated people should receive 48 weeks of treatment unless HCV RNA is still detectable at week 12, in which case treatment should be stopped. People with HCV genotype 1 whose condition has not responded to prior treatment with peginterferon alfa and ribavirin combination therapy and who are considered for re-treatment should receive 72 weeks of combination therapy. A weekly course of treatment with peginterferon alfa-2a (180 micrograms) costs £126.91 (excluding VAT; British national formulary edition 59). Costs may vary in different settings because of negotiated procurement discounts. # Peginterferon alfa-2b Peginterferon alfa-2b (ViraferonPeg, Schering-Plough) has a UK marketing authorisation for 'the treatment of adult patients with chronic hepatitis C who are positive for HCV-RNA, including patients with compensated cirrhosis and/or co-infected with clinically stable HIV'. The preferred treatment regimen is in combination with ribavirin, but monotherapy with peginterferon alfa-2b is indicated in cases of intolerance or contraindication to ribavirin. Patients may not have been treated previously or their condition may have not responded to previous treatment with interferon alpha (pegylated or non-pegylated) in combination with ribavirin or interferon alfa monotherapy. The recommended dose of peginterferon alfa-2b is 1.5 micrograms/kg body weight once a week, administered subcutaneously, for 24 or 48 weeks depending on HCV genotype, viral load at the start of treatment and response to treatment. People with HCV genotype 1 who have undetectable HCV RNA at week 12 (that is, who have an early virological response) should receive 48 weeks of treatment with peginterferon alfa-2b. People with a genotype 1 infection without an early virological response are considered unlikely to have a sustained virological response, and consideration should be given to withdrawing treatment. People with HCV genotype 4 should be treated with the same regimen as for genotype 1 infections. People with HCV genotype 2 or 3 infections should be treated for 24 weeks. People co-infected with HIV should be treated for 48 weeks regardless of HCV genotype. Following a licence extension for peginterferon alfa-2b, some people with hepatitis C are eligible for shortened courses of treatment. People with HCV genotype 1 and a low viral load (below 600,000 IU/ml) at the onset of treatment and who have undetectable HCV RNA at both week 4 and week 24 of treatment can stop treatment at 24 weeks. The marketing authorisation notes that a shortened course of 24 weeks of treatment may be associated with a higher risk of relapse than if treatment is given for 48 weeks. The marketing authorisation does not permit shorter treatment durations for people with HCV genotype 2 or 3 infections. Re-treatment with peginterferon alfa-2b in combination with ribavirin is recommended in the marketing authorisation for people whose hepatitis C has not shown an adequate response to treatment (non-response) or has responded but subsequently relapsed. All people re-treated with peginterferon alfa-2b, irrespective of HCV genotype, who have undetectable serum HCV RNA at week 12 should receive 48 weeks of treatment. People re-treated with peginterferon alfa-2b in whom HCV RNA is still detectable at week 12 are unlikely to have a sustained virological response after 48 weeks of therapy. A weekly course of peginterferon alfa-2b (average of 120 micrograms) costs £162.60 (excluding VAT; BNF 59). Costs may vary in different settings because of negotiated procurement discounts. # Ribavirin Two forms of ribavirin (Copegus, Roche Products; Rebetol, Schering-Plough) are currently available. Each product is indicated for the treatment of chronic hepatitis C and must be used only as part of a combination regimen with peginterferon alfa or interferon alfa. Ribavirin monotherapy must not be used. Each product is licensed for use only in combination with the interferon products made by the same manufacturer. The recommended doses of ribavirin range from 800 to 1400 milligrams, depending on body weight. The dose of Copegus also varies according to HCV genotype: 800 milligrams per day for genotype 2 or 3 infections and 1000 or 1200 milligrams per day for genotype 1, 4, 5 or 6 infections (1000 milligrams for body weights below 75 kg and 1200 milligrams for body weights of 75 kg or more). Both forms of ribavirin are taken orally each day in two divided doses. The weekly cost of Copegus is £111 for HCV genotype 1 infections (based on 1200 milligrams per day for an average body weight of 79 kg) and £74 for HCV genotype 2 or 3 infections (based on 800 milligrams per day). The weekly cost of Rebetol is £68, based on 1000 milligrams per day for an average body weight of 79 kg. Costs exclude VAT and are from BNF 59. Costs may vary in different settings because of negotiated procurement discounts. # Costs of combination treatment The cost of treatment with peginterferon alfa-2a plus ribavirin (Copegus) is estimated to be £3215 for 16 weeks or £4824 for 24 weeks of therapy (for people with genotypes 2 or 3), or £11,425 for 48 weeks of therapy (for people with genotypes 1 or 4). For people treated with peginterferon alfa-2b plus ribavirin (Rebetol), the cost is £5540 for 24 weeks or £11,081 for 48 weeks of therapy (for people with genotype 1). Acquisition costs are from BNF 59. Costs may vary in different settings because of negotiated procurement discounts. # Adverse effects of treatment The most common adverse effects associated with peginterferon-based anti-viral treatments include influenza-like symptoms such as headache, fatigue and fever, as well as insomnia, anorexia, dermatological symptoms, nausea, vomiting and depression. The adverse effects of anti-viral treatment for HCV, notably depression, may be more pronounced in people co-infected with HIV. For full details of adverse effects and contraindications, see the summaries of product characteristics.# Evidence and interpretation The Appraisal Committee (appendix A) considered evidence from a number of sources (appendix B). # Clinical effectiveness The Assessment Group performed a systematic review to identify randomised controlled trials (RCTs) evaluating the clinical effectiveness of peginterferon alfa plus ribavirin for the treatment of chronic hepatitis C in three specific groups: people eligible for shortened treatment courses people eligible for re-treatment following previous non-response or relapse of their condition people co-infected with HCV and HIV.Included in the review were studies in which a standard duration of combination therapy with peginterferon alfa plus ribavirin (or peginterferon monotherapy for people with contraindications to ribavirin) was compared with courses of combination therapy of a shortened duration (24 weeks for people with HCV genotype 1 treated with either peginterferon alfa-2a or -2b; 16 weeks for people with HCV genotype 2 or 3 treated with peginterferon alfa-2a only). The review also attempted to identify studies in which treatment was compared with best supportive care for subgroups that were co-infected with HIV or were being re-treated. Clinical outcomes included measures of virological response during and after treatment, and adverse effects. Six RCTs reported in eight publications were identified, all of which reported on peginterferon alfa and ribavirin combination therapy in people eligible for shortened courses of treatment. No studies were found that compared treatment with peginterferon alfa (with or without ribavirin) with best supportive care for people co-infected with HIV and HCV or for people whose hepatitis C had not responded to previous treatment or had responded but subsequently relapsed. ## Shortened treatment courses Of the six trials, four evaluated the effect of shortened treatment courses with peginterferon alfa plus ribavirin for people with HCV genotype 1 infections, while the other two trials evaluated the effect for people with genotype 2 or 3 infections. No trials assessed the effect of shortened treatment courses for people with genotype 4 infections. Five of the trials included people with a low viral load at the start of treatment. The comparator in all included studies was the same intervention for a standard duration of treatment. The dose of peginterferon alfa-2a was 180 micrograms per week and the dose of peginterferon alfa-2b was 1.5 micrograms per kg per week in all trials. All six RCTs reported sustained virological response rates as the primary outcome measure. A sustained virological response was defined as undetectable serum HCV RNA at the end of 24 weeks' follow-up in four trials, and as undetectable serum HCV RNA at the end of treatment and at the end of follow-up in the other two trials. In many of the trials the sustained virological response rates were presented for subgroups of people who had been randomised and who achieved a rapid virological response. It was not reported whether these subgroups were powered to detect a statistically significant difference between trial arms. A rapid virological response was defined as an undetectable serum concentration of HCV RNA (25 IU/ml or less) in one trial, serum HCV RNA negative (50 IU/ml or less) in three trials, serum HCV RNA of 600 IU/ml or less in one trial, and serum HCV RNA of 650 IU/ml or less in one trial, all at week 4 of treatment. In people with a low viral load (800,000 IU/ml or less) who attained a rapid virological response up to and including week 4 of treatment, sustained virological response rates were comparable between the group that received 48 weeks (standard duration) of treatment (range 83% to 100%) and the group that received shortened treatment courses (range 84% to 96%), with no statistically significant differences between the groups. Regardless of HCV genotype, sustained virological response rates were similar across studies, with the exception of one trial that reported lower rates. In two of the trials of peginterferon alfa-2a plus ribavirin, the ribavirin dose was varied according to body weight, which is no longer consistent with its marketing authorisation. The marketing authorisation specifies that ribavirin should be given as a fixed dose of 800 milligrams in people with HCV genotype 2 or 3, and both trials assessed the effectiveness of treatment only in people with HCV genotype 2 or 3 infections. The Assessment Group noted that if these two trials had been excluded on the basis of the variable ribavirin dosages, there would have been no evidence on the impact of shortened treatment durations in people with HCV genotype 2 or 3 infections. Rapid virological response rates were comparable between the groups that received the standard duration of treatment and those that received shortened courses. However, there was a large range in reported rapid virological response rates between the studies, with rates in people with HCV genotype 2 or 3 infections generally being higher than those in people with genotype 1 infections. The relapse rate in a subgroup of people with a low viral load and a rapid virological response was reported in one trial. Relapse was defined as the re-appearance of serum HCV RNA during the 24-week follow-up period in people whose condition initially responded to treatment. The rates of relapse were low and were not statistically significantly different between the treatment arms (3.6% for 24 weeks of treatment versus 0% for 48 weeks of treatment; p = 1.00). In contrast, in people with a high viral load at start of treatment and a rapid virological response later, shortening the duration of treatment was associated with a statistically significant higher rate of relapse (23.5% for 24 weeks versus 0% for 48 weeks; p = 0.045). Adverse events were presented for treatment groups as a whole, and not for the subgroup of people with a low viral load who had a rapid virological response. Overall, the frequency of adverse events did not differ statistically between treatment arms, although a lower incidence of adverse events was reported in three trials in people treated for a shorter duration with combination therapy. The most frequently occurring adverse events included influenza-like symptoms, insomnia, anorexia, dermatological symptoms and alopecia. The cumulative incidence of serious adverse events ranged from 0% to 7% over the duration of the trials, and was not considered to be substantially different between treatment arms, although levels of statistical significance were lacking in most studies. One death was reported, which was a result of re-activation of pulmonary tuberculosis at week 36 of treatment in a person who was treated with peginterferon alfa-2a plus ribavirin. One trial reported that people receiving a shortened treatment regimen were less likely to discontinue their treatment than people receiving longer courses (3% versus 10%; p = 0.045). ## Re-treatment after non-response or relapse The Assessment Group did not identify any RCTs that compared treatment with peginterferon alfa (with or without ribavirin) with best supportive care for people whose hepatitis C had not responded to previous treatment or had responded but subsequently relapsed. The Assessment Group did identify a number of RCTs comparing treatment with peginterferon alfa (with or without ribavirin) with active treatment comparators (such as non-peginterferon alfa plus ribavirin), but these did not meet the inclusion criteria for the review (based on the decision problem) because they featured an active treatment comparator. However, the Assessment Group assumed in its economic model (see section 4.2) that the sustained virological response rates for people whose condition did not respond or responded but subsequently relapsed on peginterferon alfa therapy were those reported in the clinical trials that used an active comparator. The Assessment Group noted that these reported sustained virological response rates may not be representative of people with relapsed disease because the trial participants with HCV genotype 1 infections had less intensive initial treatment than what would be regarded as standard treatment. ## HCV and HIV co-infection The Assessment Group did not identify any RCTs that compared treatment with peginterferon alfa (with or without ribavirin) with best supportive care for people with HCV and HIV co-infection. A number of RCTs were identified that compared peginterferon alfa (with or without ribavirin) with active treatment comparators (such as non-peginterferon alfa plus ribavirin) for this subgroup, but these did not meet the inclusion criteria for the review because they featured an active treatment comparator. The Assessment Group noted that it is unlikely that any studies, whether randomised or not, would be available that include a non-active treatment arm, because withholding treatment would be unlikely to be considered ethical. ## Summary of clinical-effectiveness evidence The collective evidence for combination therapy for both peginterferon alfa-2a and peginterferon alfa-2b suggests that there are no statistically significant differences in sustained virological response rates between people receiving shortened durations of treatment with peginterferon alfa plus ribavirin of 16 weeks (HCV genotype 2 or 3; peginterferon alfa-2a) or 24 weeks (HCV genotype 1; both peginterferon alfa-2a and alfa-2b) and people receiving the standard duration of treatment. Rates of relapse following a shortened course of treatment were reported to be low and not statistically significantly different from relapse rates after a standard course of treatment in people with a rapid virological response and low viral load. For people with a rapid virological response and a high viral load, shortening the duration of treatment may be associated with a higher rate of relapse. However, the Assessment Group noted that analyses of sustained virological responses in people with a low viral load at the start of treatment and a rapid virological response are likely to be underpowered because they were based on subgroups of the randomised participants, and therefore the results should be interpreted with caution. No RCTs were identified that compared peginterferon alfa (with or without ribavirin) with best supportive care for people who were re-treated after non-response or relapse of their condition, or for people with HCV and HIV co-infection. # Cost effectiveness The Assessment Group identified two studies examining the cost effectiveness of the treatment of people co-infected with HCV and HIV. The studies compared peginterferon alfa plus ribavirin with non-peginterferon plus ribavirin, peginterferon alfa monotherapy and no treatment (supportive care). One study also had an additional non-peginterferon alfa monotherapy arm. No economic evaluations were identified for people requiring re-treatment following previous non-response or relapse, or for people eligible for shortened courses of treatment. In both studies of people co-infected with HCV and HIV, peginterferon alfa monotherapy or peginterferon alfa plus ribavirin dominated (that is, treatment was more effective and less costly) the other strategies in people with HCV genotype 1. In one study, peginterferon alfa monotherapy was the most favourable option in each scenario. For people with other HCV genotypes (that is, not genotype 1), peginterferon alfa plus ribavirin was the least favourable option in one study (incremental cost-effectiveness ratios of $300,800 to $4,000,000 per quality-adjusted life year gained). In the second study peginterferon alfa plus ribavirin dominated the other strategies for all genotypes reported. The incremental costs per life year saved (LYS) for peginterferon alfa plus ribavirin in people with HCV genotypes other than genotype 1 were $39,300/LYS in women and $39,700/LYS in men and $70,000/LYS in women and $73,000/LYS in men in people with genotype 1). ## Manufacturers' models A health state transition model submitted by Roche Products was used to assess the cost effectiveness of treatment with peginterferon alfa-2a plus ribavirin in three groups: people who had been treated previously with peginterferon alfa plus ribavirin, including those whose hepatitis C did not respond to this previous treatment (by HCV genotype) and those whose condition responded but then relapsed; people with a low viral load and a rapid virological response who received shortened courses of peginterferon alfa plus ribavirin (by genotype); and people co-infected with HCV and HIV. The model used clinical-effectiveness data from published RCTs, although evidence of effectiveness for shortened treatment courses was derived from subgroup analyses. For people receiving shortened treatment courses, the sustained virological response rates for both groups in the model were taken from unpublished analyses of subgroups of clinical trial participants. For the subgroups with HCV genotypes 2 and 3 the data were taken from the ACCELERATE study reported by Shiffman and colleagues, and for the genotype 1 and 4 subgroups the data were taken from a trial reported by Hadziyannis and colleagues (study NV15942). A number of the clinical-effectiveness studies used by the manufacturer to obtain data for the economic model (namely for people who had been re-treated or had HIV co-infection) had active comparators, rather than comparing treatment with best supportive care (as outlined in the decision problem). For people with HCV and HIV co-infection, data on sustained virological response rates were taken from a clinical trial comparing non-peginterferon alfa-2a with peginterferon alfa-2a, which is not consistent with the scope for this appraisal. For people whose hepatitis C did not respond or relapsed on previous peginterferon therapy, data on sustained virological response rates were taken from two clinical trials. In the majority of situations it was assumed that people receiving best supportive care would not achieve a spontaneous sustained virological response. No discussion or critical analysis of the reliability or generalisability of the clinical-effectiveness evidence used to populate the model was provided by the manufacturer. Shortening the duration of treatment was associated with a QALY loss compared with the standard treatment duration (because of a slight reduction in the sustained virological response rate), as well as with a reduction in costs. Since both costs and outcomes were lower with shortened treatment duration, the ICERs represent savings per QALY lost. For people with HCV genotype 1 or 4 the ICER was £15,472 per QALY, and for people with genotype 2 or 3 the ICER was £2719 per QALY. The Assessment Group noted that when there are both lower costs and lower effectiveness, the analysis can be better understood by applying the net benefits framework. Using the net benefits framework, a treatment would be accepted when the value of the incremental benefits exceeds the incremental costs, resulting in a positive incremental net benefit. Using this framework, the incremental net monetary benefit for a shortened duration of treatment is positive for people with HCV genotype 1 or 4 over a wide range of willingness-to-pay values (below the ICER value of £15,472 per QALY). For people with HCV genotype 2 or 3 the incremental net monetary benefit is positive only at comparatively low threshold values (below the ICER value of £2719 per QALY). Re-treating people whose hepatitis C relapsed following previous peginterferon treatment was reported by the manufacturer as dominating best supportive care. This is the result of including a high sustained virological response rate observed in one trial that may not be generalisable to other populations of people whose condition relapses. The majority of people had HCV genotype 1 infections and their previous treatment was of shorter duration than the current standard of care (that is, 24 weeks rather than 48 weeks). The sustained virological response rates applied in the model for the re-treatment of people whose hepatitis C had not responded to previous peginterferon treatment were lower than those for people whose condition had relapsed following treatment. Treatment was associated with QALY gains and increased costs compared with best supportive care, resulting in ICERs of £3334 per QALY gained for people with HCV genotype 1 and £809 per QALY gained for people with other genotypes. The majority of people recruited to the trial whose condition did not respond to previous peginterferon treatment had HCV genotype 1; only 29 were infected with other HCV genotypes (9% of the arm used to estimate the effectiveness of treatment in the model), and the majority (66%) of these had genotype 4 infections. For people with HCV and HIV co-infection, treatment with peginterferon plus ribavirin was estimated to dominate treatment with non-peginterferon. However, this is not the comparison specified in the decision problem issued by NICE (where best supportive care was stated as the comparator). The Assessment Group extended the analysis by assuming that the sustained virological response rate for untreated people would be zero, and estimated a QALY gain (using the manufacturer's model) of 1.95 and an incremental cost of £1765 for peginterferon plus ribavirin compared with best supportive care, resulting in an ICER of £903 per QALY gained. The Assessment Group thought that the cost-effectiveness results were generally robust to variations in the limited number of parameters included in a deterministic sensitivity analysis reported in the manufacturer's submission. Probabilistic sensitivity analyses were also conducted by the manufacturer, and included the majority of parameters in the model. Although appropriate probability distributions appear to have been used for the probabilistic sensitivity analyses, the Assessment Group noted that limiting the distributions for some inputs does not appear to make the best use of data reported in the submission. Moreover, the Assessment Group felt that the manufacturer's model did not adequately consider logical relationships and potential correlations between model inputs. Rather than reporting the probability of cost effectiveness at certain willingness-to-pay thresholds, the submission identified a maximum threshold of £15,000 for all analyses. Further analyses of the manufacturer's model undertaken by the Assessment Group generally resulted in less favourable ICERs, but did not substantially alter the conclusions from those in the manufacturer's submission. The manufacturer presented cost-effectiveness results for three populations: people who had been treated previously with peginterferon and whose hepatitis C either did not respond to treatment or relapsed after treatment (broken down further by broad HCV genotype categories: genotypes 1 and 4 combined, and genotypes 2 and 3 combined) (data obtained from the EPIC3 clinical study report); and people co-infected with HCV and HIV (using effectiveness data from a trial reported by Laguno and colleagues). The manufacturer subsequently presented an analysis of the cost effectiveness of shortened compared with standard treatment durations for people with HCV genotype 1. Model-based economic evaluations were based on clinical data from the EPIC3 study (a multi-centre, non-randomised open-label uncontrolled study of re-treatment in people whose hepatitis C did not respond or relapsed after treatment) and from the study of Laguno and colleagues (a phase III open-label trial that recruited treatment-naïve people with histologically verified liver disease, who were HIV-positive with controlled disease ). As the included studies do not make the comparisons specified in the decision problem (that is, anti-viral treatment compared with best supportive care), the manufacturer assumed that people receiving best supportive care would not achieve a spontaneous sustained virological response. The model includes a low probability of a spontaneous sustained virological response for people with mild chronic hepatitis C, which is applied to the best supportive care and active treatment cohorts. The manufacturer's model is structurally similar to that used in a previous assessment report for TA106. However, it does not distinguish between people achieving a sustained virological response from any of the treatment-eligible states (mild or moderate hepatitis C and compensated cirrhosis). The parameters reflecting natural history in the model are similar to those adopted in the previous assessment report (TA106), as are the health state utilities and health state costs (inflated from 2003/4 to 2007/8 costs using the HCHS Pay and Prices Index). Re-treating people whose hepatitis C did not respond or relapsed following previous interferon treatment was estimated to result in a QALY gain of 1.03 compared with best supportive care at an incremental cost of £4536, resulting in an ICER of £4387 per QALY gained. These results were reported for a combined cohort of people with HCV genotypes 1 and 4 (84% of total) and people with genotypes 2 and 3. Separate results were also reported for the two genotype subgroups: the ICERs were £7177 per QALY gained for people with genotypes 1 and 4, and £783 per QALY gained for people with genotypes 2 and 3. Separate subgroup analyses (not stratified by genotype) for people whose condition did not respond to treatment and for people whose condition relapsed following treatment were also presented which suggested that the QALY gain was higher for the non-response subgroup than for the relapse subgroup. For a cohort of people (all HCV genotypes) co-infected with HCV and HIV, treatment with peginterferon plus ribavirin was estimated to result in a gain of 2.32 QALYs compared with best supportive care at an incremental cost of £2502, resulting in an ICER of £1077 per QALY gained. For people with genotypes 1 and 4 the ICER was estimated at £1637 per QALY gained, while for people with genotypes 2 and 3 the ICER was £403 per QALY gained. The manufacturer also conducted an analysis of the subgroup of people eligible for a shortened treatment duration. The analysis demonstrated that a shortened treatment duration of 24 weeks dominated the standard treatment duration of 48 weeks for people with HCV genotype 1. The manufacturer noted that these results should be treated with caution, as there was a large numerical difference in the rapid virological response rates at week 4 between the patient groups (standard versus shortened treatment) in the clinical trial, despite the fact that they had received the same treatment up to this point. Deterministic sensitivity analyses provided by the manufacturer showed that the ICERs for both the re-treated and co-infected groups were sensitive to variations in the early virological response rate and the sustained virological response rate, as well as to changes in body weight (since the dosing regimens of both peginterferon alfa-2b and ribavirin were weight-based). In the re-treatment group the ICERs showed a small increase in response to changes in the distribution of disease severity within the group. Probabilistic sensitivity analyses were conducted by the manufacturer which included the majority of parameters in the model. The manufacturer performed probabilistic sensitivity analyses (for overall cohort and by genotype) for each group (re-treated and co-infected). The probabilistic sensitivity analysis indicated a high probability (over 90%) that treatment with peginterferon alfa-2b plus ribavirin is cost effective for all analyses at willingness-to-pay thresholds of both £20,000 and £30,000 per QALY gained. The Assessment Group was concerned about the manufacturer's assumption that a person would achieve a sustained virological response immediately after treatment is given, and therefore accrue health benefits before entering the model. Furthermore, the Assessment Group did not consider that it was appropriate to apply the same utility values for a sustained virological response irrespective of the stage of disease when the treatment was given. Further analyses of the manufacturer's model undertaken by the Assessment Group generally resulted in less favourable ICERs, but did not substantially alter the conclusions from those in the manufacturer's submission. ## Assessment Group's model The Assessment Group adapted a previously published model to undertake an independent economic assessment of shortened treatment durations with peginterferon alfa plus ribavirin, using clinical-effectiveness data from studies included in the systematic review. The economic model was structurally similar to those developed by the manufacturers, and used similar input parameters to model disease progression, health state costs and utility. The model consists of nine health states representing stages of chronic liver disease and death. The economic model contains three health states representing cure of chronic hepatitis C, which are differentiated by the stage of the disease before treatment, as this is expected to have an impact on the subsequent risk of progressive liver disease, post-treatment surveillance and health-related quality of life. The health states mild hepatitis C, moderate hepatitis C, compensated cirrhosis, decompensated cirrhosis, hepatocellular carcinoma and liver transplant represent stages of progressive liver disease. People not exhibiting a sustained virological response are expected to have the same risk of disease progression as untreated people. These assumptions are all consistent with previous assessments and with other published economic evaluations of anti-viral treatment for chronic HCV infection. The model has a cycle length of 1 year and incorporates a half-cycle adjustment. Baseline population data in the model were based on the results of a clinical audit undertaken at a London teaching hospital. New patients were taken to represent the population of people with HCV and HIV co-infection and the population eligible to receive shortened courses of combination therapy as applicable, and existing patients were taken to represent the population of people treated previously with peginterferon alfa and ribavirin. Patients were differentiated in terms of average age and distribution across stages of chronic liver disease (mild hepatitis C, moderate hepatitis C and compensated cirrhosis). The proportion of men in the baseline cohort was based on the Assessment Group's previous assessment. The majority of these assumptions do not affect response to treatment, but relate to the risk of all-cause mortality. The influence of the stage of chronic liver disease on response to treatment, and on the cost effectiveness of the intervention, was assessed in a sensitivity analysis. Data on sustained virological response rates for the subgroup of people receiving shortened treatment courses were extracted by the Assessment Group from clinical trials included in the clinical effectiveness review. For the subgroups of people co-infected with HIV and HCV and of people whose hepatitis C did not respond to previous treatment or responded but subsequently relapsed, sustained virological response rates were taken from RCTs that included active comparators, which were not systematically reviewed by the Assessment Group. Data on sustained virological response rates were used in the model to estimate the probability of treatment-eligible people moving to the relevant state of a sustained virological response. Where applicable, early virological response rates were used to estimate the average duration of treatment and total drug acquisition costs for each anti-viral treatment strategy. Shortening the duration of treatment with peginterferon alfa-2a plus ribavirin from 48 weeks to 24 weeks for people with HCV genotype 1, a baseline low viral load and a rapid virological response resulted in a reduction in total QALYs of between 0.08 and 0.14. This shortened treatment duration was also associated with a reduction in the total cost, resulting in ICERs that reflected 'savings per QALY lost' (ranging from £34,510 to £64,880 per QALY). For people with HCV genotypes 2 and 3, a baseline low viral load and a rapid virological response, a shortened duration of treatment of 16 weeks with peginterferon alfa-2a plus ribavirin dominated the standard 24-week treatment duration. For the subgroup of people with HCV genotype 1, a baseline low viral load and a rapid virological response, a shortened duration of treatment of 24 weeks with peginterferon alfa-2b plus ribavirin dominated the standard 48-week treatment duration. The ICER for the subgroup of people who had been treated previously with peginterferon alfa-2b plus ribavirin or peginterferon monotherapy but whose hepatitis C did not respond to treatment, or responded initially to treatment but subsequently relapsed, was £23,912 per QALY gained (compared with best supportive care) for people with HCV genotypes 1 and 4. If an early stopping rule was applied, the ICER for people with genotypes 1 and 4 was reduced to £7681 per QALY gained. For people with genotypes 2 and 3, treatment with peginterferon alfa-2b plus ribavirin dominated best supportive care (with or without an early stopping rule). Re-treatment with peginterferon alfa-2a plus ribavirin of people whose hepatitis C did not respond to previous peginterferon therapy resulted in an ICER of £52,587 per QALY gained for people with HCV genotype 1 and £10,926 per QALY gained for people with other genotypes, each compared with best supportive care. If an early stopping rule was applied at 12 weeks for people re-treated with peginterferon alfa-2a plus ribavirin who did not show an early virological response at this time, the ICERs were reduced to £9169 per QALY gained for people with HCV genotype 1 and £2294 per QALY gained for people with other genotypes. For people co-infected with HCV and HIV, treatment with peginterferon alfa-2a plus ribavirin resulted in an ICER of £7941 per QALY gained for people with HCV genotypes 1 and 4 compared with best supportive care. Peginterferon alfa-2a plus ribavirin dominated best supportive care for people with genotypes 2 and 3. Treatment of people co-infected with HCV and HIV with peginterferon alfa-2b plus ribavirin resulted in an ICER of £11,806 per QALY gained for people with HCV genotypes 1 and 4 and an ICER of £2161 per QALY gained for people with genotypes 2 and 3. ## Summary of cost-effectiveness evidence Cost-effectiveness analyses indicate that adopting a shortened duration of treatment with peginterferon alfa-2a plus ribavirin for people with HCV genotype 1 is associated with fewer QALYs, but also with lower treatment costs, resulting in ICERs ranging from £34,000 to £65,000 of savings per QALY lost. For people with genotypes 2 and 3, a shortened treatment course with peginterferon alfa-2a plus ribavirin dominates the standard treatment duration. Similarly, for people with HCV genotype 1, a shortened duration of treatment with peginterferon alfa-2b plus ribavirin dominates the standard treatment duration. The results submitted by the manufacturers and those reported by the Assessment Group also indicate that treatment with peginterferon alfa plus ribavirin for people who are eligible for re-treatment following previous non-response or relapse of their condition is associated with QALY gains and an increase in costs. If an early stopping rule was applied at 12 weeks, re-treatment with peginterferon alfa plus ribavirin was associated with ICERs below £10,000 per QALY gained for people with HCV genotypes 1 and 4. For people with HCV genotypes 2 and 3, re-treatment was associated with ICERs below £2294 per QALY gained or dominated best supportive care. For people co-infected with HCV and HIV who were treated with peginterferon alfa plus ribavirin, either all ICERs were below £12,000 per QALY gained or treatment dominated best supportive care. # Consideration of the evidence The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of peginterferon alfa (2a or 2b) plus ribavirin, having considered evidence on the nature of chronic hepatitis C and the value placed on the benefits of peginterferon alfa (2a or 2b) plus ribavirin by people with the condition, those who represent them, and clinical specialists. It also took into account the effective use of NHS resources. The Committee was aware from the evidence presented that there were no statistically significant differences in sustained virological response rates between subgroups receiving shortened and standard courses of treatment with peginterferon alfa plus ribavirin. The Committee heard from the clinical specialist that, although some trials have reported that people who received shortened courses of treatment had (non-significant) lower sustained virological response rates, using shortened rather than standard courses of therapy was not expected to have clinical implications. Therefore the Committee concluded that shortened and standard treatment durations could be viewed as clinically comparable. The Committee noted that no RCTs were identified that compared peginterferon alfa (with or without ribavirin) with best supportive care for people co-infected with HIV and HCV, or for people whose hepatitis C did not respond to previous treatment or responded but subsequently relapsed. The Committee heard from the clinical specialist that it would be unethical to conduct trials without an active comparator arm for these groups, and therefore the Committee should consider the use of sustained virological response rates from trials that had an active comparator to be appropriate for these subgroups. The Committee agreed that using the results from trials that had an active comparator to derive data on clinical effectiveness for the economic model was appropriate. The Committee discussed the assumption that people who receive best supportive care for chronic hepatitis C will not have a sustained virological response. The clinical specialist stated that sustained virological response rates are generally extremely low for people not receiving active therapy. The Committee concluded that it was therefore reasonable to assume that people who receive best supportive care do not achieve a sustained virological response. The Committee heard from the patient experts that many people with chronic hepatitis C would be willing to tolerate the adverse effects of treatment with peginterferon alfa, with or without ribavirin, for the longest available treatment period to increase their chance of achieving a sustained virological response or to reduce the possibility of relapse following treatment, even if they knew that a shortened course of treatment may be associated with fewer adverse events. The Committee acknowledged that some people prefer to have a choice when considering their treatment options. In response to comments received after consultation on the ACD, the Committee noted that the definition of undetectable serum HCV RNA (which denotes clearing of HCV) varied between the clinical trials (see section 4.1.3). They acknowledged that different laboratories in the UK use different tests and set different thresholds to determine whether a virus is undetectable, and that the quality of the test used may influence treatment decisions. The Committee therefore agreed that a highly sensitive test should be used to detect serum HCV RNA, to minimise the chance of false negative results – that is, to minimise the chance that the test indicates the absence of virus, leading erroneously to a shortened course of treatment, when in fact virus is present. The Committee discussed the cost-effectiveness data presented by the manufacturers and the Assessment Group. The Committee noted that the Assessment Group adapted a previously published economic model, and that the model was structurally similar to those developed by the manufacturers, and used similar input parameters to model disease progression, health state costs and utility. The Committee noted that the model submitted by Roche Products may have overestimated the QALY gains from achieving a sustained virological response, because the model did not differentiate between mild and moderate hepatitis C and because age-specific utilities were applied to the sustained virological response state but not to other health states. The Committee considered that it was not appropriate for the model to apply age-specific utility values to only one health state, but concluded that the additional analysis carried out by the Assessment Group to correct for this issue was appropriate. The Committee was aware that the model from Schering-Plough for peginterferon alfa-2b assumed that a sustained virological response occurs at the beginning of a cycle rather than mid-cycle, and that the same utility values for a sustained virological response were used irrespective of the stage of disease when treatment starts. The Committee was satisfied that the additional analyses carried out by the Assessment Group corrected for these issues and did not substantially alter the results. The Committee considered the cost effectiveness of peginterferon alfa and ribavirin combination therapy for the three populations covered by this appraisal. For people with HCV genotype 1, a baseline low viral load and a rapid virological response, the Committee noted that the shortened treatment duration of 24 weeks with peginterferon alfa-2a plus ribavirin was associated with a reduction in both QALYs and costs compared with the standard treatment duration of 48 weeks, resulting in ICERs that reflected 'savings per QALY lost' (ranging from £34,500 to £64,900 per QALY). The Committee considered situations where an ICER is derived from decreased effectiveness and decreased costs, and concluded that the commonly assumed decision rule of accepting ICERs below a given threshold is reversed, and so ICERs that are above the threshold are considered acceptable in this case. The Committee also noted that for people with genotype 1 who had a low viral load and a rapid virological response, the shortened treatment duration of 24 weeks with peginterferon alfa-2b plus ribavirin dominated the standard treatment duration of 48 weeks. Similarly, for people with HCV genotype 2 or 3, a baseline low viral load and a rapid virological response, the shortened treatment duration of 16 weeks with peginterferon alfa-2a plus ribavirin dominated the standard treatment duration of 24 weeks. Based on these ICERs, the Committee concluded that shortened courses of peginterferon alfa (2a or 2b) and ribavirin combination therapy represent a cost-effective use of NHS resources for people eligible for this treatment regimen. The Committee noted that the cost effectiveness results also indicated that standard treatment durations were not likely to be considered cost effective compared with shortened treatment durations. Since the shortened and standard treatment durations are considered to be clinically comparable (see section 4.3.2), the Committee concluded that shortened treatment courses should be recommended rather than recommended as an option. However, the Committee was aware that shortened treatment courses are not suitable for all people. The Committee highlighted that when considering a shortened treatment course, clinicians should take into account the licensed indication of the chosen drug (peginterferon alfa-2a or peginterferon alfa-2b), the HCV genotype, the viral load at the start of treatment and the response to treatment (as indicated by the viral load). The Committee then discussed whether peginterferon alfa (2a or 2b) plus ribavirin should be recommended for people who have been treated previously with peginterferon alfa (2a or 2b) and ribavirin in combination, or with peginterferon alfa monotherapy, and whose condition either did not respond to treatment or responded initially to treatment but subsequently relapsed. The Committee concluded that the analysis that incorporates an early stopping rule at 12 weeks for people who do not show an early virological response, as specified in the marketing authorisation, was the most appropriate scenario forming the basis of the cost-effectiveness analysis (see section 4.2.24). The Committee noted that the Assessment Group's analysis for people re-treated with peginterferon alfa plus ribavirin resulted in ICERs below £10,000 per QALY gained for people with HCV genotypes 1 and 4, and re-treatment dominated best supportive care for people with HCV genotypes 2 and 3. The Committee then considered the cost-effectiveness estimates for the subgroup of people with HIV and HCV co-infection. The Committee noted that in the Assessment Group's analysis for people co-infected with HCV and HIV who were receiving peginterferon alfa (2a or 2b) plus ribavirin, either all ICERs were below £12,000 per QALY gained or treatment dominated best supportive care. The Committee concluded that the ICERs presented in the base-case analysis by the Assessment Group were plausible for both the subgroup of people being re-treated and the subgroup of people co-infected with HCV and HIV. Based on these ICERs, the Committee was satisfied that peginterferon alfa (2a or 2b) and ribavirin combination therapy represents a cost-effective use of NHS resources both for people who have been treated previously and whose condition either did not respond to treatment or responded initially to treatment but subsequently relapsed, and for people with HIV and HCV co-infection. # Summary of Appraisal Committee's key conclusions TA200 (MTA part review) Appraisal title: Peginterferon alfa and ribavirin for the treatment of chronic hepatitis C (part review of technology appraisal guidance 75 and 106) Section Key conclusions Combination therapy with peginterferon alfa (2a or 2b) and ribavirin is recommended as a treatment option for adults with chronic hepatitis C: who have been treated previously with peginterferon alfa (2a or 2b) and ribavirin in combination, or with peginterferon alfa monotherapy, and whose condition either did not respond to treatment or responded initially to treatment but subsequently relapsed or who are co-infected with HIV. Shortened courses of combination therapy with peginterferon alfa (2a or 2b) and ribavirin are recommended for the treatment of adults with chronic hepatitis C who: have a rapid virological response to treatment at week 4 that is identified by a highly sensitive test and are considered suitable for a shortened course of treatment. Current practice Clinical need of patients including the availability of alternative treatments Clinical practice for the use of these technologies is described in NICE technology appraisal guidance 75 and 106. This appraisal addresses extensions to the marketing authorisations. The technology Proposed benefits of the technology How innovative is the technology in its potential to make a significant and substantial impact on health-related benefits? Not applicable (this is a review of established technologies). What is the position of the treatment in the pathway of care for the condition? This guidance updates and replaces: section 1.2, bullet 3 only, of TA75 section 1.4 of TA75 for adults who are eligible for shortened courses of combination therapy (as described in section 1.2 of the current guidance) section 1.7, bullet 1 only, of TA75 sections 1.4 and 1.5 of TA106. All other recommendations in TA75 and TA106 still stand. Adverse effects The Committee heard from the patient experts that many people with chronic hepatitis C would be willing to tolerate the adverse effects of treatment with peginterferon alfa, with or without ribavirin, for the longest available treatment period to increase their chance of achieving a sustained virological response or to reduce the possibility of relapse following treatment, even if they knew that a shortened course of treatment may be associated with fewer adverse events. Evidence for clinical effectiveness Availability, nature and quality of evidence RCT evidence was available for shortened treatment courses. No RCTs were identified that compared peginterferon alfa (with or without ribavirin) with best supportive care for people co-infected with HIV and HCV, or for people whose hepatitis C did not respond to previous treatment or responded but subsequently relapsed. The Committee agreed that it was appropriate to use results from trials that had an active comparator to derive data on clinical effectiveness for the economic model. Relevance to general clinical practice in the NHS The clinical specialist stated that sustained virological response rates are generally extremely low for people not receiving active therapy. The Committee concluded that it was therefore reasonable to assume that people who receive best supportive care do not achieve a sustained virological response. The Committee noted that the definition of undetectable serum HCV RNA (which denotes clearing of HCV) varied between the clinical trials, and therefore that the quality of the test used may influence treatment decisions. The Committee therefore agreed that a highly sensitive test should be used to detect serum HCV RNA, to minimise the chance of false negative results. Uncertainties generated by the evidence There were no major uncertainties generated by the evidence. Are there any clinically relevant subgroups for which there is evidence of differential effectiveness? Not applicable. Estimate of the size of the clinical effectiveness including strength of supporting evidence The Committee was aware from the evidence presented that there were no statistically significant differences in sustained virological response rates between subgroups receiving shortened and standard courses of treatment with peginterferon alfa plus ribavirin. The Committee heard from the clinical specialist that, although some trials have reported that people who received shortened courses of treatment had (non-significant) lower sustained virological response rates, using shortened rather than standard courses of therapy was not expected to have clinical implications. Therefore the Committee concluded that shortened and standard treatment durations could be viewed as clinically comparable. Evidence for cost effectiveness Availability and nature of evidence Cost effectiveness data were presented by the manufacturers and the Assessment Group. The Committee noted that the Assessment Group adapted a previously published economic model, and that the model was structurally similar to those developed by the manufacturers, and used similar input parameters to model disease progression, health state costs and utility. Uncertainties around and plausibility of assumptions and inputs in the economic model There were no material uncertainties around the assumptions and inputs in the economic models presented. The Committee noted that the model submitted by Roche Products may have overestimated the QALY gains from achieving a sustained virological response, because the model did not differentiate between mild and moderate hepatitis C and because age-specific utilities were applied to the sustained virological response state but not to other health states. The Committee considered that it was not appropriate for the model to apply age-specific utility values to only one health state, but concluded that the additional analysis carried out by the Assessment Group to correct for this issue was appropriate. The Committee was aware that the model from Schering-Plough for peginterferon alfa-2b assumed that a sustained virological response occurs at the beginning of a cycle rather than mid-cycle, and that the same utility values for a sustained virological response were used irrespective of the stage of disease when treatment starts. The Committee was satisfied that the additional analyses carried out by the Assessment Group corrected for these issues and did not substantially alter the results. Incorporation of health-related quality of life benefits and utility values Have any potential significant and substantial health-related benefits been identified that were not included in the economic model, and how have they been considered? No potential significant and substantial health-related benefits were identified that were not included in the economic models. Are there specific groups of people for whom the technology is particularly cost-effective? Not applicable. Most likely cost-effectiveness estimate (given as an ICER) For people with HCV genotype 1, a baseline low viral load and a rapid virological response, the Committee noted that the shortened treatment duration of 24 weeks with peginterferon alfa-2a plus ribavirin was associated with a reduction in both QALYs and costs compared with the standard treatment duration of 48 weeks, resulting in ICERs that reflected 'savings per QALY lost' (ranging from £34,500 to £64,900 per QALY). The Committee considered situations where an ICER is derived from decreased effectiveness and decreased costs, and concluded that the commonly assumed decision rule of accepting ICERs below a given threshold is reversed, and so ICERs that are above the threshold are considered acceptable in this case. The Committee also noted that for people with genotype 1 who had a low viral load and a rapid virological response, the shortened treatment duration of 24 weeks with peginterferon alfa-2b plus ribavirin dominated the standard treatment duration of 48 weeks. Similarly, for people with HCV genotype 2 or 3, a baseline low viral load and a rapid virological response, the shortened treatment duration of 16 weeks with peginterferon alfa-2a plus ribavirin dominated the standard treatment duration of 24 weeks. The Committee noted that the Assessment Group's analysis for people re-treated with peginterferon plus ribavirin resulted in ICERs below £10,000 per QALY gained for people with HCV genotypes 1 and 4, and re-treatment dominated best supportive care for people with HCV genotypes 2 and 3. The Committee noted that in the Assessment Group's analysis for people co-infected with HCV and HIV who were receiving peginterferon alfa (2a or 2b) plus ribavirin, either all ICERs were below £12,000 per QALY gained or treatment dominated best supportive care. The Committee concluded that the ICERs presented in the base-case analysis by the Assessment Group were plausible for both the subgroup of people being re-treated and the subgroup of people co-infected with HCV and HIV. Additional factors taken into account Patient access schemes (Pharmaceutical Price Regulation Scheme ) None received. End-of-life considerations Not applicable to this appraisal. Equalities considerations, social value judgements No issues relating to equality were raised at any stage during the development of this appraisal. –# Related NICE guidance Peginterferon alfa and ribavirin for the treatment of mild chronic hepatitis C (extension of technology appraisal guidance 75). NICE technology appraisal guidance 106 (2006). Interferon alfa (pegylated and non-pegylated) and ribavirin for the treatment of chronic hepatitis C (review and extension of technology appraisal guidance 14).NICE technology appraisal guidance 75 (2004).# Review of guidance The guidance on these technologies will be considered for review by the Guidance Executive in July 2013. The Guidance Executive will decide whether the technologies should be reviewed based on information gathered by NICE, and in consultation with consultees and commentators. Andrew DillonChief ExecutiveSeptember 2010# Changes after publication February 2014: implementation section updated to clarify that peginterferon alfa and ribavirin is recommended as an option for treating chronic hepatitis C. Additional minor maintenance update also carried out. March 2012: minor maintenance# About this guidance NICE technology appraisal guidance is about the use of new and existing medicines and treatments in the NHS in England and Wales. This guidance was developed using the NICE multiple technology appraisal process. This guidance should be read in conjunction with the following NICE guidance: NICE technology appraisal guidance 75 (TA75) 'Interferon alfa (pegylated and non-pegylated) and ribavirin for the treatment of chronic hepatitis C' (which covers moderate to severe hepatitis C) NICE technology appraisal guidance 106 (TA106) 'Peginterferon alfa and ribavirin for the treatment of mild chronic hepatitis C'. This appraisal addresses extensions to the marketing authorisations for peginterferon alfa-2a and peginterferon alfa-2b. This guidance updates and replaces: section 1.2, bullet 3 only, of TA75 section 1.4 of TA75 for adults who are eligible for shortened courses of combination therapy (as described in section 1.2 of the current guidance) section 1.7, bullet 1 only, of TA75 sections 1.4 and 1.5 of TA106. All other recommendations in TA75 and TA106 still stand. We have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available. Your responsibility This guidance represents the views of NICE and was arrived at after careful consideration of the evidence available. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. However, the guidance does not override the individual responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or guardian or carer. Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties. Copyright © National Institute for Health and Clinical Excellence 2010. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.	{'Guidance': "This guidance should be read in conjunction with the following NICE guidance:\n\nNICE technology appraisal guidance 75 (TA75) 'Interferon alfa (pegylated and non-pegylated) and ribavirin for the treatment of chronic hepatitis C' (which covers moderate to severe hepatitis C)\n\nNICE technology appraisal guidance 106 (TA106) 'Peginterferon alfa and ribavirin for the treatment of mild chronic hepatitis C'.\n\nThis appraisal addresses extensions to the marketing authorisations for peginterferon alfa-2a and peginterferon alfa-2b. This guidance updates and replaces:\n\nsection 1.2, bullet 3 only, of TA75\n\nsection 1.4 of TA75 for adults who are eligible for shortened courses of combination therapy (as described in section 1.2 of the current guidance)\n\nsection 1.7, bullet 1 only, of TA75\n\nsections 1.4 and 1.5 of TA106.\n\nAll other recommendations in TA75 and TA106 still stand.\n\nCombination therapy with peginterferon alfa (2a or 2b) and ribavirin is recommended as a treatment option for adults with chronic hepatitis C:\n\nwho have been treated previously with peginterferon alfa (2a or 2b) and ribavirin in combination, or with peginterferon alfa monotherapy, and whose condition either did not respond to treatment or responded initially to treatment but subsequently relapsed or\n\nwho are co-infected with HIV.\n\nShortened courses of combination therapy with peginterferon alfa (2a or 2b) and ribavirin are recommended for the treatment of adults with chronic hepatitis C who:\n\nhave a rapid virological response to treatment at week 4 that is identified by a highly sensitive test and\n\nare considered suitable for a shortened course of treatment.\n\nWhen deciding on the duration of combination therapy, clinicians should take into account the licensed indication of the chosen drug (peginterferon alfa-2a or peginterferon alfa-2b), the genotype of the hepatitis C virus, the viral load at the start of treatment and the response to treatment (as indicated by the viral load).", 'Clinical need and practice': "Hepatitis C is an infectious disease of the liver caused by the hepatitis C virus (HCV). The virus is acquired primarily through percutaneous exposure to contaminated blood. People infected with HCV are often asymptomatic, but about 20% develop acute hepatitis. In approximately 80% of people who are infected, the virus is not cleared and they go on to develop chronic hepatitis C. Chronic hepatitis C is categorised as mild, moderate or severe depending on the extent of liver damage. The rate of progression from mild to severe disease is slow but variable, taking about 20 to 50 years from the time of infection. About 30% of infected people develop cirrhosis within 20 to 30 years, and some of these develop hepatocellular carcinoma. Some people with end-stage liver disease or hepatocellular carcinoma may require liver transplantation.\n\nEstimates from the Health Protection Agency suggest that approximately 142,000 people between the ages of 15 and 59\xa0years had chronic HCV infection in England and Wales in 2003, a prevalence of 0.44% in this age group. The prevalence of chronic HCV infection varies by sex and age, and it is most common in men and in people aged 25 to 44 years. In 2007, the number of confirmed new HCV infections in England and Wales was 7540.\n\nSix genetic types of HCV, known as genotypes, have been found. Genotype 1 is the most common in the UK, accounting for about 40% to 50% of those infected with HCV. Genotypes 2 and 3 together contribute another 40% to 50%, while genotypes 4, 5 and 6 account for the remaining infections. In England and Wales, genotypes 1 and 3 represent more than 90% of all diagnosed HCV infections.\n\nThe primary aim of treatment is to clear the virus from the blood. Successful treatment is usually indicated by a sustained virological response, which is defined as undetectable serum HCV RNA 6\xa0months after the end of treatment. A sustained virological response is considered to indicate permanent resolution of infection, although relapse may occur in approximately 5% of people after 5 years.\n\nPrevious NICE guidance (TA106 and TA75) recommends combination therapy with ribavirin and either peginterferon alfa-2a or peginterferon alfa-2b for adults with chronic hepatitis C. The previous guidance also recommends that monotherapy with peginterferon alfa-2a or peginterferon alfa-2b should be used only by people who are unable to tolerate ribavirin or for whom ribavirin is contraindicated. The recommended duration of treatment is 24 or 48 weeks depending on a combination of factors, including the HCV genotype, the viral load at the start of treatment and whether a person has a rapid virological response to treatment. For people with mild HCV infection, the person and their clinician should decide whether to treat immediately or adopt an approach of 'watchful waiting' (see TA106). The use of peginterferon alfa and ribavirin combination therapy is also considered suitable for people who are co-infected with HCV and HIV, unless it is contraindicated.\n\nApproximately 75% to 85% of people with moderate or severe infection with HCV genotype 2 or 3 have a sustained virological response 6\xa0months after finishing a course of treatment with peginterferon alfa plus ribavirin. The proportion of people with HCV genotype 1 who show a sustained virological response after the end of treatment is about 40% to 50%, while for the other genotypes (4, 5 and 6) the proportion is generally reported to be between 50% and 75%. Clinical advice indicates that a substantial proportion of people treated in specialist clinics in England and Wales have had previous treatment, but their condition has not responded or has relapsed.", 'The technologies': "# Peginterferon alfa-2a\n\nPeginterferon alfa-2a (Pegasys, Roche Products) has a UK marketing authorisation for 'the treatment of chronic hepatitis C in adult patients who are positive for serum HCV-RNA, including patients with compensated cirrhosis and/or who are co-infected with clinically stable HIV'. The preferred treatment regimen is in combination with ribavirin, but monotherapy is indicated in cases of intolerance or contraindication to ribavirin. Patients may not have been previously treated or their condition may have not responded to previous treatment with interferon alfa (pegylated or non-pegylated) alone or in combination with ribavirin. The recommended dose is 180\xa0micrograms once a week, administered subcutaneously, for 16, 24 or 48 weeks depending on HCV genotype, baseline viral load and response to treatment. The recommended duration of peginterferon alfa-2a monotherapy is 48\xa0weeks.\n\nWhen peginterferon alfa-2a is given in combination with ribavirin, people with HCV genotype 1 or 4 infections who have detectable HCV RNA at week 4 (that is, there is not a rapid virological response) should receive 48 weeks of treatment. People with genotype 2 or 3 infections and undetectable HCV RNA at week 4 (that is, a rapid virological response) should receive 24 weeks of treatment.\n\nAn extension to the licence for peginterferon alfa-2a now means that some people with hepatitis C are eligible for shortened courses of treatment. People with HCV genotype 1 and a low viral load (equal to or less than 800,000 IU/ml) at the start of treatment, a rapid virological response at week 4 and undetectable HCV RNA at week 24 may complete treatment at week 24 rather than receiving the standard 48\xa0weeks of therapy. The licence extension also allows people with HCV genotype 2 or 3 who have a low viral load (equal to or less than 800,000 IU/ml), undetectable HCV RNA by week 4 (that is, a rapid virological response) and undetectable HCV RNA at week 16 to stop treatment at week 16 rather than receiving the standard 24\xa0weeks of therapy. People with HCV genotype 4 may be treated in line with the regimen for people with genotype 1, but without requiring a low viral load. People with genotype 5 or 6 should be treated for 48 weeks. People co-infected with HIV should also be treated for 48 weeks, regardless of genotype.\n\nRe-treatment with peginterferon alfa-2a plus ribavirin may be offered to people whose hepatitis C has not shown an adequate response to treatment (non-response) or has responded but subsequently relapsed. Re-treated people should receive 48\xa0weeks of treatment unless HCV RNA is still detectable at week 12, in which case treatment should be stopped. People with HCV genotype 1 whose condition has not responded to prior treatment with peginterferon alfa and ribavirin combination therapy and who are considered for re-treatment should receive 72\xa0weeks of combination therapy.\n\nA weekly course of treatment with peginterferon alfa-2a (180\xa0micrograms) costs £126.91 (excluding VAT; British national formulary [BNF] edition 59). Costs may vary in different settings because of negotiated procurement discounts.\n\n# Peginterferon alfa-2b\n\nPeginterferon alfa-2b (ViraferonPeg, Schering-Plough) has a UK marketing authorisation for 'the treatment of adult patients with chronic hepatitis C who are positive for HCV-RNA, including patients with compensated cirrhosis and/or co-infected with clinically stable HIV'. The preferred treatment regimen is in combination with ribavirin, but monotherapy with peginterferon alfa-2b is indicated in cases of intolerance or contraindication to ribavirin. Patients may not have been treated previously or their condition may have not responded to previous treatment with interferon alpha (pegylated or non-pegylated) in combination with ribavirin or interferon alfa monotherapy.\n\nThe recommended dose of peginterferon alfa-2b is 1.5\xa0micrograms/kg body weight once a week, administered subcutaneously, for 24 or 48 weeks depending on HCV genotype, viral load at the start of treatment and response to treatment. People with HCV genotype 1 who have undetectable HCV RNA at week 12 (that is, who have an early virological response) should receive 48 weeks of treatment with peginterferon alfa-2b. People with a genotype 1 infection without an early virological response are considered unlikely to have a sustained virological response, and consideration should be given to withdrawing treatment. People with HCV genotype 4 should be treated with the same regimen as for genotype 1 infections. People with HCV genotype 2 or 3 infections should be treated for 24 weeks. People co-infected with HIV should be treated for 48 weeks regardless of HCV genotype.\n\nFollowing a licence extension for peginterferon alfa-2b, some people with hepatitis C are eligible for shortened courses of treatment. People with HCV genotype 1 and a low viral load (below 600,000 IU/ml) at the onset of treatment and who have undetectable HCV RNA at both week 4 and week 24 of treatment can stop treatment at 24 weeks. The marketing authorisation notes that a shortened course of 24 weeks of treatment may be associated with a higher risk of relapse than if treatment is given for 48 weeks. The marketing authorisation does not permit shorter treatment durations for people with HCV genotype 2 or 3 infections.\n\nRe-treatment with peginterferon alfa-2b in combination with ribavirin is recommended in the marketing authorisation for people whose hepatitis C has not shown an adequate response to treatment (non-response) or has responded but subsequently relapsed. All people re-treated with peginterferon alfa-2b, irrespective of HCV genotype, who have undetectable serum HCV RNA at week 12 should receive 48 weeks of treatment. People re-treated with peginterferon alfa-2b in whom HCV RNA is still detectable at week 12 are unlikely to have a sustained virological response after 48\xa0weeks of therapy.\n\nA weekly course of peginterferon alfa-2b (average of 120\xa0micrograms) costs £162.60 (excluding VAT; BNF 59). Costs may vary in different settings because of negotiated procurement discounts.\n\n# Ribavirin\n\nTwo forms of ribavirin (Copegus, Roche Products; Rebetol, Schering-Plough) are currently available. Each product is indicated for the treatment of chronic hepatitis C and must be used only as part of a combination regimen with peginterferon alfa or interferon alfa. Ribavirin monotherapy must not be used. Each product is licensed for use only in combination with the interferon products made by the same manufacturer. The recommended doses of ribavirin range from 800\xa0to 1400\xa0milligrams, depending on body weight. The dose of Copegus also varies according to HCV genotype: 800\xa0milligrams per day for genotype 2 or 3 infections and 1000 or 1200\xa0milligrams per day for genotype 1, 4, 5 or 6 infections (1000\xa0milligrams for body weights below 75 kg and 1200\xa0milligrams for body weights of 75 kg or more). Both forms of ribavirin are taken orally each day in two divided doses.\n\nThe weekly cost of Copegus is £111 for HCV genotype 1 infections (based on 1200 milligrams per day for an average body weight of 79\xa0kg) and £74 for HCV genotype 2 or 3 infections (based on 800\xa0milligrams per day). The weekly cost of Rebetol is £68, based on 1000 milligrams per day for an average body weight of 79\xa0kg. Costs exclude VAT and are from BNF 59. Costs may vary in different settings because of negotiated procurement discounts.\n\n# Costs of combination treatment\n\nThe cost of treatment with peginterferon alfa-2a plus ribavirin (Copegus) is estimated to be £3215 for 16 weeks or £4824 for 24 weeks of therapy (for people with genotypes 2 or 3), or £11,425 for 48\xa0weeks of therapy (for people with genotypes 1 or 4). For people treated with peginterferon alfa-2b plus ribavirin (Rebetol), the cost is £5540 for 24 weeks or £11,081 for 48 weeks of therapy (for people with genotype 1). Acquisition costs are from BNF 59. Costs may vary in different settings because of negotiated procurement discounts.\n\n# Adverse effects of treatment\n\nThe most common adverse effects associated with peginterferon-based anti-viral treatments include influenza-like symptoms such as headache, fatigue and fever, as well as insomnia, anorexia, dermatological symptoms, nausea, vomiting and depression. The adverse effects of anti-viral treatment for HCV, notably depression, may be more pronounced in people co-infected with HIV. For full details of adverse effects and contraindications, see the summaries of product characteristics.", 'Evidence and interpretation': "The Appraisal Committee (appendix A) considered evidence from a number of sources (appendix B).\n\n# Clinical effectiveness\n\nThe Assessment Group performed a systematic review to identify randomised controlled trials (RCTs) evaluating the clinical effectiveness of peginterferon alfa plus ribavirin for the treatment of chronic hepatitis C in three specific groups:\n\npeople eligible for shortened treatment courses\n\npeople eligible for re-treatment following previous non-response or relapse of their condition\n\npeople co-infected with HCV and HIV.Included in the review were studies in which a standard duration of combination therapy with peginterferon alfa plus ribavirin (or peginterferon monotherapy for people with contraindications to ribavirin) was compared with courses of combination therapy of a shortened duration (24 weeks for people with HCV genotype 1 treated with either peginterferon alfa-2a or -2b; 16\xa0weeks for people with HCV genotype 2 or 3 treated with peginterferon alfa-2a only). The review also attempted to identify studies in which treatment was compared with best supportive care for subgroups that were co-infected with HIV or were being re-treated. Clinical outcomes included measures of virological response during and after treatment, and adverse effects.\n\nSix RCTs reported in eight publications were identified, all of which reported on peginterferon alfa and ribavirin combination therapy in people eligible for shortened courses of treatment. No studies were found that compared treatment with peginterferon alfa (with or without ribavirin) with best supportive care for people co-infected with HIV and HCV or for people whose hepatitis C had not responded to previous treatment or had responded but subsequently relapsed.\n\n## Shortened treatment courses\n\nOf the six trials, four evaluated the effect of shortened treatment courses with peginterferon alfa plus ribavirin for people with HCV genotype 1 infections, while the other two trials evaluated the effect for people with genotype 2 or 3 infections. No trials assessed the effect of shortened treatment courses for people with genotype 4 infections. Five of the trials included people with a low viral load at the start of treatment. The comparator in all included studies was the same intervention for a standard duration of treatment. The dose of peginterferon alfa-2a was 180\xa0micrograms per week and the dose of peginterferon alfa-2b was 1.5 micrograms per kg per week in all trials. All six RCTs reported sustained virological response rates as the primary outcome measure. A sustained virological response was defined as undetectable serum HCV RNA at the end of 24\xa0weeks' follow-up in four trials, and as undetectable serum HCV RNA at the end of treatment and at the end of follow-up in the other two trials. In many of the trials the sustained virological response rates were presented for subgroups of people who had been randomised and who achieved a rapid virological response. It was not reported whether these subgroups were powered to detect a statistically significant difference\xa0between trial arms. A rapid virological response was defined as an undetectable serum concentration of HCV RNA (25\xa0IU/ml or less) in one trial, serum HCV RNA negative (50 IU/ml or less) in three trials, serum HCV RNA of 600 IU/ml or less in one trial, and serum HCV RNA of 650\xa0IU/ml or less in one trial, all at week 4 of treatment.\n\nIn people with a low viral load (800,000 IU/ml or less) who attained a rapid virological response up to and including week 4 of treatment, sustained virological response rates were comparable between the group that received 48 weeks (standard duration) of treatment (range 83% to 100%) and the group that received shortened treatment courses (range 84% to 96%), with no statistically significant differences between the groups. Regardless of HCV genotype, sustained virological response rates were similar across studies, with the exception of one trial that reported lower rates.\n\nIn two of the trials of peginterferon alfa-2a plus ribavirin, the ribavirin dose was varied according to body weight, which is no longer consistent with its marketing authorisation. The marketing authorisation specifies that ribavirin should be given as a fixed dose of 800\xa0milligrams in people with HCV genotype 2 or 3, and both trials assessed the effectiveness of treatment only in people with HCV genotype 2 or 3 infections. The Assessment Group noted that if these two trials had been excluded on the basis of the variable ribavirin dosages, there would have been no evidence on the impact of shortened treatment durations in people with HCV genotype 2 or 3 infections.\n\nRapid virological response rates were comparable between the groups that received the standard duration of treatment and those that received shortened courses. However, there was a large range in reported rapid virological response rates between the studies, with rates in people with HCV genotype 2 or 3 infections generally being higher than those in people with genotype 1 infections.\n\nThe relapse rate in a subgroup of people with a low viral load and a rapid virological response was reported in one trial. Relapse was defined as the re-appearance of serum HCV RNA during the 24-week follow-up period in people whose condition initially responded to treatment. The rates of relapse were low and were not statistically significantly different between the treatment arms (3.6% for 24\xa0weeks of treatment versus 0% for 48 weeks of treatment; p\xa0=\xa01.00). In contrast, in people with a high viral load at start of treatment and a rapid virological response later, shortening the duration of treatment was associated with a statistically significant higher rate of relapse (23.5% for 24\xa0weeks versus 0% for 48\xa0weeks; p\xa0=\xa00.045).\n\nAdverse events were presented for treatment groups as a whole, and not for the subgroup of people with a low viral load who had a rapid virological response. Overall, the frequency of adverse events did not differ statistically between treatment arms, although a lower incidence of adverse events was reported in three trials in people treated for a shorter duration with combination therapy. The most frequently occurring adverse events included influenza-like symptoms, insomnia, anorexia, dermatological symptoms and alopecia.\n\nThe cumulative incidence of serious adverse events ranged from 0% to 7% over the duration of the trials, and was not considered to be substantially different between treatment arms, although levels of statistical significance were lacking in most studies. One death was reported, which was a result of re-activation of pulmonary tuberculosis at week 36 of treatment in a person who was treated with peginterferon alfa-2a plus ribavirin. One trial reported that people receiving a shortened treatment regimen were less likely to discontinue their treatment than people receiving longer courses (3% versus 10%; p\xa0=\xa00.045).\n\n## Re-treatment after non-response or relapse\n\nThe Assessment Group did not identify any RCTs that compared treatment with peginterferon alfa (with or without ribavirin) with best supportive care for people whose hepatitis C had not responded to previous treatment or had responded but subsequently relapsed. The Assessment Group did identify a number of RCTs comparing treatment with peginterferon alfa (with or without ribavirin) with active treatment comparators (such as non-peginterferon alfa plus ribavirin), but these did not meet the inclusion criteria for the review (based on the decision problem) because they featured an active treatment comparator. However, the Assessment Group assumed in its economic model (see section 4.2) that the sustained virological response rates for people whose condition did not respond or responded but subsequently relapsed on peginterferon alfa therapy were those reported in the clinical trials that used an active comparator. The Assessment Group noted that these reported sustained virological response rates may not be representative of people with relapsed disease because the trial participants with HCV genotype 1 infections had less intensive initial treatment than what would be regarded as standard treatment.\n\n## HCV and HIV co-infection\n\nThe Assessment Group did not identify any RCTs that compared treatment with peginterferon alfa (with or without ribavirin) with best supportive care for people with HCV and HIV co-infection. A number of RCTs were identified that compared peginterferon alfa (with or without ribavirin) with active treatment comparators (such as non-peginterferon alfa plus ribavirin) for this subgroup, but these did not meet the inclusion criteria for the review because they featured an active treatment comparator. The Assessment Group noted that it is unlikely that any studies, whether randomised or not, would be available that include a non-active treatment arm, because withholding treatment would be unlikely to be considered ethical.\n\n## Summary of clinical-effectiveness evidence\n\nThe collective evidence for combination therapy for both peginterferon alfa-2a and peginterferon alfa-2b suggests that there are no statistically significant differences in sustained virological response rates between people receiving shortened durations of treatment with peginterferon alfa plus ribavirin of 16 weeks (HCV genotype 2 or 3; peginterferon alfa-2a) or 24 weeks (HCV genotype\xa01; both peginterferon alfa-2a and alfa-2b) and people receiving the standard duration of treatment. Rates of relapse following a shortened course of treatment were reported to be low and not statistically significantly different from relapse rates after a standard course of treatment in people with a rapid virological response and low viral load. For people with a rapid virological response and a high viral load, shortening the duration of treatment may be associated with a higher rate of relapse. However, the Assessment Group noted that analyses of sustained virological responses in people with a low viral load at the start of treatment and a rapid virological response are likely to be underpowered because they were based on subgroups of the randomised participants, and therefore the results should be interpreted with caution. No RCTs were identified that compared peginterferon alfa (with or without ribavirin) with best supportive care for people who were re-treated after non-response or relapse of their condition, or for people with HCV and HIV co-infection.\n\n# Cost effectiveness\n\nThe Assessment Group identified two studies examining the cost effectiveness of the treatment of people co-infected with HCV and HIV. The studies compared peginterferon alfa plus ribavirin with non-peginterferon plus ribavirin, peginterferon alfa monotherapy and no treatment (supportive care). One study also had an additional non-peginterferon alfa monotherapy arm. No economic evaluations were identified for people requiring re-treatment following previous non-response or relapse, or for people eligible for shortened courses of treatment.\n\nIn both studies of people co-infected with HCV and HIV, peginterferon alfa monotherapy or peginterferon alfa plus ribavirin dominated (that is, treatment was more effective and less costly) the other strategies in people with HCV genotype 1. In one study, peginterferon alfa monotherapy was the most favourable option in each scenario. For people with other HCV genotypes (that is, not genotype 1), peginterferon alfa plus ribavirin was the least favourable option in one study (incremental cost-effectiveness ratios [ICERs] of $300,800 to $4,000,000 per quality-adjusted life year [QALY] gained). In the second study peginterferon alfa plus ribavirin dominated the other strategies for all genotypes reported. The incremental costs per life year saved (LYS) for peginterferon alfa plus ribavirin in people with HCV genotypes other than genotype 1 were $39,300/LYS in women and $39,700/LYS in men and $70,000/LYS in women and $73,000/LYS in men in people with genotype 1).\n\n## Manufacturers' models\n\nA health state transition model submitted by Roche Products was used to assess the cost effectiveness of treatment with peginterferon alfa-2a plus ribavirin in three groups: people who had been treated previously with peginterferon alfa plus ribavirin, including those whose hepatitis C did not respond to this previous treatment (by HCV genotype) and those whose condition responded but then relapsed; people with a low viral load and a rapid virological response who received shortened courses of peginterferon alfa plus ribavirin (by genotype); and people co-infected with HCV and HIV.\n\nThe model used clinical-effectiveness data from published RCTs, although evidence of effectiveness for shortened treatment courses was derived from subgroup analyses. For people receiving shortened treatment courses, the sustained virological response rates for both groups in the model were taken from unpublished analyses of subgroups of clinical trial participants. For the subgroups with HCV genotypes 2 and 3 the data were taken from the ACCELERATE study reported by Shiffman and colleagues, and for the genotype 1 and 4 subgroups the data were taken from a trial reported by Hadziyannis and colleagues (study NV15942).\n\nA number of the clinical-effectiveness studies used by the manufacturer to obtain data for the economic model (namely for people who had been re-treated or had HIV co-infection) had active comparators, rather than comparing treatment with best supportive care (as outlined in the decision problem). For people with HCV and HIV co-infection, data on sustained virological response rates were taken from a clinical trial comparing non-peginterferon alfa-2a with peginterferon alfa-2a, which is not consistent with the scope for this appraisal. For people whose hepatitis C did not respond or relapsed on previous peginterferon therapy, data on sustained virological response rates were taken from two clinical trials. In the majority of situations it was assumed that people receiving best supportive care would not achieve a spontaneous sustained virological response. No discussion or critical analysis of the reliability or generalisability of the clinical-effectiveness evidence used to populate the model was provided by the manufacturer.\n\nShortening the duration of treatment was associated with a QALY loss compared with the standard treatment duration (because of a slight reduction in the sustained virological response rate), as well as with a reduction in costs. Since both costs and outcomes were lower with shortened treatment duration, the ICERs represent savings per QALY lost. For people with HCV genotype 1 or 4 the ICER was £15,472 per QALY, and for people with genotype 2 or 3 the ICER was £2719 per QALY. The Assessment Group noted that when there are both lower costs and lower effectiveness, the analysis can be better understood by applying the net benefits framework. Using the net benefits framework, a treatment would be accepted when the value of the incremental benefits exceeds the incremental costs, resulting in a positive incremental net benefit. Using this framework, the incremental net monetary benefit for a shortened duration of treatment is positive for people with HCV genotype 1 or 4 over a wide range of willingness-to-pay values (below the ICER value of £15,472 per QALY). For people with HCV genotype 2 or 3 the incremental net monetary benefit is positive only at comparatively low threshold values (below the ICER value of £2719 per QALY).\n\nRe-treating people whose hepatitis C relapsed following previous peginterferon treatment was reported by the manufacturer as dominating best supportive care. This is the result of including a high sustained virological response rate observed in one trial that may not be generalisable to other populations of people whose condition relapses. The majority of people had HCV genotype 1 infections and their previous treatment was of shorter duration than the current standard of care (that is, 24 weeks rather than 48\xa0weeks). The sustained virological response rates applied in the model for the re-treatment of people whose hepatitis C had not responded to previous peginterferon treatment were lower than those for people whose condition had relapsed following treatment. Treatment was associated with QALY gains and increased costs compared with best supportive care, resulting in ICERs of £3334 per QALY gained for people with HCV genotype 1 and £809 per QALY gained for people with other genotypes. The majority of people recruited to the trial whose condition did not respond to previous peginterferon treatment had HCV genotype 1; only 29 were infected with other HCV genotypes (9% of the arm used to estimate the effectiveness of treatment in the model), and the majority (66%) of these had genotype 4 infections.\n\nFor people with HCV and HIV co-infection, treatment with peginterferon plus ribavirin was estimated to dominate treatment with non-peginterferon. However, this is not the comparison specified in the decision problem issued by NICE (where best supportive care was stated as the comparator). The Assessment Group extended the analysis by assuming that the sustained virological response rate for untreated people would be zero, and estimated a QALY gain (using the manufacturer's model) of 1.95 and an incremental cost of £1765 for peginterferon plus ribavirin compared with best supportive care, resulting in an ICER of £903 per QALY gained.\n\nThe Assessment Group thought that the cost-effectiveness results were generally robust to variations in the limited number of parameters included in a deterministic sensitivity analysis reported in the manufacturer's submission. Probabilistic sensitivity analyses were also conducted by the manufacturer, and included the majority of parameters in the model. Although appropriate probability distributions appear to have been used for the probabilistic sensitivity analyses, the Assessment Group noted that limiting the distributions for some inputs does not appear to make the best use of data reported in the submission. Moreover, the Assessment Group felt that the manufacturer's model did not adequately consider logical relationships and potential correlations between model inputs. Rather than reporting the probability of cost effectiveness at certain willingness-to-pay thresholds, the submission identified a maximum threshold of £15,000 for all analyses. Further analyses of the manufacturer's model undertaken by the Assessment Group generally resulted in less favourable ICERs, but did not substantially alter the conclusions from those in the manufacturer's submission.\n\nThe manufacturer presented cost-effectiveness results for three populations: people who had been treated previously with peginterferon and whose hepatitis C either did not respond to treatment or relapsed after treatment (broken down further by broad HCV genotype categories: genotypes 1 and 4 combined, and genotypes 2 and 3 combined) (data obtained from the EPIC3 clinical study report); and people co-infected with HCV and HIV (using effectiveness data from a trial reported by Laguno and colleagues). The manufacturer subsequently presented an analysis of the cost effectiveness of shortened compared with standard treatment durations for people with HCV genotype 1.\n\nModel-based economic evaluations were based on clinical data from the EPIC3 study (a multi-centre, non-randomised open-label uncontrolled study of re-treatment in people whose hepatitis C did not respond or relapsed after treatment) and from the study of Laguno and colleagues (a phase III open-label trial that recruited treatment-naïve [naïve to combination therapy] people with histologically verified liver disease, who were HIV-positive with controlled disease [for people with HCV and HIV co-infection]). As the included studies do not make the comparisons specified in the decision problem (that is, anti-viral treatment compared with best supportive care), the manufacturer assumed that people receiving best supportive care would not achieve a spontaneous sustained virological response. The model includes a low probability of a spontaneous sustained virological response for people with mild chronic hepatitis C, which is applied to the best supportive care and active treatment cohorts.\n\nThe manufacturer's model is structurally similar to that used in a previous assessment report for TA106. However, it does not distinguish between people achieving a sustained virological response from any of the treatment-eligible states (mild or moderate hepatitis C and compensated cirrhosis). The parameters reflecting natural history in the model are similar to those adopted in the previous assessment report (TA106), as are the health state utilities and health state costs (inflated from 2003/4 to 2007/8 costs using the HCHS Pay and Prices Index).\n\nRe-treating people whose hepatitis C did not respond or relapsed following previous interferon treatment was estimated to result in a QALY gain of 1.03 compared with best supportive care at an incremental cost of £4536, resulting in an ICER of £4387 per QALY gained. These results were reported for a combined cohort of people with HCV genotypes 1 and 4 (84% of total) and people with genotypes 2 and 3. Separate results were also reported for the two genotype subgroups: the ICERs were £7177 per QALY gained for people with genotypes 1 and 4, and £783 per QALY gained for people with genotypes 2 and 3. Separate subgroup analyses (not stratified by genotype) for people whose condition did not respond to treatment and for people whose condition relapsed following treatment were also presented which suggested that the QALY gain was higher for the non-response subgroup than for the relapse subgroup.\n\nFor a cohort of people (all HCV genotypes) co-infected with HCV and HIV, treatment with peginterferon plus ribavirin was estimated to result in a gain of 2.32 QALYs compared with best supportive care at an incremental cost of £2502, resulting in an ICER of £1077 per QALY gained. For people with genotypes 1 and 4 the ICER was estimated at £1637 per QALY gained, while for people with genotypes 2 and 3 the ICER was £403 per QALY gained.\n\nThe manufacturer also conducted an analysis of the subgroup of people eligible for a shortened treatment duration. The analysis demonstrated that a shortened treatment duration of 24 weeks dominated the standard treatment duration of 48 weeks for people with HCV genotype 1. The manufacturer noted that these results should be treated with caution, as there was a large numerical difference in the rapid virological response rates at week 4 between the patient groups (standard versus shortened treatment) in the clinical trial, despite the fact that they had received the same treatment up to this point.\n\nDeterministic sensitivity analyses provided by the manufacturer showed that the ICERs for both the re-treated and co-infected groups were sensitive to variations in the early virological response rate and the sustained virological response rate, as well as to changes in body weight (since the dosing regimens of both peginterferon alfa-2b and ribavirin were weight-based). In the re-treatment group the ICERs showed a small increase in response to changes in the distribution of disease severity within the group.\n\nProbabilistic sensitivity analyses were conducted by the manufacturer which included the majority of parameters in the model. The manufacturer performed probabilistic sensitivity analyses (for overall cohort and by genotype) for each group (re-treated and co-infected). The probabilistic sensitivity analysis indicated a high probability (over 90%) that treatment with peginterferon alfa-2b plus ribavirin is cost effective for all analyses at willingness-to-pay thresholds of both £20,000 and £30,000 per QALY gained.\n\nThe Assessment Group was concerned about the manufacturer's assumption that a person would achieve a sustained virological response immediately after treatment is given, and therefore accrue health benefits before entering the model. Furthermore, the Assessment Group did not consider that it was appropriate to apply the same utility values for a sustained virological response irrespective of the stage of disease when the treatment was given. Further analyses of the manufacturer's model undertaken by the Assessment Group generally resulted in less favourable ICERs, but did not substantially alter the conclusions from those in the manufacturer's submission.\n\n## Assessment Group's model\n\nThe Assessment Group adapted a previously published model to undertake an independent economic assessment of shortened treatment durations with peginterferon alfa plus ribavirin, using clinical-effectiveness data from studies included in the systematic review. The economic model was structurally similar to those developed by the manufacturers, and used similar input parameters to model disease progression, health state costs and utility. The model consists of nine health states representing stages of chronic liver disease and death.\n\nThe economic model contains three health states representing cure of chronic hepatitis C, which are differentiated by the stage of the disease before treatment, as this is expected to have an impact on the subsequent risk of progressive liver disease, post-treatment surveillance and health-related quality of life. The health states mild hepatitis C, moderate hepatitis C, compensated cirrhosis, decompensated cirrhosis, hepatocellular carcinoma and liver transplant represent stages of progressive liver disease. People not exhibiting a sustained virological response are expected to have the same risk of disease progression as untreated people. These assumptions are all consistent with previous assessments and with other published economic evaluations of anti-viral treatment for chronic HCV infection. The model has a cycle length of 1\xa0year and incorporates a half-cycle adjustment.\n\nBaseline population data in the model were based on the results of a clinical audit undertaken at a London teaching hospital. New patients were taken to represent the population of people with HCV and HIV co-infection and the population eligible to receive shortened courses of combination therapy as applicable, and existing patients were taken to represent the population of people treated previously with peginterferon alfa and ribavirin. Patients were differentiated in terms of average age and distribution across stages of chronic liver disease (mild hepatitis C, moderate hepatitis C and compensated cirrhosis). The proportion of men in the baseline cohort was based on the Assessment Group's previous assessment. The majority of these assumptions do not affect response to treatment, but relate to the risk of all-cause mortality. The influence of the stage of chronic liver disease on response to treatment, and on the cost effectiveness of the intervention, was assessed in a sensitivity analysis.\n\nData on sustained virological response rates for the subgroup of people receiving shortened treatment courses were extracted by the Assessment Group from clinical trials included in the clinical effectiveness review. For the subgroups of people co-infected with HIV and HCV and of people whose hepatitis C did not respond to previous treatment or responded but subsequently relapsed, sustained virological response rates were taken from RCTs that included active comparators, which were not systematically reviewed by the Assessment Group. Data on sustained virological response rates were used in the model to estimate the probability of treatment-eligible people moving to the relevant state of a sustained virological response. Where applicable, early virological response rates were used to estimate the average duration of treatment and total drug acquisition costs for each anti-viral treatment strategy.\n\nShortening the duration of treatment with peginterferon alfa-2a plus ribavirin from 48\xa0weeks to 24 weeks for people with HCV genotype 1, a baseline low viral load and a rapid virological response resulted in a reduction in total QALYs of between 0.08 and 0.14. This shortened treatment duration was also associated with a reduction in the total cost, resulting in ICERs that reflected 'savings per QALY lost' (ranging from £34,510 to £64,880 per QALY). For people with HCV genotypes 2 and 3, a baseline low viral load and a rapid virological response, a shortened duration of treatment of 16\xa0weeks with peginterferon alfa-2a plus ribavirin dominated the standard 24-week treatment duration. For the subgroup of people with HCV genotype 1, a baseline low viral load and a rapid virological response, a shortened duration of treatment of 24\xa0weeks with peginterferon alfa-2b plus ribavirin dominated the standard 48-week treatment duration.\n\nThe ICER for the subgroup of people who had been treated previously with peginterferon alfa-2b plus ribavirin or peginterferon monotherapy but whose hepatitis C did not respond to treatment, or responded initially to treatment but subsequently relapsed, was £23,912 per QALY gained (compared with best supportive care) for people with HCV genotypes 1 and 4. If an early stopping rule was applied, the ICER for people with genotypes 1 and 4 was reduced to £7681 per QALY gained. For people with genotypes 2 and 3, treatment with peginterferon alfa-2b plus ribavirin dominated best supportive care (with or without an early stopping rule). Re-treatment with peginterferon alfa-2a plus ribavirin of people whose hepatitis C did not respond to previous peginterferon therapy resulted in an ICER of £52,587 per QALY gained for people with HCV genotype 1 and £10,926 per QALY gained for people with other genotypes, each compared with best supportive care. If an early stopping rule was applied at 12 weeks for people re-treated with peginterferon alfa-2a plus ribavirin who did not show an early virological response at this time, the ICERs were reduced to £9169 per QALY gained for people with HCV genotype 1 and £2294 per QALY gained for people with other genotypes.\n\nFor people co-infected with HCV and HIV, treatment with peginterferon alfa-2a plus ribavirin resulted in an ICER of £7941 per QALY gained for people with HCV genotypes 1 and 4 compared with best supportive care. Peginterferon alfa-2a plus ribavirin dominated best supportive care for people with genotypes 2 and 3. Treatment of people co-infected with HCV and HIV with peginterferon alfa-2b plus ribavirin resulted in an ICER of £11,806 per QALY gained for people with HCV genotypes 1 and 4 and an ICER of £2161 per QALY gained for people with genotypes 2 and 3.\n\n## Summary of cost-effectiveness evidence\n\nCost-effectiveness analyses indicate that adopting a shortened duration of treatment with peginterferon alfa-2a plus ribavirin for people with HCV genotype 1 is associated with fewer QALYs, but also with lower treatment costs, resulting in ICERs ranging from £34,000 to £65,000 of savings per QALY lost. For people with genotypes 2 and 3, a shortened treatment course with peginterferon alfa-2a plus ribavirin dominates the standard treatment duration. Similarly, for people with HCV genotype 1, a shortened duration of treatment with peginterferon alfa-2b plus ribavirin dominates the standard treatment duration. The results submitted by the manufacturers and those reported by the Assessment Group also indicate that treatment with peginterferon alfa plus ribavirin for people who are eligible for re-treatment following previous non-response or relapse of their condition is associated with QALY gains and an increase in costs. If an early stopping rule was applied at 12 weeks, re-treatment with peginterferon alfa plus ribavirin was associated with ICERs below £10,000 per QALY gained for people with HCV genotypes 1 and 4. For people with HCV genotypes 2 and 3, re-treatment was associated with ICERs below £2294 per QALY gained or dominated best supportive care. For people co-infected with HCV and HIV who were treated with peginterferon alfa plus ribavirin, either all ICERs were below £12,000 per QALY gained or treatment dominated best supportive care.\n\n# Consideration of the evidence\n\nThe Appraisal Committee reviewed the data available on the clinical and cost effectiveness of peginterferon alfa (2a or 2b) plus ribavirin, having considered evidence on the nature of chronic hepatitis C and the value placed on the benefits of peginterferon alfa (2a or 2b) plus ribavirin by people with the condition, those who represent them, and clinical specialists. It also took into account the effective use of NHS resources.\n\nThe Committee was aware from the evidence presented that there were no statistically significant differences in sustained virological response rates between subgroups receiving shortened and standard courses of treatment with peginterferon alfa plus ribavirin. The Committee heard from the clinical specialist that, although some trials have reported that people who received shortened courses of treatment had (non-significant) lower sustained virological response rates, using shortened rather than standard courses of therapy was not expected to have clinical implications. Therefore the Committee concluded that shortened and standard treatment durations could be viewed as clinically comparable.\n\nThe Committee noted that no RCTs were identified that compared peginterferon alfa (with or without ribavirin) with best supportive care for people co-infected with HIV and HCV, or for people whose hepatitis C did not respond to previous treatment or responded but subsequently relapsed. The Committee heard from the clinical specialist that it would be unethical to conduct trials without an active comparator arm for these groups, and therefore the Committee should consider the use of sustained virological response rates from trials that had an active comparator to be appropriate for these subgroups. The Committee agreed that using the results from trials that had an active comparator to derive data on clinical effectiveness for the economic model was appropriate.\n\nThe Committee discussed the assumption that people who receive best supportive care for chronic hepatitis C will not have a sustained virological response. The clinical specialist stated that sustained virological response rates are generally extremely low for people not receiving active therapy. The Committee concluded that it was therefore reasonable to assume that people who receive best supportive care do not achieve a sustained virological response.\n\nThe Committee heard from the patient experts that many people with chronic hepatitis C would be willing to tolerate the adverse effects of treatment with peginterferon alfa, with or without ribavirin, for the longest available treatment period to increase their chance of achieving a sustained virological response or to reduce the possibility of relapse following treatment, even if they knew that a shortened course of treatment may be associated with fewer adverse events. The Committee acknowledged that some people prefer to have a choice when considering their treatment options.\n\nIn response to comments received after consultation on the ACD, the Committee noted that the definition of undetectable serum HCV RNA (which denotes clearing of HCV) varied between the clinical trials (see section 4.1.3). They acknowledged that different laboratories in the UK use different tests and set different thresholds to determine whether a virus is undetectable, and that the quality of the test used may influence treatment decisions. The Committee therefore agreed that a highly sensitive test should be used to detect serum HCV RNA, to minimise the chance of false negative results – that is, to minimise the chance that the test indicates the absence of virus, leading erroneously to a shortened course of treatment, when in fact virus is present.\n\nThe Committee discussed the cost-effectiveness data presented by the manufacturers and the Assessment Group. The Committee noted that the Assessment Group adapted a previously published economic model, and that the model was structurally similar to those developed by the manufacturers, and used similar input parameters to model disease progression, health state costs and utility. The Committee noted that the model submitted by Roche Products may have overestimated the QALY gains from achieving a sustained virological response, because the model did not differentiate between mild and moderate hepatitis C and because age-specific utilities were applied to the sustained virological response state but not to other health states. The Committee considered that it was not appropriate for the model to apply age-specific utility values to only one health state, but concluded that the additional analysis carried out by the Assessment Group to correct for this issue was appropriate.\n\nThe Committee was aware that the model from Schering-Plough for peginterferon alfa-2b assumed that a sustained virological response occurs at the beginning of a cycle rather than mid-cycle, and that the same utility values for a sustained virological response were used irrespective of the stage of disease when treatment starts. The Committee was satisfied that the additional analyses carried out by the Assessment Group corrected for these issues and did not substantially alter the results.\n\nThe Committee considered the cost effectiveness of peginterferon alfa and ribavirin combination therapy for the three populations covered by this appraisal. For people with HCV genotype 1, a baseline low viral load and a rapid virological response, the Committee noted that the shortened treatment duration of 24\xa0weeks with peginterferon alfa-2a plus ribavirin was associated with a reduction in both QALYs and costs compared with the standard treatment duration of 48\xa0weeks, resulting in ICERs that reflected 'savings per QALY lost' (ranging from £34,500 to £64,900 per QALY). The Committee considered situations where an ICER is derived from decreased effectiveness and decreased costs, and concluded that the commonly assumed decision rule of accepting ICERs below a given threshold is reversed, and so ICERs that are above the threshold are considered acceptable in this case. The Committee also noted that for people with genotype 1 who had a low viral load and a rapid virological response, the shortened treatment duration of 24\xa0weeks with peginterferon alfa-2b plus ribavirin dominated the standard treatment duration of 48 weeks. Similarly, for people with HCV genotype 2 or 3, a baseline low viral load and a rapid virological response, the shortened treatment duration of 16\xa0weeks with peginterferon alfa-2a plus ribavirin dominated the standard treatment duration of 24\xa0weeks. Based on these ICERs, the Committee concluded that shortened courses of peginterferon alfa (2a or 2b) and ribavirin combination therapy represent a cost-effective use of NHS resources for people eligible for this treatment regimen. The Committee noted that the cost effectiveness results also indicated that standard treatment durations were not likely to be considered cost effective compared with shortened treatment durations. Since the shortened and standard treatment durations are considered to be clinically comparable (see section 4.3.2), the Committee concluded that shortened treatment courses should be recommended rather than recommended as an option. However, the Committee was aware that shortened treatment courses are not suitable for all people. The Committee highlighted that when considering a shortened treatment course, clinicians should take into account the licensed indication of the chosen drug (peginterferon alfa-2a or peginterferon alfa-2b), the HCV genotype, the viral load at the start of treatment and the response to treatment (as indicated by the viral load).\n\nThe Committee then discussed whether peginterferon alfa (2a or 2b) plus ribavirin should be recommended for people who have been treated previously with peginterferon alfa (2a or 2b) and ribavirin in combination, or with peginterferon alfa monotherapy, and whose condition either did not respond to treatment or responded initially to treatment but subsequently relapsed. The Committee concluded that the analysis that incorporates an early stopping rule at 12\xa0weeks for people who do not show an early virological response, as specified in the marketing authorisation, was the most appropriate scenario forming the basis of the cost-effectiveness analysis (see section 4.2.24). The Committee noted that the Assessment Group's analysis for people re-treated with peginterferon alfa plus ribavirin resulted in ICERs below £10,000 per QALY gained for people with HCV genotypes 1 and 4, and re-treatment dominated best supportive care for people with HCV genotypes 2 and 3. The Committee then considered the cost-effectiveness estimates for the subgroup of people with HIV and HCV co-infection. The Committee noted that in the Assessment Group's analysis for people co-infected with HCV and HIV who were receiving peginterferon alfa (2a or 2b) plus ribavirin, either all ICERs were below £12,000 per QALY gained or treatment dominated best supportive care. The Committee concluded that the ICERs presented in the base-case analysis by the Assessment Group were plausible for both the subgroup of people being re-treated and the subgroup of people co-infected with HCV and HIV. Based on these ICERs, the Committee was satisfied that peginterferon alfa (2a or 2b) and ribavirin combination therapy represents a cost-effective use of NHS resources both for people who have been treated previously and whose condition either did not respond to treatment or responded initially to treatment but subsequently relapsed, and for people with HIV and HCV co-infection.\n\n# Summary of Appraisal Committee's key conclusions\n\nTA200\n\n(MTA part review)\n\n\n\nAppraisal title: Peginterferon alfa and ribavirin for the treatment of chronic hepatitis\xa0C (part review of technology appraisal guidance 75 and 106)\n\nSection\n\nKey conclusions\n\nCombination therapy with peginterferon alfa (2a or 2b) and ribavirin is recommended as a treatment option for adults with chronic hepatitis C:\n\nwho have been treated previously with peginterferon alfa (2a or 2b) and ribavirin in combination, or with peginterferon alfa monotherapy, and whose condition either did not respond to treatment or responded initially to treatment but subsequently relapsed or\n\nwho are co-infected with HIV.\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\nShortened courses of combination therapy with peginterferon alfa (2a or 2b) and ribavirin are recommended for the treatment of adults with chronic hepatitis C who:\n\nhave a rapid virological response to treatment at week 4 that is identified by a highly sensitive test and\n\nare considered suitable for a shortened course of treatment.\n\n\n\n\n\nCurrent practice\n\nClinical need of patients including the availability of alternative treatments\n\n\n\nClinical practice for the use of these technologies is described in NICE technology appraisal guidance 75 and 106. This appraisal addresses extensions to the marketing authorisations.\n\n–\n\nThe technology\n\nProposed benefits of the technology\n\n\n\nHow innovative is the technology in its potential to make a significant and substantial impact on health-related benefits?\n\nNot applicable (this is a review of established technologies).\n\n_\n\nWhat is the position of the treatment in the pathway of care for the condition?\n\n\n\nThis guidance updates and replaces:\n\nsection 1.2, bullet 3 only, of TA75\n\nsection 1.4 of TA75 for adults who are eligible for shortened courses of combination therapy (as described in section 1.2 of the current guidance)\n\nsection 1.7, bullet 1 only, of TA75\n\nsections 1.4 and 1.5 of TA106.\n\nAll other recommendations in TA75 and TA106 still stand.\n\n–\n\nAdverse effects\n\nThe Committee heard from the patient experts that many people with chronic hepatitis C would be willing to tolerate the adverse effects of treatment with peginterferon alfa, with or without ribavirin, for the longest available treatment period to increase their chance of achieving a sustained virological response or to reduce the possibility of relapse following treatment, even if they knew that a shortened course of treatment may be associated with fewer adverse events.\n\n\n\nEvidence for clinical effectiveness\n\nAvailability, nature and quality of evidence\n\n\n\nRCT evidence was available for shortened treatment courses. No RCTs were identified that compared peginterferon alfa (with or without ribavirin) with best supportive care for people co-infected with HIV and HCV, or for people whose hepatitis C did not respond to previous treatment or responded but subsequently relapsed. The Committee agreed that it was appropriate to use results from trials that had an active comparator to derive data on clinical effectiveness for the economic model.\n\n\n\nRelevance to general clinical practice in the NHS\n\n\n\nThe clinical specialist stated that sustained virological response rates are generally extremely low for people not receiving active therapy. The Committee concluded that it was therefore reasonable to assume that people who receive best supportive care do not achieve a sustained virological response.\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\nThe Committee noted that the definition of undetectable serum HCV RNA (which denotes clearing of HCV) varied between the clinical trials, and therefore that the quality of the test used may influence treatment decisions. The Committee therefore agreed that a highly sensitive test should be used to detect serum HCV RNA, to minimise the chance of false negative results.\n\n\n\n\n\nUncertainties generated by the evidence\n\nThere were no major uncertainties generated by the evidence.\n\n–\n\nAre there any clinically relevant subgroups for which there is evidence of differential effectiveness?\n\nNot applicable.\n\n–\n\nEstimate of the size of the clinical effectiveness including strength of supporting evidence\n\n\n\nThe Committee was aware from the evidence presented that there were no statistically significant differences in sustained virological response rates between subgroups receiving shortened and standard courses of treatment with peginterferon alfa plus ribavirin. The Committee heard from the clinical specialist that, although some trials have reported that people who received shortened courses of treatment had (non-significant) lower sustained virological response rates, using shortened rather than standard courses of therapy was not expected to have clinical implications. Therefore the Committee concluded that shortened and standard treatment durations could be viewed as clinically comparable.\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\nEvidence for cost effectiveness\n\nAvailability and nature of evidence\n\n\n\nCost effectiveness data were presented by the manufacturers and the Assessment Group.\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\nThe Committee noted that the Assessment Group adapted a previously published economic model, and that the model was structurally similar to those developed by the manufacturers, and used similar input parameters to model disease progression, health state costs and utility.\n\n\n\nUncertainties around and plausibility of assumptions and inputs in the economic model\n\nThere were no material uncertainties around the assumptions and inputs in the economic models presented.\n\n\n\n\n\n\n\n–\n\n\n\n\n\n\n\n\n\nThe Committee noted that the model submitted by Roche Products may have overestimated the QALY gains from achieving a sustained virological response, because the model did not differentiate between mild and moderate hepatitis C and because age-specific utilities were applied to the sustained virological response state but not to other health states. The Committee considered that it was not appropriate for the model to apply age-specific utility values to only one health state, but concluded that the additional analysis carried out by the Assessment Group to correct for this issue was appropriate.\n\n\n\n\n\n\n\nThe Committee was aware that the model from Schering-Plough for peginterferon alfa-2b assumed that a sustained virological response occurs at the beginning of a cycle rather than mid-cycle, and that the same utility values for a sustained virological response were used irrespective of the stage of disease when treatment starts. The Committee was satisfied that the additional analyses carried out by the Assessment Group corrected for these issues and did not substantially alter the results.\n\n\n\n\n\nIncorporation of health-related quality of life benefits and utility values\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\nHave any potential significant and substantial health-related benefits been identified that were not included in the economic model, and how have they been considered?\n\nNo potential significant and substantial health-related benefits were identified that were not included in the economic models.\n\n–\n\nAre there specific groups of people for whom the technology is particularly cost-effective?\n\nNot applicable.\n\n–\n\nMost likely cost-effectiveness estimate (given as an ICER)\n\n\n\nFor people with HCV genotype 1, a baseline low viral load and a rapid virological response, the Committee noted that the shortened treatment duration of 24\xa0weeks with peginterferon alfa-2a plus ribavirin was associated with a reduction in both QALYs and costs compared with the standard treatment duration of 48\xa0weeks, resulting in ICERs that reflected 'savings per QALY lost' (ranging from £34,500 to £64,900 per QALY).\n\n\n\nThe Committee considered situations where an ICER is derived from decreased effectiveness and decreased costs, and concluded that the commonly assumed decision rule of accepting ICERs below a given threshold is reversed, and so ICERs that are above the threshold are considered acceptable in this case.\n\n\n\nThe Committee also noted that for people with genotype 1 who had a low viral load and a rapid virological response, the shortened treatment duration of 24\xa0weeks with peginterferon alfa-2b plus ribavirin dominated the standard treatment duration of 48\xa0weeks. Similarly, for people with HCV genotype 2 or 3, a baseline low viral load and a rapid virological response, the shortened treatment duration of 16\xa0weeks with peginterferon alfa-2a plus ribavirin dominated the standard treatment duration of 24 weeks.\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\nThe Committee noted that the Assessment Group's analysis for people re-treated with peginterferon plus ribavirin resulted in ICERs below £10,000 per QALY gained for people with HCV genotypes 1 and 4, and re-treatment dominated best supportive care for people with HCV genotypes 2 and 3.\n\n\n\nThe Committee noted that in the Assessment Group's analysis for people co-infected with HCV and HIV who were receiving peginterferon alfa (2a or 2b) plus ribavirin, either all ICERs were below £12,000 per QALY gained or treatment dominated best supportive care. The Committee concluded that the ICERs presented in the base-case analysis by the Assessment Group were plausible for both the subgroup of people being re-treated and the subgroup of people co-infected with HCV and HIV.\n\n\n\n\n\nAdditional factors taken into account\n\nPatient access schemes\n\n(Pharmaceutical Price Regulation Scheme [PPRS])\n\nNone received.\n\n–\n\nEnd-of-life considerations\n\nNot applicable to this appraisal.\n\n–\n\nEqualities considerations, social value judgements\n\n\n\nNo issues relating to equality were raised at any stage during the development of this appraisal.\n\n–", 'Related NICE guidance': 'Peginterferon alfa and ribavirin for the treatment of mild chronic hepatitis C (extension of technology appraisal guidance 75). NICE technology appraisal guidance 106 (2006).\n\nInterferon alfa (pegylated and non-pegylated) and ribavirin for the treatment of chronic hepatitis C (review and extension of technology appraisal guidance 14).NICE technology appraisal guidance 75 (2004).', 'Review of guidance': 'The guidance on these technologies will be considered for review by the Guidance Executive in July 2013. The Guidance Executive will decide whether the technologies should be reviewed based on information gathered by NICE, and in consultation with consultees and commentators.\n\nAndrew DillonChief ExecutiveSeptember 2010', 'Changes after publication': 'February 2014: implementation section updated to clarify that peginterferon alfa and ribavirin is recommended as an option for treating chronic hepatitis C. Additional minor maintenance update also carried out.\n\nMarch 2012: minor maintenance', 'About this guidance': "NICE technology appraisal guidance is about the use of new and existing medicines and treatments in the NHS in England and Wales.\n\nThis guidance was developed using the NICE multiple technology appraisal process.\n\nThis guidance should be read in conjunction with the following NICE guidance:\n\nNICE technology appraisal guidance 75 (TA75) 'Interferon alfa (pegylated and non-pegylated) and ribavirin for the treatment of chronic hepatitis C' (which covers moderate to severe hepatitis C)\n\nNICE technology appraisal guidance 106 (TA106) 'Peginterferon alfa and ribavirin for the treatment of mild chronic hepatitis C'.\n\nThis appraisal addresses extensions to the marketing authorisations for peginterferon alfa-2a and peginterferon alfa-2b. This guidance updates and replaces:\n\nsection 1.2, bullet 3 only, of TA75\n\nsection 1.4 of TA75 for adults who are eligible for shortened courses of combination therapy (as described in section 1.2 of the current guidance)\n\nsection 1.7, bullet 1 only, of TA75\n\nsections 1.4 and 1.5 of TA106.\n\nAll other recommendations in TA75 and TA106 still stand.\n\nWe have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available.\n\nYour responsibility\n\nThis guidance represents the views of NICE and was arrived at after careful consideration of the evidence available. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. However, the guidance does not override the individual responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.\n\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.\n\nCopyright\n\n© National Institute for Health and Clinical Excellence 2010. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE."}	https://www.nice.org.uk/guidance/ta200	Evidence-based recommendations on peginterferon alfa (Pegasys; ViraferonPeg) and ribavirin for treating chronic hepatitis C in adults.
31e46698022e49d1921fcd11b7cdbaf6d70c242a	nice	Pregnancy and complex social factors: a model for service provision for pregnant women with complex social factors	Pregnancy and complex social factors: a model for service provision for pregnant women with complex social factors This guideline covers antenatal care for all pregnant women with complex social factors (particularly alcohol or drug misuse, recent migrant or asylum seeker status, difficulty reading or speaking English, aged under 20, domestic abuse). It offers advice on improving access to care, maintaining contact with antenatal carers, and additional information and support for these women. # Introduction The NICE guideline on antenatal care outlines the care that women should be offered during pregnancy. However, pregnant women with complex social factors may have additional needs. This guideline sets out what healthcare professionals as individuals, and antenatal services as a whole, can do to address these needs and improve pregnancy outcomes in this group of women. The guideline has been developed in collaboration with the Social Care Institute for Excellence. It is for professional groups who are routinely involved in the care of pregnant women, including midwives, GPs and primary care professionals who may encounter pregnant women with complex social factors in the course of their professional duties. It is also for those who are responsible for commissioning and planning healthcare and social services. In addition, the guideline will be of relevance to professionals working in social services and education/childcare settings, for example school nurses, substance misuse service workers, reception centre workers and domestic abuse support workers. The guideline applies to all pregnant women with complex social factors and contains a number of recommendations on standards of care for this population as a whole. However, 4 groups of women were identified as exemplars: women who misuse substances (alcohol and/or drugs) women who are recent migrants, asylum seekers or refugees, or who have difficulty reading or speaking English young women aged under 20 women who experience domestic abuse. Because there are differences in the barriers to care and particular needs of these four groups, specific recommendations have been made for each group. The guideline describes how access to care can be improved, how contact with antenatal carers can be maintained, the additional support and consultations that are required and the additional information that should be offered to pregnant women with complex social factors. Specific issues that are addressed in the guideline include: the most appropriate healthcare setting for antenatal care provision practice models for overcoming barriers and facilitating access, including access to interpreting services and all necessary care ways of communicating information to women so that they can make appropriate choices -ptimisation of resources. In addition to the recommendations in this guideline, the principles of woman-centred care and informed decision making outlined in the NICE guideline on antenatal care, specifically recommendations on the provision of antenatal information and individualised care, are of particular relevance to women with complex social factors.# Recommendations Women have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care. Making decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding. The following guidance is based on the best available evidence. The full guideline gives details of the methods and the evidence used to develop the guidance. In this guideline the following definitions are used. Domestic abuse: an incident of threatening behaviour, violence or abuse (psychological, physical, sexual, financial or emotional) between adults who are or have been intimate partners or family members, regardless of gender or sexuality. It can also include forced marriage, female genital mutilation and 'honour violence'. Recent migrants: women who moved to the UK within the previous 12 months. Substance misuse (alcohol and/or drugs): regular use of recreational drugs, misuse of over-the-counter medications, misuse of prescription medications, misuse of alcohol or misuse of volatile substances (such as solvents or inhalants) to an extent whereby physical dependence or harm is a risk to the woman and/or her unborn baby. # General recommendations The recommendations in this section apply to all pregnant women covered in this guideline. ## Service organisation In order to inform mapping of their local population to guide service provision, commissioners should ensure that the following are recorded: The number of women presenting for antenatal care with any complex social factor. Examples of complex social factors in pregnancy include: poverty; homelessness; substance misuse; recent arrival as a migrant; asylum seeker or refugee status; difficulty speaking or understanding English; age under 20; domestic abuse. Complex social factors may vary, both in type and prevalence, across different local populations. The number of women within each complex social factor grouping identified locally. Commissioners should ensure that the following are recorded separately for each complex social factor grouping: The number of women who: attend for booking by 10, 12+6 and 20 weeks. attend for the recommended number of antenatal appointments, in line with national guidance, see the NICE guideline on antenatal care. experience, or have babies who experience, mortality or significant morbidity. Significant morbidity is morbidity that has a lasting impact on either the woman or the child. The number of appointments each woman attends. The number of scheduled appointments each woman does not attend. Commissioners should ensure that women with complex social factors presenting for antenatal care are asked about their satisfaction with the services provided; and the women's responses are: recorded and monitored used to guide service development. Commissioners should involve women and their families in determining local needs and how these might be met. Those responsible for the organisation of local maternity services should enable women to take a copy of their hand-held maternity notes when moving from one area or hospital to another. ## Training for healthcare staff Healthcare professionals should be given training on multi-agency needs assessment and national guidelines on information sharing. See information sharing advice for safeguarding practitioners. ## Care provision Consider initiating a multi-agency needs assessment, including safeguarding issues, so that the woman has a coordinated care plan. See information sharing advice for safeguarding practitioners, information sharing to protect vulnerable children and families and Multi Agency Risk Assessment Conference. Respect the woman's right to confidentiality and sensitively discuss her fears in a non-judgemental manner. Tell the woman why and when information about her pregnancy may need to be shared with other agencies. Ensure that the hand-held maternity notes contain a full record of care received and the results of all antenatal tests. ## Information and support for women For women who do not have a booking appointment at the first contact with any healthcare professional: discuss the need for antenatal care -ffer the woman a booking appointment in the first trimester, ideally before 10 weeks if she wishes to continue the pregnancy, or offer referral to sexual health services if she is considering termination of the pregnancy. At the first contact and at the booking appointment, ask the woman to tell her healthcare professional if her address changes, and ensure that she has a telephone number for this purpose. At the booking appointment, give the woman a telephone number to enable her to contact a healthcare professional outside of normal working hours, for example the telephone number of the hospital triage contact, the labour ward or the birth centre. In order to facilitate discussion of sensitive issues, provide each woman with a one-to-one consultation, without her partner, a family member or a legal guardian present, on at least one occasion. # Pregnant women who misuse substances (alcohol and/or drugs) Pregnant women who misuse substances may be anxious about the attitudes of healthcare staff and the potential role of social services. They may also be overwhelmed by the involvement of multiple agencies. These women need supportive and coordinated care during pregnancy. Work with social care professionals to overcome barriers to care for women who misuse substances. Particular attention should be paid to: integrating care from different services ensuring that the attitudes of staff do not prevent women from using services addressing women's fears about the involvement of children's services and potential removal of their child, by providing information tailored to their needs addressing women's feelings of guilt about their misuse of substances and the potential effects on their baby. ## Service organisation Healthcare commissioners and those responsible for providing local antenatal services should work with local agencies, including social care and third-sector agencies that provide substance misuse services, to coordinate antenatal care by, for example: jointly developing care plans across agencies including information about opiate replacement therapy in care plans co-locating services -ffering women information about the services provided by other agencies. Consider ways of ensuring that, for each woman who misuses substances: progress is tracked through the relevant agencies involved in her care notes from the different agencies involved in her care are combined into a single document there is a coordinated care plan. Offer the woman a named midwife or doctor who has specialised knowledge of, and experience in, the care of women who misuse substances, and provide a direct-line telephone number for the named midwife or doctor. ## Training for healthcare staff Healthcare professionals should be given training on the social and psychological needs of women who misuse substances. Healthcare staff and non-clinical staff such as receptionists should be given training on how to communicate sensitively with women who misuse substances. ## Information and support for women The first time a woman who misuses substances discloses that she is pregnant, offer her referral to an appropriate substance misuse programme. Use a variety of methods, for example text messages, to remind women of upcoming and missed appointments. The named midwife or doctor should tell the woman about relevant additional services (such as drug and alcohol misuse support services) and encourage her to use them according to her individual needs. Offer the woman information about the potential effects of substance misuse on her unborn baby, and what to expect when the baby is born, for example what medical care the baby may need, where he or she will be cared for and any potential involvement of social services. Offer information about help with transportation to appointments if needed to support the woman's attendance. # Pregnant women who are recent migrants, asylum seekers or refugees, or who have difficulty reading or speaking English Pregnant women who are recent migrants, asylum seekers or refugees, or who have difficulty reading or speaking English, may not make full use of antenatal care services. This may be because of unfamiliarity with the health service or because they find it hard to communicate with healthcare staff. Healthcare professionals should help support these women's uptake of antenatal care services by: using a variety of means to communicate with women telling women about antenatal care services and how to use them undertaking training in the specific needs of women in these groups. ## Service organisation Commissioners should monitor emergent local needs and plan and adjust services accordingly. Healthcare professionals should ensure they have accurate information about a woman's current address and contact details during her pregnancy by working with local agencies that provide housing and other services for recent migrants, asylum seekers and refugees, such as asylum centres. To allow sufficient time for interpretation, commissioners and those responsible for the organisation of local antenatal services should offer flexibility in the number and length of antenatal appointments when interpreting services are used, over and above the appointments outlined in national guidance (see NICE's guideline on antenatal care). Those responsible for the organisation of local antenatal services should provide information about pregnancy and antenatal services, including how to find and use antenatal services, in a variety of: formats, such as posters, notices, leaflets, photographs, drawings/diagrams, online video clips, audio clips and DVDs settings, including pharmacies, community centres, faith groups and centres, GP surgeries, family planning clinics, children's centres, reception centres and hostels languages. ## Training for healthcare staff Healthcare professionals should be given training on: the specific health needs of women who are recent migrants, asylum seekers or refugees, such as needs arising from female genital mutilation or HIV the specific social, religious and psychological needs of women in these groups the most recent government policies on access and entitlement to care for recent migrants, asylum seekers and refugees (see the Department of Health and Social Care and Maternity Action). ## Information and support for women Offer the woman information on access and entitlement to healthcare. At the booking appointment discuss with the woman the importance of keeping her hand-held maternity record with her at all times. Avoid making assumptions based on a woman's culture, ethnic origin or religious beliefs. ## Communication with women who have difficulty reading or speaking English Provide the woman with an interpreter (who may be a link worker or advocate and should not be a member of the woman's family, her legal guardian or her partner) who can communicate with her in her preferred language. When giving spoken information, ask the woman about her understanding of what she has been told to ensure she has understood it correctly. # Young pregnant women aged under 20 Young pregnant women aged under 20 may feel uncomfortable using antenatal care services in which the majority of service users are in older age groups. They may be reluctant to recognise their pregnancy or inhibited by embarrassment and fear of parental reaction. They may also have practical problems such as difficulty getting to and from antenatal appointments. Healthcare professionals should encourage young women aged under 20 to use antenatal care services by: -ffering age-appropriate services being aware that the young woman may be dealing with other social problems -ffering information about help with transportation to and from appointments -ffering antenatal care for young women in the community providing opportunities for the partner/father of the baby to be involved in the young woman's antenatal care, with her agreement. ## Service organisation Commissioners should work in partnership with local education authorities and third-sector agencies to improve access to, and continuing contact with, antenatal care services for young women aged under 20. Commissioners should consider commissioning a specialist antenatal service for young women aged under 20, using a flexible model of care tailored to the needs of the local population. Components may include: antenatal care and education in peer groups in a variety of settings, such as GP surgeries, children's centres and schools antenatal education in peer groups offered at the same time as antenatal appointments and at the same location, such as a 'one-stop shop' (where a range of services can be accessed at the same time). Offer the young woman aged under 20 a named midwife, who should take responsibility for and provide the majority of her antenatal care, and provide a direct-line telephone number for the named midwife. ## Training for healthcare staff Healthcare professionals should be given training to ensure they are knowledgeable about safeguarding responsibilities for both the young woman and her unborn baby, and the most recent government guidance on consent for examination or treatment. (See the Department of Health and Social Care.) ## Information and support for women Offer young women aged under 20 information that is suitable for their age – including information about care services, antenatal peer group education or drop-in sessions, housing benefit and other benefits – in a variety of formats. # Pregnant women who experience domestic abuse A woman who is experiencing domestic abuse may have particular difficulties using antenatal care services: for example, the perpetrator of the abuse may try to prevent her from attending appointments. The woman may be afraid that disclosure of the abuse to a healthcare professional will worsen her situation, or anxious about the reaction of the healthcare professional. Women who experience domestic abuse should be supported in their use of antenatal care services by: training healthcare professionals in the identification and care of women who experience domestic abuse making available information and support tailored to women who experience or are suspected to be experiencing domestic abuse providing a more flexible series of appointments if needed addressing women's fears about the involvement of children's services by providing information tailored to their needs. ## Service organisation Commissioners and those responsible for the organisation of local antenatal services should ensure that local voluntary and statutory organisations that provide domestic abuse support services recognise the need to provide coordinated care and support for service users during pregnancy. (See also the NICE guideline on domestic violence and abuse: multi-agency working.) Commissioners and those responsible for the organisation of local antenatal services should ensure that a local protocol is written, which: is developed jointly with social care providers, the police and third-sector agencies by a healthcare professional with expertise in the care of women experiencing domestic abuse includes: clear referral pathways that set out the information and care that should be offered to women the latest government guidance on responding to domestic abuse (see the Department of Health and Social Care's guidance on domestic abuse: a resource for health professionals) sources of support for women, including addresses and telephone numbers, such as social services, the police, support groups and women's refuges safety information for women plans for follow-up care, such as additional appointments or referral to a domestic abuse support worker -btaining a telephone number that is agreed with the woman and on which it is safe to contact her contact details of other people who should be told that the woman is experiencing domestic abuse, including her GP. Commissioners and those responsible for the organisation of local antenatal services should provide for flexibility in the length and frequency of antenatal appointments, over and above those outlined in national guidance (see NICE's guideline on antenatal care) to allow more time for women to discuss the domestic abuse they are experiencing. Offer the woman a named midwife, who should take responsibility for and provide the majority of her antenatal care. ## Training for healthcare staff Commissioners of healthcare services and social care services should consider commissioning joint training for health and social care professionals to facilitate greater understanding between the two agencies of each other's roles, and enable healthcare professionals to inform and reassure women who are apprehensive about the involvement of social services. Healthcare professionals need to be alert to features suggesting domestic abuse and offer women the opportunity to disclose it in an environment in which the woman feels secure. Healthcare professionals should be given training on the care of women known or suspected to be experiencing domestic abuse that includes: local protocols local resources for both the woman and the healthcare professional features suggesting domestic abuse how to discuss domestic abuse with women experiencing it how to respond to disclosure of domestic abuse. ## Information and support for women Tell the woman that the information she discloses will be kept in a confidential record and will not be included in her hand-held record. Offer the woman information about other agencies, including third-sector agencies, which provide support for women who experience domestic abuse. Give the woman a credit card-sized information card that includes local and national helpline numbers. Consider offering the woman referral to a domestic abuse support worker.# Recommendations for research The Guideline Development Group (GDG) has made the following recommendations for research, based on its review of evidence, to improve NICE guidance and antenatal care in the future. The GDG's full set of recommendations for research are detailed in the full guideline. # Training for healthcare staff What training should be provided to improve staff behaviour towards pregnant women with complex social factors? ## Why this is important The evidence reviewed suggests that women facing complex social problems are deterred from attending antenatal appointments, including booking appointments, because of the perceived negative attitude of healthcare staff, including non-clinical staff such as receptionists. It is expected that education and training for staff in order to help them understand the issues faced by women with complex social factors and how their own behaviour can affect these women will reduce negative behaviour and language. A number of training options currently exist that could be used in this context; however, which of these (if any) bring about the anticipated positive changes is not known. Given the resource implications of providing training across the NHS it is important to ascertain the most cost-effective way of providing this. # Effect of early booking on obstetric and neonatal outcomes Does early booking (by 10 weeks, or 12+6 weeks) improve outcomes for pregnant women with complex social problems compared with later booking? ## Why this is important The NICE guideline on antenatal care recommends that the booking appointment should ideally take place before 10 weeks and policy by the Department of Health on maternity matters: choice, access and continuity of care in a safe service, supports booking by 12 weeks for all women. The main rationale behind these recommendations is to allow women to participate in antenatal screening programmes for haemoglobinopathies and Down's syndrome in a timely fashion, to have their pregnancies accurately dated using ultrasound scan, and to develop a plan of care for the pregnancy which sets out the number of visits required and additional appointments that may need to be made. Pregnant women with complex social factors are known to book later, on average, than other women and late booking is known to be associated with poor obstetric and neonatal outcomes (see the report of the Confidential Enquiry into Maternal Deaths in the United Kingdom). It seems likely that facilitating early booking for these women is even more important than for the general population of pregnant women. There is, however, no current evidence that putting measures in place to allow this to happen improves pregnancy outcomes for women with complex social factors and their babies. # How can different service models be assessed? What data should be collected and how should they be collected, and shared, in order to assess the quality of different models of services? ## Why this is important There is a paucity of routinely collected data about the effectiveness of different models of care in relation to demography. Although mortality data are accurately reflected in reports published by the Centre for Maternal and Child Enquiries, morbidity and pregnancy outcomes are not often linked back to pregnancies in women with complex social factors. Most research in the area of social complexity and pregnancy is qualitative, descriptive and non-comparative. In order to evaluate the financial and clinical effectiveness of specialised models of care there is a need for baseline data on these pregnancies and their outcomes in relation to specific models of care. A national database of routinely collected pregnancy data is needed. The GDG is aware that a national maternity dataset is currently in development and it is hoped that this will ensure that data are collected in a similar format across England and Wales to allow for comparisons of different models of care. # Models of service provision What models of service provision exist in the UK for the four populations addressed in this guideline who experience socially complex pregnancies (women who misuse substances, women who are recent migrants, asylum seekers or refugees or who have difficulty reading or speaking English, young women aged under 20 and women who experience domestic abuse)? How do these models compare, both with each other and with standard care, in terms of outcomes? ## Why this is important The evidence reviewed by the GDG was poor in several respects. Many of the studies were conducted in other parts of the world, and it was not clear whether they would be applicable to the UK. Many of the interventions being studied were multifaceted, and it was not clear from the research which aspect of the intervention led to a change in outcome or whether it would lead to a similar change in the UK. Also, in some instances it was not clear whether a particular intervention, for example a specialist service for teenagers, made any difference to the outcomes being studied. Developing a clear and detailed map of existing services in the UK for pregnant women with complex social factors, and the effectiveness of these services, would enable a benchmark of good practice to be set that local providers could adapt to suit their own populations and resources. A map of providers, their services and outcomes may also enable commissioners and providers to learn from each other, work together to develop joint services and share information in a way that would lead to continuous improvement in services for these groups of women. # Antenatal appointments for women who misuse substances What methods help and encourage women who misuse substances to maintain contact with antenatal services/attend antenatal appointments? What additional consultations (if any) do women who misuse substances need, over and above the care described in the NICE guideline 'Antenatal care' (NICE clinical guideline 62)? ## Why this is important Women who misuse substances are known to have poorer obstetric and neonatal outcomes than other women. Late booking and poor attendance for antenatal care are known to be associated with poor outcomes and therefore it is important that measures are put in place to encourage these women to attend antenatal care on a regular basis. Some of the evidence examined by the GDG suggested that some interventions could improve attendance for antenatal care, but this evidence was undermined by the use of self-selected comparison groups, so that the effect of the intervention was unclear. In relation to additional consultations, the GDG was unable to identify any particular intervention that had a positive effect on outcomes, although there was low-quality evidence that additional support seemed to improve outcomes. Much of the evidence was from the US and there was a lack of high-quality UK data. It seems likely that making it easier for these women to attend antenatal appointments and providing tailored care will improve outcomes, but at present it is not clear how this should be done.	{'Introduction': 'The NICE guideline on antenatal care outlines the care that women should be offered during pregnancy. However, pregnant women with complex social factors may have additional needs. This guideline sets out what healthcare professionals as individuals, and antenatal services as a whole, can do to address these needs and improve pregnancy outcomes in this group of women.\n\nThe guideline has been developed in collaboration with the Social Care Institute for Excellence. It is for professional groups who are routinely involved in the care of pregnant women, including midwives, GPs and primary care professionals who may encounter pregnant women with complex social factors in the course of their professional duties. It is also for those who are responsible for commissioning and planning healthcare and social services. In addition, the guideline will be of relevance to professionals working in social services and education/childcare settings, for example school nurses, substance misuse service workers, reception centre workers and domestic abuse support workers.\n\nThe guideline applies to all pregnant women with complex social factors and contains a number of recommendations on standards of care for this population as a whole. However, 4\xa0groups of women were identified as exemplars:\n\nwomen who misuse substances (alcohol and/or drugs)\n\nwomen who are recent migrants, asylum seekers or refugees, or who have difficulty reading or speaking English\n\nyoung women aged under\xa020\n\nwomen who experience domestic abuse.\n\nBecause there are differences in the barriers to care and particular needs of these four groups, specific recommendations have been made for each group.\n\nThe guideline describes how access to care can be improved, how contact with antenatal carers can be maintained, the additional support and consultations that are required and the additional information that should be offered to pregnant women with complex social factors.\n\nSpecific issues that are addressed in the guideline include:\n\nthe most appropriate healthcare setting for antenatal care provision\n\npractice models for overcoming barriers and facilitating access, including access to interpreting services and all necessary care\n\nways of communicating information to women so that they can make appropriate choices\n\noptimisation of resources.\n\nIn addition to the recommendations in this guideline, the principles of woman-centred care and informed decision making outlined in the NICE guideline on antenatal care, specifically recommendations on the provision of antenatal information and individualised care, are of particular relevance to women with complex social factors.', 'Recommendations': "Women have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.\n\nMaking decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.\n\nThe following guidance is based on the best available evidence. The full guideline gives details of the methods and the evidence used to develop the guidance.\n\nIn this guideline the following definitions are used.\n\nDomestic abuse: an incident of threatening behaviour, violence or abuse (psychological, physical, sexual, financial or emotional) between adults who are or have been intimate partners or family members, regardless of gender or sexuality. It can also include forced marriage, female genital mutilation and 'honour violence'.\n\nRecent migrants: women who moved to the UK within the previous 12 months.\n\nSubstance misuse (alcohol and/or drugs): regular use of recreational drugs, misuse of over-the-counter medications, misuse of prescription medications, misuse of alcohol or misuse of volatile substances (such as solvents or inhalants) to an extent whereby physical dependence or harm is a risk to the woman and/or her unborn baby.\n\n# General recommendations\n\nThe recommendations in this section apply to all pregnant women covered in this guideline.\n\n## Service organisation\n\nIn order to inform mapping of their local population to guide service provision, commissioners should ensure that the following are recorded:\n\nThe number of women presenting for antenatal care with any complex social factor. Examples of complex social factors in pregnancy include: poverty; homelessness; substance misuse; recent arrival as a migrant; asylum seeker or refugee status; difficulty speaking or understanding English; age under\xa020; domestic abuse. Complex social factors may vary, both in type and prevalence, across different local populations.\n\nThe number of women within each complex social factor grouping identified locally.\n\nCommissioners should ensure that the following are recorded separately for each complex social factor grouping:\n\nThe number of women who:\n\n\n\nattend for booking by 10, 12+6 and 20\xa0weeks.\n\nattend for the recommended number of antenatal appointments, in line with national guidance, see the NICE guideline on antenatal care.\n\nexperience, or have babies who experience, mortality or significant morbidity. Significant morbidity is morbidity that has a lasting impact on either the woman or the child.\n\n\n\nThe number of appointments each woman attends.\n\nThe number of scheduled appointments each woman does not attend.\n\nCommissioners should ensure that women with complex social factors presenting for antenatal care are asked about their satisfaction with the services provided; and the women's responses are:\n\nrecorded and monitored\n\nused to guide service development.\n\nCommissioners should involve women and their families in determining local needs and how these might be met.\n\nThose responsible for the organisation of local maternity services should enable women to take a copy of their hand-held maternity notes when moving from one area or hospital to another.\n\n## Training for healthcare staff\n\nHealthcare professionals should be given training on multi-agency needs assessment and national guidelines on information sharing. See information sharing advice for safeguarding practitioners.\n\n## Care provision\n\nConsider initiating a multi-agency needs assessment, including safeguarding issues, so that the woman has a coordinated care plan. See information sharing advice for safeguarding practitioners, information sharing to protect vulnerable children and families and Multi Agency Risk Assessment Conference.\n\nRespect the woman's right to confidentiality and sensitively discuss her fears in a non-judgemental manner.\n\nTell the woman why and when information about her pregnancy may need to be shared with other agencies.\n\nEnsure that the hand-held maternity notes contain a full record of care received and the results of all antenatal tests.\n\n## Information and support for women\n\nFor women who do not have a booking appointment at the first contact with any healthcare professional:\n\ndiscuss the need for antenatal care\n\noffer the woman a booking appointment in the first trimester, ideally before 10\xa0weeks if she wishes to continue the pregnancy, or offer referral to sexual health services if she is considering termination of the pregnancy.\n\nAt the first contact and at the booking appointment, ask the woman to tell her healthcare professional if her address changes, and ensure that she has a telephone number for this purpose.\n\nAt the booking appointment, give the woman a telephone number to enable her to contact a healthcare professional outside of normal working hours, for example the telephone number of the hospital triage contact, the labour ward or the birth centre.\n\nIn order to facilitate discussion of sensitive issues, provide each woman with a one-to-one consultation, without her partner, a family member or a legal guardian present, on at least one occasion.\n\n# Pregnant women who misuse substances (alcohol and/or drugs)\n\nPregnant women who misuse substances may be anxious about the attitudes of healthcare staff and the potential role of social services. They may also be overwhelmed by the involvement of multiple agencies. These women need supportive and coordinated care during pregnancy.\n\nWork with social care professionals to overcome barriers to care for women who misuse substances. Particular attention should be paid to:\n\nintegrating care from different services\n\nensuring that the attitudes of staff do not prevent women from using services\n\naddressing women's fears about the involvement of children's services and potential removal of their child, by providing information tailored to their needs\n\naddressing women's feelings of guilt about their misuse of substances and the potential effects on their baby.\n\n## Service organisation\n\nHealthcare commissioners and those responsible for providing local antenatal services should work with local agencies, including social care and third-sector agencies that provide substance misuse services, to coordinate antenatal care by, for example:\n\njointly developing care plans across agencies\n\nincluding information about opiate replacement therapy in care plans\n\nco-locating services\n\noffering women information about the services provided by other agencies.\n\nConsider ways of ensuring that, for each woman who misuses substances:\n\nprogress is tracked through the relevant agencies involved in her care\n\nnotes from the different agencies involved in her care are combined into a single document\n\nthere is a coordinated care plan.\n\nOffer the woman a named midwife or doctor who has specialised knowledge of, and experience in, the care of women who misuse substances, and provide a direct-line telephone number for the named midwife or doctor.\n\n## Training for healthcare staff\n\nHealthcare professionals should be given training on the social and psychological needs of women who misuse substances.\n\nHealthcare staff and non-clinical staff such as receptionists should be given training on how to communicate sensitively with women who misuse substances.\n\n## Information and support for women\n\nThe first time a woman who misuses substances discloses that she is pregnant, offer her referral to an appropriate substance misuse programme.\n\nUse a variety of methods, for example text messages, to remind women of upcoming and missed appointments.\n\nThe named midwife or doctor should tell the woman about relevant additional services (such as drug and alcohol misuse support services) and encourage her to use them according to her individual needs.\n\nOffer the woman information about the potential effects of substance misuse on her unborn baby, and what to expect when the baby is born, for example what medical care the baby may need, where he or she will be cared for and any potential involvement of social services.\n\nOffer information about help with transportation to appointments if needed to support the woman's attendance.\n\n# Pregnant women who are recent migrants, asylum seekers or refugees, or who have difficulty reading or speaking English\n\nPregnant women who are recent migrants, asylum seekers or refugees, or who have difficulty reading or speaking English, may not make full use of antenatal care services. This may be because of unfamiliarity with the health service or because they find it hard to communicate with healthcare staff.\n\nHealthcare professionals should help support these women's uptake of antenatal care services by:\n\nusing a variety of means to communicate with women\n\ntelling women about antenatal care services and how to use them\n\nundertaking training in the specific needs of women in these groups.\n\n## Service organisation\n\nCommissioners should monitor emergent local needs and plan and adjust services accordingly.\n\nHealthcare professionals should ensure they have accurate information about a woman's current address and contact details during her pregnancy by working with local agencies that provide housing and other services for recent migrants, asylum seekers and refugees, such as asylum centres.\n\nTo allow sufficient time for interpretation, commissioners and those responsible for the organisation of local antenatal services should offer flexibility in the number and length of antenatal appointments when interpreting services are used, over and above the appointments outlined in national guidance (see NICE's guideline on antenatal care).\n\nThose responsible for the organisation of local antenatal services should provide information about pregnancy and antenatal services, including how to find and use antenatal services, in a variety of:\n\nformats, such as posters, notices, leaflets, photographs, drawings/diagrams, online video clips, audio clips and DVDs\n\nsettings, including pharmacies, community centres, faith groups and centres, GP surgeries, family planning clinics, children's centres, reception centres and hostels\n\nlanguages.\n\n## Training for healthcare staff\n\nHealthcare professionals should be given training on:\n\nthe specific health needs of women who are recent migrants, asylum seekers or refugees, such as needs arising from female genital mutilation or HIV\n\nthe specific social, religious and psychological needs of women in these groups\n\nthe most recent government policies on access and entitlement to care for recent migrants, asylum seekers and refugees (see the Department of Health and Social Care and Maternity Action).\n\n## Information and support for women\n\nOffer the woman information on access and entitlement to healthcare.\n\nAt the booking appointment discuss with the woman the importance of keeping her hand-held maternity record with her at all times.\n\nAvoid making assumptions based on a woman's culture, ethnic origin or religious beliefs.\n\n## Communication with women who have difficulty reading or speaking English\n\nProvide the woman with an interpreter (who may be a link worker or advocate and should not be a member of the woman's family, her legal guardian or her partner) who can communicate with her in her preferred language.\n\nWhen giving spoken information, ask the woman about her understanding of what she has been told to ensure she has understood it correctly.\n\n# Young pregnant women aged under\xa020\n\nYoung pregnant women aged under\xa020 may feel uncomfortable using antenatal care services in which the majority of service users are in older age groups. They may be reluctant to recognise their pregnancy or inhibited by embarrassment and fear of parental reaction. They may also have practical problems such as difficulty getting to and from antenatal appointments.\n\nHealthcare professionals should encourage young women aged under\xa020 to use antenatal care services by:\n\noffering age-appropriate services\n\nbeing aware that the young woman may be dealing with other social problems\n\noffering information about help with transportation to and from appointments\n\noffering antenatal care for young women in the community\n\nproviding opportunities for the partner/father of the baby to be involved in the young woman's antenatal care, with her agreement.\n\n## Service organisation\n\nCommissioners should work in partnership with local education authorities and third-sector agencies to improve access to, and continuing contact with, antenatal care services for young women aged under\xa020.\n\nCommissioners should consider commissioning a specialist antenatal service for young women aged under\xa020, using a flexible model of care tailored to the needs of the local population. Components may include:\n\nantenatal care and education in peer groups in a variety of settings, such as GP surgeries, children's centres and schools\n\nantenatal education in peer groups offered at the same time as antenatal appointments and at the same location, such as a 'one-stop shop' (where a range of services can be accessed at the same time).\n\nOffer the young woman aged under\xa020 a named midwife, who should take responsibility for and provide the majority of her antenatal care, and provide a direct-line telephone number for the named midwife.\n\n## Training for healthcare staff\n\nHealthcare professionals should be given training to ensure they are knowledgeable about safeguarding responsibilities for both the young woman and her unborn baby, and the most recent government guidance on consent for examination or treatment. (See the Department of Health and Social Care.)\n\n## Information and support for women\n\nOffer young women aged under\xa020 information that is suitable for their age – including information about care services, antenatal peer group education or drop-in sessions, housing benefit and other benefits – in a variety of formats.\n\n# Pregnant women who experience domestic abuse\n\nA woman who is experiencing domestic abuse may have particular difficulties using antenatal care services: for example, the perpetrator of the abuse may try to prevent her from attending appointments. The woman may be afraid that disclosure of the abuse to a healthcare professional will worsen her situation, or anxious about the reaction of the healthcare professional.\n\nWomen who experience domestic abuse should be supported in their use of antenatal care services by:\n\ntraining healthcare professionals in the identification and care of women who experience domestic abuse\n\nmaking available information and support tailored to women who experience or are suspected to be experiencing domestic abuse\n\nproviding a more flexible series of appointments if needed\n\naddressing women's fears about the involvement of children's services by providing information tailored to their needs.\n\n## Service organisation\n\nCommissioners and those responsible for the organisation of local antenatal services should ensure that local voluntary and statutory organisations that provide domestic abuse support services recognise the need to provide coordinated care and support for service users during pregnancy. (See also the NICE guideline on domestic violence and abuse: multi-agency working.)\n\nCommissioners and those responsible for the organisation of local antenatal services should ensure that a local protocol is written, which:\n\nis developed jointly with social care providers, the police and third-sector agencies by a healthcare professional with expertise in the care of women experiencing domestic abuse\n\nincludes:\n\n\n\nclear referral pathways that set out the information and care that should be offered to women\n\nthe latest government guidance on responding to domestic abuse (see the Department of Health and Social Care's guidance on domestic abuse: a resource for health professionals)\n\nsources of support for women, including addresses and telephone numbers, such as social services, the police, support groups and women's refuges\n\nsafety information for women\n\nplans for follow-up care, such as additional appointments or referral to a domestic abuse support worker\n\nobtaining a telephone number that is agreed with the woman and on which it is safe to contact her\n\ncontact details of other people who should be told that the woman is experiencing domestic abuse, including her GP.\n\n\n\nCommissioners and those responsible for the organisation of local antenatal services should provide for flexibility in the length and frequency of antenatal appointments, over and above those outlined in national guidance (see NICE's guideline on antenatal care) to allow more time for women to discuss the domestic abuse they are experiencing.\n\nOffer the woman a named midwife, who should take responsibility for and provide the majority of her antenatal care.\n\n## Training for healthcare staff\n\nCommissioners of healthcare services and social care services should consider commissioning joint training for health and social care professionals to facilitate greater understanding between the two agencies of each other's roles, and enable healthcare professionals to inform and reassure women who are apprehensive about the involvement of social services.\n\nHealthcare professionals need to be alert to features suggesting domestic abuse and offer women the opportunity to disclose it in an environment in which the woman feels secure. Healthcare professionals should be given training on the care of women known or suspected to be experiencing domestic abuse that includes:\n\nlocal protocols\n\nlocal resources for both the woman and the healthcare professional\n\nfeatures suggesting domestic abuse\n\nhow to discuss domestic abuse with women experiencing it\n\nhow to respond to disclosure of domestic abuse.\n\n## Information and support for women\n\nTell the woman that the information she discloses will be kept in a confidential record and will not be included in her hand-held record.\n\nOffer the woman information about other agencies, including third-sector agencies, which provide support for women who experience domestic abuse.\n\nGive the woman a credit card-sized information card that includes local and national helpline numbers.\n\nConsider offering the woman referral to a domestic abuse support worker.", 'Recommendations for research': "The Guideline Development Group (GDG) has made the following recommendations for research, based on its review of evidence, to improve NICE guidance and antenatal care in the future. The GDG's full set of recommendations for research are detailed in the full guideline.\n\n# Training for healthcare staff\n\nWhat training should be provided to improve staff behaviour towards pregnant women with complex social factors?\n\n## Why this is important\n\nThe evidence reviewed suggests that women facing complex social problems are deterred from attending antenatal appointments, including booking appointments, because of the perceived negative attitude of healthcare staff, including non-clinical staff such as receptionists. It is expected that education and training for staff in order to help them understand the issues faced by women with complex social factors and how their own behaviour can affect these women will reduce negative behaviour and language. A number of training options currently exist that could be used in this context; however, which of these (if any) bring about the anticipated positive changes is not known. Given the resource implications of providing training across the NHS it is important to ascertain the most cost-effective way of providing this.\n\n# Effect of early booking on obstetric and neonatal outcomes\n\nDoes early booking (by 10\xa0weeks, or 12+6\xa0weeks) improve outcomes for pregnant women with complex social problems compared with later booking?\n\n## Why this is important\n\nThe NICE guideline on antenatal care recommends that the booking appointment should ideally take place before 10\xa0weeks and policy by the Department of Health on maternity matters: choice, access and continuity of care in a safe service, supports booking by 12\xa0weeks for all women. The main rationale behind these recommendations is to allow women to participate in antenatal screening programmes for haemoglobinopathies and Down's syndrome in a timely fashion, to have their pregnancies accurately dated using ultrasound scan, and to develop a plan of care for the pregnancy which sets out the number of visits required and additional appointments that may need to be made.\n\nPregnant women with complex social factors are known to book later, on average, than other women and late booking is known to be associated with poor obstetric and neonatal outcomes (see the report of the Confidential Enquiry into Maternal Deaths in the United Kingdom). It seems likely that facilitating early booking for these women is even more important than for the general population of pregnant women. There is, however, no current evidence that putting measures in place to allow this to happen improves pregnancy outcomes for women with complex social factors and their babies.\n\n# How can different service models be assessed?\n\nWhat data should be collected and how should they be collected, and shared, in order to assess the quality of different models of services?\n\n## Why this is important\n\nThere is a paucity of routinely collected data about the effectiveness of different models of care in relation to demography. Although mortality data are accurately reflected in reports published by the Centre for Maternal and Child Enquiries, morbidity and pregnancy outcomes are not often linked back to pregnancies in women with complex social factors. Most research in the area of social complexity and pregnancy is qualitative, descriptive and non-comparative. In order to evaluate the financial and clinical effectiveness of specialised models of care there is a need for baseline data on these pregnancies and their outcomes in relation to specific models of care.\n\nA national database of routinely collected pregnancy data is needed. The GDG is aware that a national maternity dataset is currently in development and it is hoped that this will ensure that data are collected in a similar format across England and Wales to allow for comparisons of different models of care.\n\n# Models of service provision\n\nWhat models of service provision exist in the UK for the four populations addressed in this guideline who experience socially complex pregnancies (women who misuse substances, women who are recent migrants, asylum seekers or refugees or who have difficulty reading or speaking English, young women aged under 20 and women who experience domestic abuse)? How do these models compare, both with each other and with standard care, in terms of outcomes?\n\n## Why this is important\n\nThe evidence reviewed by the GDG was poor in several respects. Many of the studies were conducted in other parts of the world, and it was not clear whether they would be applicable to the UK. Many of the interventions being studied were multifaceted, and it was not clear from the research which aspect of the intervention led to a change in outcome or whether it would lead to a similar change in the UK. Also, in some instances it was not clear whether a particular intervention, for example a specialist service for teenagers, made any difference to the outcomes being studied.\n\nDeveloping a clear and detailed map of existing services in the UK for pregnant women with complex social factors, and the effectiveness of these services, would enable a benchmark of good practice to be set that local providers could adapt to suit their own populations and resources. A map of providers, their services and outcomes may also enable commissioners and providers to learn from each other, work together to develop joint services and share information in a way that would lead to continuous improvement in services for these groups of women.\n\n# Antenatal appointments for women who misuse substances\n\nWhat methods help and encourage women who misuse substances to maintain contact with antenatal services/attend antenatal appointments? What additional consultations (if any) do women who misuse substances need, over and above the care described in the NICE guideline 'Antenatal care' (NICE clinical guideline 62)?\n\n## Why this is important\n\nWomen who misuse substances are known to have poorer obstetric and neonatal outcomes than other women. Late booking and poor attendance for antenatal care are known to be associated with poor outcomes and therefore it is important that measures are put in place to encourage these women to attend antenatal care on a regular basis. Some of the evidence examined by the GDG suggested that some interventions could improve attendance for antenatal care, but this evidence was undermined by the use of self-selected comparison groups, so that the effect of the intervention was unclear.\n\nIn relation to additional consultations, the GDG was unable to identify any particular intervention that had a positive effect on outcomes, although there was low-quality evidence that additional support seemed to improve outcomes. Much of the evidence was from the US and there was a lack of high-quality UK data.\n\nIt seems likely that making it easier for these women to attend antenatal appointments and providing tailored care will improve outcomes, but at present it is not clear how this should be done."}	https://www.nice.org.uk/guidance/cg110	This guideline covers antenatal care for all pregnant women with complex social factors (particularly alcohol or drug misuse, recent migrant or asylum seeker status, difficulty reading or speaking English, aged under 20, domestic abuse). It offers advice on improving access to care, maintaining contact with antenatal carers, and additional information and support for these women.
4739325dfafb9e9b1acb06d1278981f16a2626a5	nice	Laparoscopic hysterectomy (including laparoscopic total hysterectomy and laparoscopically assisted vaginal hysterectomy) for endometrial cancer	Laparoscopic hysterectomy (including laparoscopic total hysterectomy and laparoscopically assisted vaginal hysterectomy) for endometrial cancer # Guidance Current evidence on the safety and efficacy of laparoscopic hysterectomy (including laparoscopic total hysterectomy and laparoscopically assisted vaginal hysterectomy) for endometrial cancer is adequate to support the use of this procedure provided that normal arrangements are in place for clinical governance, consent and audit. Patient selection for laparoscopic hysterectomy for endometrial cancer should be carried out by a multidisciplinary gynaecological oncology team. Advanced laparoscopic skills are required for this procedure and clinicians should undergo special training and mentorship. The Royal College of Obstetricians and Gynaecologists has developed an Advanced Training Skills Module. This needs to be supplemented by further training to achieve the skills required for laparoscopic hysterectomy for endometrial cancer. Long-term follow-up data on recurrence and survival following laparoscopic hysterectomy for endometrial cancer would assist any future review of the procedure by NICE.# The procedure # Indications and current treatments The uterus is the fourth most common site of malignancy among women in the UK, and endometrial cancer is the most common type of uterine cancer. The predominant symptom of endometrial cancer is abnormal vaginal bleeding, especially in postmenopausal women. The International Federation of Gynecology and Obstetrics (FIGO) system is used to stage endometrial cancer from stage I (cancer confined to the uterus) to stage IV (cancer that has spread to another body organ). Endometrial cancer is usually treated by total hysterectomy with bilateral salpingo-oophorectomy. Radiotherapy, hormone therapy and chemotherapy may also be used. # Outline of the procedure The aim of a laparoscopic approach to hysterectomy is to provide a treatment option with smaller incisions and scars, shorter hospital stay and shorter recovery period than for open surgery. Laparoscopic hysterectomy is usually carried out with the patient under general anaesthesia. Several small incisions provide access for the laparoscope and surgical instruments. The abdomen is insufflated with carbon dioxide. The uterus, supporting ligaments and the upper vagina are removed. Sometimes, the pelvic and para-aortic lymph nodes are also removed. The uterus is removed vaginally. The other tissues can be removed vaginally or through the abdominal incisions. Sections 2.3 and 2.4 describe efficacy and safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview. # Efficacy In a meta-analysis, 3 randomised-controlled trials (RCTs) including a total of 359 patients treated by laparoscopic hysterectomy or by abdominal hysterectomy reported overall survival rates of 92% (169/184) and 88% (154/175) respectively (p = 0.976) and disease-free survival rates of 88% (161/184) and 88% (154/175) respectively (p = 0.986) at follow-up of a maximum of 36 months. A non-randomised comparative study of 309 patients reported 5-year overall survival rates of 98% both for patients treated by laparoscopic (n = 165) and abdominal (n = 144) hysterectomy. The 5-year progression-free survival rate was 96% for patients after laparoscopic hysterectomy and 97% for patients after abdominal hysterectomy (p = 0.74). Hospital stay after laparoscopic hysterectomy was significantly shorter than after abdominal hysterectomy in the RCTs of 159 and 122 patients (2 days vs 5 days, p < 0.01; 8 days vs 11 days, p = 0.001 respectively). The proportion of patients staying in hospital for more than 2 days was significantly higher after abdominal hysterectomy compared with laparoscopic hysterectomy (94% vs 52%, p < 0.0001) in the RCT of 2616 patients. The Specialist Advisers listed key efficacy outcomes as overall survival, recurrence rate, quality of life, operative time and length of hospital stay. # Safety Rates of conversion to laparotomy were reported as 26% (434/1682), 0% (0/81), 8% (5/63), 5% (10/188), 5% (11/226) and 5% (4/73) among patients treated by laparoscopic hysterectomy in RCTs of 2616,159 and 122 patients, and non-randomised comparative studies of 309, 510 and 169 patients respectively. The RCT of 2616 patients treated by laparoscopic or abdominal hysterectomy reported no significant difference in the rate of intraoperative complications (10% vs 8% , p = 0.106) but significantly fewer postoperative complications after laparoscopic compared with abdominal hysterectomy (14% vs 21% , p < 0.001). The meta-analysis including a total of 498 patients reported no significant difference in the rate of intraoperative complications for patients treated by laparoscopic compared with abdominal hysterectomy (8% vs 12% , p = 0.39). Significantly fewer postoperative complications were reported associated with laparoscopic compared with abdominal hysterectomy in the same study (17% vs 32% , p = 0.007). The RCT of 2616 patients and the non-randomised comparative study of 309 patients reported intraoperative complications of bowel injury (2% and less than 1% ), vascular injury (4% and 1% ), bladder injury (1% ) and ureter injury (less than 1% ) among patients treated by laparoscopic hysterectomy. In the non-randomised comparative study of 309 patients treated by laparoscopic or abdominal hysterectomy, intra-abdominal abscess was reported in 2% (4/165) and 6% (8/144) of patients respectively. The RCT of 84 patients reported port-site recurrence in 1 of 40 patients treated by laparoscopic hysterectomy after a median 79-month follow-up. The non-randomised comparative study of 309 patients treated by laparoscopic or abdominal hysterectomy reported bladder dysfunction in 1 patient in each group (1/165 and 1/144 respectively). The Specialist Advisers listed adverse events reported in the literature as conversion to open surgery, damage to abdominal or pelvic structures, respiratory difficulties, port-site herniation and port-site metastasis. They reported dehiscence of the vaginal vault after laparoscopic suturing as an anecdotal adverse event.# Further information For related NICE guidance see our website. # Information for patients NICE has produced information on this procedure for patients and carers ('Understanding NICE guidance'). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.# About this guidance NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland. This guidance was developed using the NICE interventional procedure guidance process. We have produced a summary of this guidance for patients and carers. Information about the evidence it is based on is also available. Changes since publication January 2012: minor maintenance. Your responsibility This guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer. Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties. Copyright © National Institute for Health and Clinical Excellence 2010. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE. Contact NICE National Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT www.nice.org.uk nice@nice.org.uk	{'Guidance': 'Current evidence on the safety and efficacy of laparoscopic hysterectomy (including laparoscopic total hysterectomy and laparoscopically assisted vaginal hysterectomy) for endometrial cancer is adequate to support the use of this procedure provided that normal arrangements are in place for clinical governance, consent and audit.\n\nPatient selection for laparoscopic hysterectomy for endometrial cancer should be carried out by a multidisciplinary gynaecological oncology team.\n\nAdvanced laparoscopic skills are required for this procedure and clinicians should undergo special training and mentorship. The Royal College of Obstetricians and Gynaecologists has developed an Advanced Training Skills Module. This needs to be supplemented by further training to achieve the skills required for laparoscopic hysterectomy for endometrial cancer.\n\nLong-term follow-up data on recurrence and survival following laparoscopic hysterectomy for endometrial cancer would assist any future review of the procedure by NICE.', 'The procedure': '# Indications and current treatments\n\nThe uterus is the fourth most common site of malignancy among women in the UK, and endometrial cancer is the most common type of uterine cancer. The predominant symptom of endometrial cancer is abnormal vaginal bleeding, especially in postmenopausal women.\n\nThe International Federation of Gynecology and Obstetrics (FIGO) system is used to stage endometrial cancer from stage I (cancer confined to the uterus) to stage IV (cancer that has spread to another body organ).\n\nEndometrial cancer is usually treated by total hysterectomy with bilateral salpingo-oophorectomy. Radiotherapy, hormone therapy and chemotherapy may also be used.\n\n# Outline of the procedure\n\nThe aim of a laparoscopic approach to hysterectomy is to provide a treatment option with smaller incisions and scars, shorter hospital stay and shorter recovery period than for open surgery.\n\nLaparoscopic hysterectomy is usually carried out with the patient under general anaesthesia. Several small incisions provide access for the laparoscope and surgical instruments. The abdomen is insufflated with carbon dioxide. The uterus, supporting ligaments and the upper vagina are removed. Sometimes, the pelvic and para-aortic lymph nodes are also removed. The uterus is removed vaginally. The other tissues can be removed vaginally or through the abdominal incisions.\n\nSections 2.3 and 2.4 describe efficacy and safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview.\n\n# Efficacy\n\nIn a meta-analysis, 3 randomised-controlled trials (RCTs) including a total of 359 patients treated by laparoscopic hysterectomy or by abdominal hysterectomy reported overall survival rates of 92% (169/184) and 88% (154/175) respectively (p = 0.976) and disease-free survival rates of 88% (161/184) and 88% (154/175) respectively (p = 0.986) at follow-up of a maximum of 36 months.\n\nA non-randomised comparative study of 309 patients reported 5-year overall survival rates of 98% both for patients treated by laparoscopic (n = 165) and abdominal (n = 144) hysterectomy. The 5-year progression-free survival rate was 96% for patients after laparoscopic hysterectomy and 97% for patients after abdominal hysterectomy (p = 0.74).\n\nHospital stay after laparoscopic hysterectomy was significantly shorter than after abdominal hysterectomy in the RCTs of 159 and 122 patients (2 days vs 5 days, p < 0.01; 8 days vs 11 days, p = 0.001 respectively). The proportion of patients staying in hospital for more than 2 days was significantly higher after abdominal hysterectomy compared with laparoscopic hysterectomy (94% vs 52%, p < 0.0001) in the RCT of 2616 patients.\n\nThe Specialist Advisers listed key efficacy outcomes as overall survival, recurrence rate, quality of life, operative time and length of hospital stay.\n\n# Safety\n\nRates of conversion to laparotomy were reported as 26% (434/1682), 0% (0/81), 8% (5/63), 5% (10/188), 5% (11/226) and 5% (4/73) among patients treated by laparoscopic hysterectomy in RCTs of 2616,159 and 122 patients, and non-randomised comparative studies of 309, 510 and 169 patients respectively.\n\nThe RCT of 2616 patients treated by laparoscopic or abdominal hysterectomy reported no significant difference in the rate of intraoperative complications (10% [160/1682] vs 8% [69/909], p = 0.106) but significantly fewer postoperative complications after laparoscopic compared with abdominal hysterectomy (14% [240/1682] vs 21% [191/909], p < 0.001).\n\nThe meta-analysis including a total of 498 patients reported no significant difference in the rate of intraoperative complications for patients treated by laparoscopic compared with abdominal hysterectomy (8% [14/169] vs 12% [19/162], p = 0.39). Significantly fewer postoperative complications were reported associated with laparoscopic compared with abdominal hysterectomy in the same study (17% [27/158] vs 32% [50/155], p = 0.007).\n\nThe RCT of 2616 patients and the non-randomised comparative study of 309 patients reported intraoperative complications of bowel injury (2% [37/1682] and less than 1% [1/165]), vascular injury (4% [75/1682] and 1% [2/165]), bladder injury (1% [21/1682 and 2/165]) and ureter injury (less than 1% [14/1682 and 1/165]) among patients treated by laparoscopic hysterectomy.\n\nIn the non-randomised comparative study of 309 patients treated by laparoscopic or abdominal hysterectomy, intra-abdominal abscess was reported in 2% (4/165) and 6% (8/144) of patients respectively.\n\nThe RCT of 84 patients reported port-site recurrence in 1 of 40 patients treated by laparoscopic hysterectomy after a median 79-month follow-up.\n\nThe non-randomised comparative study of 309 patients treated by laparoscopic or abdominal hysterectomy reported bladder dysfunction in 1 patient in each group (1/165 and 1/144 respectively).\n\nThe Specialist Advisers listed adverse events reported in the literature as conversion to open surgery, damage to abdominal or pelvic structures, respiratory difficulties, port-site herniation and port-site metastasis. They reported dehiscence of the vaginal vault after laparoscopic suturing as an anecdotal adverse event.', 'Further information': "For related NICE guidance see our website.\n\n# Information for patients\n\nNICE has produced information on this procedure for patients and carers ('Understanding NICE guidance'). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.", 'About this guidance': 'NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland.\n\nThis guidance was developed using the NICE interventional procedure guidance process.\n\nWe have produced a summary of this guidance for patients and carers. Information about the evidence it is based on is also available.\n\nChanges since publication\n\nJanuary 2012: minor maintenance.\n\nYour responsibility\n\nThis guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.\n\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.\n\nCopyright\n\n© National Institute for Health and Clinical Excellence 2010. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.\n\nContact NICE\n\nNational Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT\n\nwww.nice.org.uk\n \n nice@nice.org.uk\n 0845 033 7780'}	https://www.nice.org.uk/guidance/ipg356
dec58f4b9c664aa31c63228fc90bacdf3360ddd8	nice	Endoscopic submucosal dissection of oesophageal dysplasia and neoplasia	Endoscopic submucosal dissection of oesophageal dysplasia and neoplasia # Guidance Current evidence on the efficacy of endoscopic submucosal dissection (ESD) in patients with oesophageal adenocarcinoma or high-grade dysplasia in Barrett's oesophagus is limited in quantity and there are safety concerns specifically regarding the risk of oesophageal perforation. Therefore, in these patients, the procedure should only be used in the context of research. Current evidence on the efficacy of ESD in patients with oesophageal squamous carcinoma or squamous dysplasia is limited. This evidence is mostly from Japan where the epidemiology of oesophageal cancer is different from the UK. There are safety concerns specifically regarding the risk of oesophageal perforation. Therefore, in these patients, the procedure should only be used with special arrangements for clinical governance, consent and audit or research. Clinicians wishing to undertake ESD for oesophageal squamous carcinoma or squamous dysplasia should take the following actions. Inform the clinical governance leads in their Trusts. Ensure that patients and their carers understand the uncertainty about the procedure's safety and efficacy and provide them with clear written information. In addition, the use of NICE's information for patients ('Understanding NICE guidance') is recommended. Audit and review clinical outcomes of all patients having ESD for oesophageal squamous carcinoma or squamous dysplasia (see section 3.1). Patient selection should be carried out by an upper gastrointestinal cancer multidisciplinary team. The procedure is technically challenging and should be carried out only by clinicians with specific training in the technique. NICE encourages further research into the procedure. Studies should define clearly the type, grade and stage of cancer or dysplasia being treated. Efficacy outcomes should include adequacy of resection and the proportion of patients free from local recurrence. Safety outcomes should include perforation and stricture, and the consequences of these complications.# The procedure # Indications and current treatments Malignant or premalignant changes in the oesophagus may take the form of either squamous cell carcinoma or adenocarcinoma, or their respective premalignant (dysplastic) forms. In the UK, approximately two thirds of all oesophageal cancers are adenocarcinomas and one third are squamous carcinomas. Depending on the type and stage of cancer or dysplasia, current treatment options include oesophagectomy, chemotherapy, radiotherapy, ablative procedures such as radiofrequency ablation, and endoscopic mucosal resection (EMR). The latter usually removes lesions piecemeal, in contrast to ESD which aims to remove lesions intact and with a margin of healthy tissue. # Outline of the procedure ESD is usually preceded by diagnostic endoscopy, biopsy and imaging. The procedure is done with the patient under sedation or general anaesthesia. Under endoscopic visualisation, the submucosa is injected with saline to help lift the lesion. This fluid may contain pigment to help delineate the lesion, and adrenaline to reduce bleeding. A circumferential mucosal incision is made with an electrocautery knife around the lesion. Submucosal dissection is then carried out, parallel to the muscle layer, and the lesion is removed. A transparent hood can be used to retract the already dissected part of the lesion out of the visual field. Thermocoagulation is used to achieve haemostasis. Endoscopic clips can be used for larger vessels or to manage perforation. Sections 2.3 and 2.4 describe efficacy and safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview. # Efficacy A comparative case series of 136 patients treated by ESD or by 1 of 2 different EMR techniques, reported en-bloc resection rates of 100% (31/31) for ESD, and 87% (59/68) and 71% (51/72) for the two EMR procedures (p < 0.05). A comparative case series of 77 patients treated by ESD or EMR reported en-bloc resection in 91% (29/32) and 11% (5/46) of lesions respectively. Case series of 84 and 43 patients (including 107 and 58 neoplastic or dysplastic squamous lesions, respectively) reported en-bloc resection of all lesions in both series, and R0 resection (both lateral and basal margins free) in 88% (94/107) and 78% (45/58) of lesions respectively. The comparative case series of 77 patients treated by ESD or EMR reported local recurrence in 4% (1/26) and 25% (11/44) of patients respectively (follow-up and significance not stated). The Specialist Advisers listed key efficacy outcomes as adequacy of cancer treatment (complete resection with clear margins on histology) and survival. # Safety Perforation during ESD causing pneumomediastinum was reported in 5% (4/84) of patients in the case series of 84 patients and 1 patient in the comparative case series of 136 patients (all successfully treated by antibiotics). Perforation with pneumomediastinum was reported in 7% (4/58) of lesion dissections in the case series of 43 patients: all were successfully treated by endoscopic clipping with the pneumomediastinum resolving spontaneously within a week. Pneumomediastinum was reported in 6% (6/102) of cases in the series of 102, all successfully treated with antibiotics, fasting and intravenous infusion. Oesophageal stricture was reported in 16% (9/58) of lesion dissections in the case series of 43 patients, all successfully treated by balloon dilatation. In case series of 102 cases and 65 patients, oesophageal stenosis requiring balloon dilatation during follow-up was reported in 7% (7/102) of cases (mean follow-up 21 months) and 17% (11/65) of patients (follow-up of up to 47 months) respectively. The Specialist Advisers considered possible adverse events to be aspiration pneumonia, uncontrollable bleeding and the need for emergency oesophagectomy. # Other comments The Committee considered that ESD could be suitable for a national register.# Further information This guidance requires that clinicians undertaking ESD for oesophageal squamous carcinoma or squamous dysplasia make special arrangements for audit. NICE has identified relevant audit criteria and has developed an audit tool (which is for use at local discretion). For related NICE guidance see our website. # Information for patients NICE has produced information on this procedure for patients and carers ('Understanding NICE guidance'). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.# About this guidance NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland. This guidance was developed using the NICE interventional procedure guidance process. We have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available. Changes since publication January 2012: minor maintenance. Your responsibility This guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer. Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties. Copyright © National Institute for Health and Clinical Excellence 2010. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE. Contact NICE National Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT www.nice.org.uk nice@nice.org.uk	{'Guidance ': "Current evidence on the efficacy of endoscopic submucosal dissection (ESD) in patients with oesophageal adenocarcinoma or high-grade dysplasia in Barrett's oesophagus is limited in quantity and there are safety concerns specifically regarding the risk of oesophageal perforation. Therefore, in these patients, the procedure should only be used in the context of research.\n\nCurrent evidence on the efficacy of ESD in patients with oesophageal squamous carcinoma or squamous dysplasia is limited. This evidence is mostly from Japan where the epidemiology of oesophageal cancer is different from the UK. There are safety concerns specifically regarding the risk of oesophageal perforation. Therefore, in these patients, the procedure should only be used with special arrangements for clinical governance, consent and audit or research.\n\nClinicians wishing to undertake ESD for oesophageal squamous carcinoma or squamous dysplasia should take the following actions.\n\nInform the clinical governance leads in their Trusts.\n\nEnsure that patients and their carers understand the uncertainty about the procedure's safety and efficacy and provide them with clear written information. In addition, the use of NICE's information for patients ('Understanding NICE guidance') is recommended.\n\nAudit and review clinical outcomes of all patients having ESD for oesophageal squamous carcinoma or squamous dysplasia (see section 3.1).\n\nPatient selection should be carried out by an upper gastrointestinal cancer multidisciplinary team.\n\nThe procedure is technically challenging and should be carried out only by clinicians with specific training in the technique.\n\nNICE encourages further research into the procedure. Studies should define clearly the type, grade and stage of cancer or dysplasia being treated. Efficacy outcomes should include adequacy of resection and the proportion of patients free from local recurrence. Safety outcomes should include perforation and stricture, and the consequences of these complications.", 'The procedure ': '# Indications and current treatments\n\nMalignant or premalignant changes in the oesophagus may take the form of either squamous cell carcinoma or adenocarcinoma, or their respective premalignant (dysplastic) forms. In the UK, approximately two thirds of all oesophageal cancers are adenocarcinomas and one third are squamous carcinomas.\n\nDepending on the type and stage of cancer or dysplasia, current treatment options include oesophagectomy, chemotherapy, radiotherapy, ablative procedures such as radiofrequency ablation, and endoscopic mucosal resection (EMR). The latter usually removes lesions piecemeal, in contrast to ESD which aims to remove lesions intact and with a margin of healthy tissue.\n\n# Outline of the procedure\n\nESD is usually preceded by diagnostic endoscopy, biopsy and imaging. The procedure is done with the patient under sedation or general anaesthesia. Under endoscopic visualisation, the submucosa is injected with saline to help lift the lesion. This fluid may contain pigment to help delineate the lesion, and adrenaline to reduce bleeding. A circumferential mucosal incision is made with an electrocautery knife around the lesion. Submucosal dissection is then carried out, parallel to the muscle layer, and the lesion is removed. A transparent hood can be used to retract the already dissected part of the lesion out of the visual field. Thermocoagulation is used to achieve haemostasis. Endoscopic clips can be used for larger vessels or to manage perforation.\n\nSections 2.3 and 2.4 describe efficacy and safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview.\n\n# Efficacy\n\nA comparative case series of 136 patients treated by ESD or by 1 of 2 different EMR techniques, reported en-bloc resection rates of 100% (31/31) for ESD, and 87% (59/68) and 71% (51/72) for the two EMR procedures (p < 0.05). A comparative case series of 77 patients treated by ESD or EMR reported en-bloc resection in 91% (29/32) and 11% (5/46) of lesions respectively. Case series of 84 and 43 patients (including 107 and 58 neoplastic or dysplastic squamous lesions, respectively) reported en-bloc resection of all lesions in both series, and R0 resection (both lateral and basal margins free) in 88% (94/107) and 78% (45/58) of lesions respectively.\n\nThe comparative case series of 77 patients treated by ESD or EMR reported local recurrence in 4% (1/26) and 25% (11/44) of patients respectively (follow-up and significance not stated).\n\nThe Specialist Advisers listed key efficacy outcomes as adequacy of cancer treatment (complete resection with clear margins on histology) and survival.\n\n# Safety\n\nPerforation during ESD causing pneumomediastinum was reported in 5% (4/84) of patients in the case series of 84 patients and 1 patient in the comparative case series of 136 patients (all successfully treated by antibiotics). Perforation with pneumomediastinum was reported in 7% (4/58) of lesion dissections in the case series of 43 patients: all were successfully treated by endoscopic clipping with the pneumomediastinum resolving spontaneously within a week.\n\nPneumomediastinum was reported in 6% (6/102) of cases in the series of 102, all successfully treated with antibiotics, fasting and intravenous infusion.\n\nOesophageal stricture was reported in 16% (9/58) of lesion dissections in the case series of 43 patients, all successfully treated by balloon dilatation.\n\nIn case series of 102 cases and 65 patients, oesophageal stenosis requiring balloon dilatation during follow-up was reported in 7% (7/102) of cases (mean follow-up 21 months) and 17% (11/65) of patients (follow-up of up to 47 months) respectively.\n\nThe Specialist Advisers considered possible adverse events to be aspiration pneumonia, uncontrollable bleeding and the need for emergency oesophagectomy.\n\n# Other comments\n\nThe Committee considered that ESD could be suitable for a national register.', 'Further information': "This guidance requires that clinicians undertaking ESD for oesophageal squamous carcinoma or squamous dysplasia make special arrangements for audit. NICE has identified relevant audit criteria and has developed an audit tool (which is for use at local discretion).\n\nFor related NICE guidance see our website.\n\n# Information for patients\n\nNICE has produced information on this procedure for patients and carers ('Understanding NICE guidance'). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.", 'About this guidance': 'NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland.\n\nThis guidance was developed using the NICE interventional procedure guidance process.\n\nWe have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available.\n\nChanges since publication\n\nJanuary 2012: minor maintenance.\n\nYour responsibility\n\nThis guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.\n\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.\n\nCopyright\n\n© National Institute for Health and Clinical Excellence 2010. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.\n\nContact NICE\n\nNational Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT\n\nwww.nice.org.uk\n \n nice@nice.org.uk\n 0845 033 7780'}	https://www.nice.org.uk/guidance/ipg355
4e94ed481d25e573475508564021d754d2caf1fe	nice	Percutaneous intradiscal laser ablation in the lumbar spine	Percutaneous intradiscal laser ablation in the lumbar spine # Guidance This guidance replaces previous guidance on laser lumbar discectomy (interventional procedure guidance 27). Current evidence on the safety and efficacy of percutaneous intradiscal laser ablation in the lumbar spine is adequate to support the use of this procedure provided that normal arrangements are in place for clinical governance, consent and audit. Patients selected for the procedure should be limited to those with severe pain refractory to conservative treatment, in whom imaging studies show bulging of an intact disc, and who do not have neurological deficit requiring surgical decompression.# The procedure # Indications and current treatments Symptomatic herniation (prolapse) of a lumbar intravertebral disc is a common cause of chronic low back pain and sciatica. Disc herniation is a result of the protrusion of the nucleus pulposus through a tear in the annulus fibrosus. The annulus fibrosus may rupture completely, resulting in an extruded disc, or it may remain intact but stretched, resulting in a contained (bulging) disc prolapse. Protruding discs may compress one or more nerve roots, resulting in pain and numbness in the leg. Conservative treatment options include rest, analgesic or anti-inflammatory medication, epidural injection and physical therapies. Current surgical treatment options include microdiscectomy, percutaneous intradiscal electrothermal therapy, percutaneous intradiscal radiofrequency thermocoagulation and percutaneous disc decompression using coblation. Surgical decompression is considered when there is nerve compression causing weakness or persistent symptoms that are unresponsive to conservative treatment. # Outline of the procedure The aim of percutaneous intradiscal laser ablation (also commonly referred to in the literature as percutaneous laser disc decompression) is to vaporise part of a prolapsed disc. It can only be carried out if the prolapse is contained (that is, the disc is bulging but the nucleus pulposus has not extruded through the annulus fibrosus). The procedure is usually carried out under local anaesthesia and sedation, with the patient in the prone position. Under fluoroscopic guidance, a spinal needle is inserted through the annulus fibrosus into the nucleus pulposus, and an optical fibre is introduced through the needle. Laser energy is then delivered through the optical fibre to vaporise part of the nucleus pulposus. Several types of laser are available for this procedure. Sections 2.3 and 2.4 describe efficacy and safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview. # Efficacy A non-randomised comparative study of 1000 patients reported 'excellent' or 'good' MacNab criteria scores (pain relieved by 50% or more and improved motor function) in 84% (419/500) of patients treated by the procedure and 86% (428/500) of patients treated by microdiscectomy at mean 2-year follow-up (significance not stated). A non-randomised comparative study of 106 patients reported 'excellent' MacNab criteria scores (pain relieved by 75% or more and no limitation of motor function) in 48% (29/60) of patients treated by the procedure compared with 48% (22/46) of patients treated by automated percutaneous lumbar discectomy (APLD) (follow-up not stated; difference reported as not significant). A case series of 518 patients reported an overall success rate (using MacNab criteria; not otherwise described) of 75% (absolute figures and follow-up not stated). The non-randomised comparative study of 1000 patients reported reoperation for herniation or persistent leg or back pain in 3% (16/500) of patients treated by the procedure and 7% (35/500) of patients treated by microdiscectomy at a mean 2-year follow-up. A case series of 576 patients reported that 61% of patients were satisfied with the overall outcome of the procedure (absolute figures and follow-up not stated). The Specialist Advisers listed key efficacy outcomes as recurrence rate, reoperation rate, leg and back pain score, Oswestry Disability Index score and successful decompression. # Safety Aseptic discitis (post-procedural inflammatory pain) requiring up to 3 days of hospitalisation with steroid treatment was reported in 2 patients treated by the procedure in a non-randomised comparative study of 81 patients. Case series of 576 and 518 patients reported aseptic discitis in 4 and 2 patients respectively. In the second series both patients developed aseptic discitis up to 4 days after the procedure (not otherwise described) and were treated successfully with bed rest and analgesics. Septic discitis 3 days after the procedure (confirmed by magnetic resonance imaging and needle puncture culture, which was positive for Staphylococcus aureus) was reported in 2 patients in the case series of 518 patients. Both patients were treated with parenteral vancomycin for 6 weeks. Intervertebral disc infection (not otherwise described) was reported in no patients treated by the procedure and 1 patient treated by APLD in the non-randomised comparative study of 106 patients (timing of event not stated). Subchondral vertebral osteonecrosis (confirmed by MRI) was reported in 2% (4/182) of patients in the case series of 182 patients: 1 patient underwent surgical treatment for persistent severe back pain, which resolved 1 year after the initial procedure, and 3 patients had conservative management of their pain which had diminished at 2-year follow-up after the initial procedure. A case series of 10 patients who required salvage operations after the procedure to address herniated discs reported that all patients showed evidence of heat-induced cell necrosis and carbonisation, with herniating masses completely compressing and adhering to nerve roots. The Specialist Advisers stated that bowel perforation was described in the literature. They considered theoretical adverse events to include dural tear, heat damage due to incorrect placement of the probe, recurrent protrusion of disc, nerve damage, infection, vertebral body collapse, loss of disc height and perineural scarring.# Further information For related NICE guidance see our website. # Information for patients NICE has produced information on this procedure for patients and carers ('Understanding NICE guidance'). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.# About this guidance NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland. This guidance was developed using the NICE interventional procedure guidance process. It updates and replaces NICE interventional procedure guidance 27. We have produced a summary of this guidance for patients and carers. Information about the evidence it is based on is also available. Changes since publication January 2012: minor maintenance. Your responsibility This guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer. Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties. Copyright © National Institute for Health and Clinical Excellence 2010. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE. Contact NICE National Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT www.nice.org.uk nice@nice.org.uk	{'Guidance': 'This guidance replaces previous guidance on laser lumbar discectomy (interventional procedure guidance 27).\n\nCurrent evidence on the safety and efficacy of percutaneous intradiscal laser ablation in the lumbar spine is adequate to support the use of this procedure provided that normal arrangements are in place for clinical governance, consent and audit.\n\nPatients selected for the procedure should be limited to those with severe pain refractory to conservative treatment, in whom imaging studies show bulging of an intact disc, and who do not have neurological deficit requiring surgical decompression.', 'The procedure': "# Indications and current treatments\n\nSymptomatic herniation (prolapse) of a lumbar intravertebral disc is a common cause of chronic low back pain and sciatica. Disc herniation is a result of the protrusion of the nucleus pulposus through a tear in the annulus fibrosus. The annulus fibrosus may rupture completely, resulting in an extruded disc, or it may remain intact but stretched, resulting in a contained (bulging) disc prolapse. Protruding discs may compress one or more nerve roots, resulting in pain and numbness in the leg.\n\nConservative treatment options include rest, analgesic or anti-inflammatory medication, epidural injection and physical therapies. Current surgical treatment options include microdiscectomy, percutaneous intradiscal electrothermal therapy, percutaneous intradiscal radiofrequency thermocoagulation and percutaneous disc decompression using coblation. Surgical decompression is considered when there is nerve compression causing weakness or persistent symptoms that are unresponsive to conservative treatment.\n\n# Outline of the procedure\n\nThe aim of percutaneous intradiscal laser ablation (also commonly referred to in the literature as percutaneous laser disc decompression) is to vaporise part of a prolapsed disc. It can only be carried out if the prolapse is contained (that is, the disc is bulging but the nucleus pulposus has not extruded through the annulus fibrosus).\n\nThe procedure is usually carried out under local anaesthesia and sedation, with the patient in the prone position. Under fluoroscopic guidance, a spinal needle is inserted through the annulus fibrosus into the nucleus pulposus, and an optical fibre is introduced through the needle. Laser energy is then delivered through the optical fibre to vaporise part of the nucleus pulposus.\n\nSeveral types of laser are available for this procedure.\n\nSections 2.3 and 2.4 describe efficacy and safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview.\n\n# Efficacy\n\nA non-randomised comparative study of 1000 patients reported 'excellent' or 'good' MacNab criteria scores (pain relieved by 50% or more and improved motor function) in 84% (419/500) of patients treated by the procedure and 86% (428/500) of patients treated by microdiscectomy at mean 2-year follow-up (significance not stated).\n\nA non-randomised comparative study of 106 patients reported 'excellent' MacNab criteria scores (pain relieved by 75% or more and no limitation of motor function) in 48% (29/60) of patients treated by the procedure compared with 48% (22/46) of patients treated by automated percutaneous lumbar discectomy (APLD) (follow-up not stated; difference reported as not significant).\n\nA case series of 518 patients reported an overall success rate (using MacNab criteria; not otherwise described) of 75% (absolute figures and follow-up not stated).\n\nThe non-randomised comparative study of 1000 patients reported reoperation for herniation or persistent leg or back pain in 3% (16/500) of patients treated by the procedure and 7% (35/500) of patients treated by microdiscectomy at a mean 2-year follow-up.\n\nA case series of 576 patients reported that 61% of patients were satisfied with the overall outcome of the procedure (absolute figures and follow-up not stated).\n\nThe Specialist Advisers listed key efficacy outcomes as recurrence rate, reoperation rate, leg and back pain score, Oswestry Disability Index score and successful decompression.\n\n# Safety\n\nAseptic discitis (post-procedural inflammatory pain) requiring up to 3 days of hospitalisation with steroid treatment was reported in 2 patients treated by the procedure in a non-randomised comparative study of 81 patients. Case series of 576 and 518 patients reported aseptic discitis in 4 and 2 patients respectively. In the second series both patients developed aseptic discitis up to 4 days after the procedure (not otherwise described) and were treated successfully with bed rest and analgesics.\n\nSeptic discitis 3 days after the procedure (confirmed by magnetic resonance imaging [MRI] and needle puncture culture, which was positive for Staphylococcus aureus) was reported in 2 patients in the case series of 518 patients. Both patients were treated with parenteral vancomycin for 6 weeks. Intervertebral disc infection (not otherwise described) was reported in no patients treated by the procedure and 1 patient treated by APLD in the non-randomised comparative study of 106 patients (timing of event not stated).\n\nSubchondral vertebral osteonecrosis (confirmed by MRI) was reported in 2% (4/182) of patients in the case series of 182 patients: 1 patient underwent surgical treatment for persistent severe back pain, which resolved 1 year after the initial procedure, and 3 patients had conservative management of their pain which had diminished at 2-year follow-up after the initial procedure.\n\nA case series of 10 patients who required salvage operations after the procedure to address herniated discs reported that all patients showed evidence of heat-induced cell necrosis and carbonisation, with herniating masses completely compressing and adhering to nerve roots.\n\nThe Specialist Advisers stated that bowel perforation was described in the literature. They considered theoretical adverse events to include dural tear, heat damage due to incorrect placement of the probe, recurrent protrusion of disc, nerve damage, infection, vertebral body collapse, loss of disc height and perineural scarring.", 'Further information': "For related NICE guidance see our website.\n\n# Information for patients\n\nNICE has produced information on this procedure for patients and carers ('Understanding NICE guidance'). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.", 'About this guidance': 'NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland.\n\nThis guidance was developed using the NICE interventional procedure guidance process.\n\nIt updates and replaces NICE interventional procedure guidance 27.\n\nWe have produced a summary of this guidance for patients and carers. Information about the evidence it is based on is also available.\n\nChanges since publication\n\nJanuary 2012: minor maintenance.\n\nYour responsibility\n\nThis guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.\n\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.\n\nCopyright\n\n© National Institute for Health and Clinical Excellence 2010. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.\n\nContact NICE\n\nNational Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT\n\nwww.nice.org.uk\n \n nice@nice.org.uk\n 0845 033 7780'}	https://www.nice.org.uk/guidance/ipg357
653d138f37546133b2e281d5cdd73cdd9b565acb	nice	Phototherapeutic laser keratectomy for corneal surface irregularities	Phototherapeutic laser keratectomy for corneal surface irregularities # Guidance Current evidence on the safety and efficacy of phototherapeutic laser keratectomy for corneal surface irregularities is adequate to support the use of this procedure provided that normal arrangements are in place for clinical governance, consent and audit. Patient selection and treatment should be carried out only by ophthalmologists who specialise in corneal surgery.# The procedure # Indications and current treatments Symptomatic corneal surface irregularities may result from a range of pathologies including band keratopathy, corneal scarring, nodular degeneration, epithelial basement membrane dystrophy or other dystrophies. Symptoms may include loss of visual acuity, pain, sensitivity to light and foreign body sensation. Treatment aims to restore a normal regular corneal surface and adherence between the epithelium and Bowman's membrane (a basement membrane that lies between the outer layer of stratified epithelium and the substance of the cornea) with associated improvement in visual acuity and comfort. Standard treatment includes lubrication of the ocular surface, bandage contact lens placement or topical medication. Surgical procedures may include anterior stromal puncture, mechanical debridement, lamellar keratoplasty or resurfacing keratectomy using a diamond burr. Corneal transplantation may be considered in eyes refractory to treatment. # Outline of the procedure The aim of phototherapeutic laser keratectomy for corneal surface irregularities is to create a smooth stromal surface to improve postoperative corneal clarity, decrease existing scarring and facilitate subsequent epithelial adhesion. Local anaesthetic eye drops are applied and the corneal epithelium is mechanically removed. A laser is used to sequentially ablate uniformly thin layers of corneal tissue, creating a smooth surface which then becomes re-epithelialised. Postoperative management consists of an eye pad, topical antibiotics, sedatives and non-steroidal anti-inflammatory drugs. Sections 2.3 and 2.4 describe efficacy and safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview. # Efficacy A non-randomised controlled study of 39 patients (42 eyes) reported no significant difference in overall change in best corrected visual acuity (BCVA) between patients treated by phototherapeutic laser keratectomy and those treated by diamond burr polishing at 7-month follow-up (p = 0.6): BCVA improved in 36% (5/14) and 14% (3/21) of eyes, remained unchanged in 64% (9/14) and 81% (17/21) of eyes and worsened in 0% (0/14) and 5% (1/21) of eyes respectively. In a case series of 211 patients (232 eyes) mean BCVA improved by 1.4 lines from baseline at 2-year follow-up (p < 0.002). No significant difference was reported in BCVA improvement between subgroups of patients with corneal dystrophy, nodular degeneration, corneal scar, or band keratopathy (absolute figures not stated) (p = 0.15). In a case series of 216 patients (252 eyes), among eyes with recurrent erosion at baseline, further recurrent erosion was reported in 9% (9/103) of eyes at 12-month follow-up. The case series of 216 patients reported that 100% (29/29) of eyes with band-like keratopathy were pain free by 6-day follow-up. A case series of 191 patients (203 eyes) reported that significantly fewer patients with bullous keratopathy had severe symptoms of pain, photosensitivity and/or watering at 6-month follow-up (n = 15) compared with baseline (n = 56) (p < 0.017). Similarly, significantly fewer patients with corneal scarring had severe symptoms at 6-month follow-up (n = 4) compared with baseline (n = 13) (p < 0.0001). The Specialist Advisers listed key efficacy outcomes as visual acuity, ocular surface health, ocular comfort and pain relief. # Safety Recurrent keratitis requiring penetrating keratoplasty was reported in 1% (3/232) of eyes at up to 2-year follow-up in the case series of 211 patients. One occurrence each of progressing keratolysis at 8-day follow-up, circular subepithelial corneal scarring at 5-month follow-up (both requiring penetrating keratoplasty), progressive kerectasia at 6 months (sequelae not reported), and a sterile corneal immune ring at 4-day follow-up, were described in 4 separate case reports. A loss of BCVA of 2 lines or more was reported in 13% (3/24) of patients at 2-year follow-up in the case series of 211 patients. Idiopathic iritis and a marginal corneal ulcer developed in 1 eye each at up to 2-year follow-up in the case series of 211 patients. Mild postoperative haze was reported in 11% (22/203) of eyes in the case series of 191 patients; this resolved in 12 eyes by 6-month follow-up. There was no significant difference in the occurrence of mild haze between patients treated by laser phototherapeutic keratectomy (33% of eyes) or by diamond burr polishing (26% of eyes) in the non-randomised controlled study of 39 patients at 7-month follow-up (p = 0.38). The Specialist Advisers identified corneal infection as an adverse event reported in the literature. They considered theoretical adverse events to include epithelial defect, corneal ectasia, scarring and induction of astigmatism or refractive error. # Other comments The Committee noted that the published evidence comprised a mixture of different indications and outcomes, but nevertheless they considered that the case for safety and efficacy was adequately supported by this evidence and by specialist advice. NICE received 3 completed questionnaires from patients treated by the procedure. They reported improvements in quality of life including reduced photosensitivity (which had required sunglasses) and the ability to walk with more confidence.# Further information # Information for patients NICE has produced information on this procedure for patients and carers ('Understanding NICE guidance'). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind. A large print version is also available.# About this guidance NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland. This guidance was developed using the NICE interventional procedure guidance process. We have produced a summary of this guidance for patients and carers. Information about the evidence it is based on is also available. Changes since publication January 2012: minor maintenance. Your responsibility This guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer. Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties. Copyright © National Institute for Health and Clinical Excellence 2010. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE. Contact NICE National Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT www.nice.org.uk nice@nice.org.uk	{'Guidance': 'Current evidence on the safety and efficacy of phototherapeutic laser keratectomy for corneal surface irregularities is adequate to support the use of this procedure provided that normal arrangements are in place for clinical governance, consent and audit.\n\nPatient selection and treatment should be carried out only by ophthalmologists who specialise in corneal surgery.', 'The procedure': "# Indications and current treatments\n\nSymptomatic corneal surface irregularities may result from a range of pathologies including band keratopathy, corneal scarring, nodular degeneration, epithelial basement membrane dystrophy or other dystrophies. Symptoms may include loss of visual acuity, pain, sensitivity to light and foreign body sensation.\n\nTreatment aims to restore a normal regular corneal surface and adherence between the epithelium and Bowman's membrane (a basement membrane that lies between the outer layer of stratified epithelium and the substance of the cornea) with associated improvement in visual acuity and comfort.\n\nStandard treatment includes lubrication of the ocular surface, bandage contact lens placement or topical medication. Surgical procedures may include anterior stromal puncture, mechanical debridement, lamellar keratoplasty or resurfacing keratectomy using a diamond burr. Corneal transplantation may be considered in eyes refractory to treatment.\n\n# Outline of the procedure\n\nThe aim of phototherapeutic laser keratectomy for corneal surface irregularities is to create a smooth stromal surface to improve postoperative corneal clarity, decrease existing scarring and facilitate subsequent epithelial adhesion.\n\nLocal anaesthetic eye drops are applied and the corneal epithelium is mechanically removed. A laser is used to sequentially ablate uniformly thin layers of corneal tissue, creating a smooth surface which then becomes re-epithelialised. Postoperative management consists of an eye pad, topical antibiotics, sedatives and non-steroidal anti-inflammatory drugs.\n\nSections 2.3 and 2.4 describe efficacy and safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview.\n\n# Efficacy\n\nA non-randomised controlled study of 39 patients (42 eyes) reported no significant difference in overall change in best corrected visual acuity (BCVA) between patients treated by phototherapeutic laser keratectomy and those treated by diamond burr polishing at 7-month follow-up (p = 0.6): BCVA improved in 36% (5/14) and 14% (3/21) of eyes, remained unchanged in 64% (9/14) and 81% (17/21) of eyes and worsened in 0% (0/14) and 5% (1/21) of eyes respectively.\n\nIn a case series of 211 patients (232 eyes) mean BCVA improved by 1.4 lines from baseline at 2-year follow-up (p < 0.002). No significant difference was reported in BCVA improvement between subgroups of patients with corneal dystrophy, nodular degeneration, corneal scar, or band keratopathy (absolute figures not stated) (p = 0.15).\n\nIn a case series of 216 patients (252 eyes), among eyes with recurrent erosion at baseline, further recurrent erosion was reported in 9% (9/103) of eyes at 12-month follow-up.\n\nThe case series of 216 patients reported that 100% (29/29) of eyes with band-like keratopathy were pain free by 6-day follow-up.\n\nA case series of 191 patients (203 eyes) reported that significantly fewer patients with bullous keratopathy had severe symptoms of pain, photosensitivity and/or watering at 6-month follow-up (n = 15) compared with baseline (n = 56) (p < 0.017). Similarly, significantly fewer patients with corneal scarring had severe symptoms at 6-month follow-up (n = 4) compared with baseline (n = 13) (p < 0.0001).\n\nThe Specialist Advisers listed key efficacy outcomes as visual acuity, ocular surface health, ocular comfort and pain relief.\n\n# Safety\n\nRecurrent keratitis requiring penetrating keratoplasty was reported in 1% (3/232) of eyes at up to 2-year follow-up in the case series of 211 patients.\n\nOne occurrence each of progressing keratolysis at 8-day follow-up, circular subepithelial corneal scarring at 5-month follow-up (both requiring penetrating keratoplasty), progressive kerectasia at 6 months (sequelae not reported), and a sterile corneal immune ring at 4-day follow-up, were described in 4 separate case reports.\n\nA loss of BCVA of 2 lines or more was reported in 13% (3/24) of patients at 2-year follow-up in the case series of 211 patients.\n\nIdiopathic iritis and a marginal corneal ulcer developed in 1 eye each at up to 2-year follow-up in the case series of 211 patients.\n\nMild postoperative haze was reported in 11% (22/203) of eyes in the case series of 191 patients; this resolved in 12 eyes by 6-month follow-up. There was no significant difference in the occurrence of mild haze between patients treated by laser phototherapeutic keratectomy (33% [5/15] of eyes) or by diamond burr polishing (26% [7/27] of eyes) in the non-randomised controlled study of 39 patients at 7-month follow-up (p = 0.38).\n\nThe Specialist Advisers identified corneal infection as an adverse event reported in the literature. They considered theoretical adverse events to include epithelial defect, corneal ectasia, scarring and induction of astigmatism or refractive error.\n\n# Other comments\n\nThe Committee noted that the published evidence comprised a mixture of different indications and outcomes, but nevertheless they considered that the case for safety and efficacy was adequately supported by this evidence and by specialist advice.\n\nNICE received 3 completed questionnaires from patients treated by the procedure. They reported improvements in quality of life including reduced photosensitivity (which had required sunglasses) and the ability to walk with more confidence.", 'Further information': "# Information for patients\n\nNICE has produced information on this procedure for patients and carers ('Understanding NICE guidance'). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind. A large print version is also available.", 'About this guidance': 'NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland.\n\nThis guidance was developed using the NICE interventional procedure guidance process.\n\nWe have produced a summary of this guidance for patients and carers. Information about the evidence it is based on is also available.\n\nChanges since publication\n\nJanuary 2012: minor maintenance.\n\nYour responsibility\n\nThis guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.\n\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.\n\nCopyright\n\n© National Institute for Health and Clinical Excellence 2010. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.\n\nContact NICE\n\nNational Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT\n\nwww.nice.org.uk\n \n nice@nice.org.uk\n 0845 033 7780'}	https://www.nice.org.uk/guidance/ipg358
09ff2a5a76f3c2c26cd8a3a7498d1771bd193cdb	nice	Adalimumab, etanercept, infliximab, rituximab and abatacept for the treatment of rheumatoid arthritis after the failure of a TNF inhibitor	Adalimumab, etanercept, infliximab, rituximab and abatacept for the treatment of rheumatoid arthritis after the failure of a TNF inhibitor Evidence-based recommendations on adalimumab (Humira), etanercept (Enbrel), infliximab (Remicade), rituximab (MabThera) and abatacept (Orencia). These drugs are for adults with severe rheumatoid arthritis who have tried other disease-modifying antirheumatic drugs (DMARDs) but cannot tolerate them or they haven’t worked well enough. # Guidance This guidance replaces NICE technology appraisal guidance 126 and 141 issued in August 2007 and April 2008 respectively. It also replaces the remaining recommendations in NICE technology appraisal guidance 36 issued in March 2002. For details, see 'About this guidance'. Rituximab in combination with methotrexate is recommended as an option for the treatment of adults with severe active rheumatoid arthritis who have had an inadequate response to, or are intolerant of, other disease-modifying anti-rheumatic drugs (DMARDs), including at least one tumour necrosis factor (TNF) inhibitor. Treatment with rituximab should be given no more frequently than every 6 months. Treatment with rituximab in combination with methotrexate should be continued only if there is an adequate response following initiation of therapy and if an adequate response is maintained following retreatment with a dosing interval of at least 6 months. An adequate response is defined as an improvement in disease activity score (DAS28) of 1.2 points or more. Adalimumab, etanercept, infliximab and abatacept, each in combination with methotrexate, are recommended as treatment options only for adults with severe active rheumatoid arthritis who have had an inadequate response to, or have an intolerance of, other DMARDs, including at least one TNF inhibitor, and who cannot receive rituximab therapy because they have a contraindication to rituximab, or when rituximab is withdrawn because of an adverse event. Adalimumab monotherapy and etanercept monotherapy are recommended as treatment options for adults with severe active rheumatoid arthritis who have had an inadequate response to, or have an intolerance of, other DMARDs, including at least one TNF inhibitor, and who cannot receive rituximab therapy because they have a contraindication to methotrexate, or when methotrexate is withdrawn because of an adverse event. Treatment with adalimumab, etanercept, infliximab and abatacept should be continued only if there is an adequate response (as defined in 1.2) 6 months after initiation of therapy. Treatment should be monitored, with assessment of DAS28, at least every 6 months and continued only if an adequate response is maintained. When using DAS28, healthcare professionals should take into account any physical, sensory or learning disabilities, communication difficulties, or disease characteristics that could adversely affect patient assessment and make any adjustments they consider appropriate. A team experienced in the diagnosis and treatment of rheumatoid arthritis and working under the supervision of a rheumatologist should initiate, supervise and assess response to treatment with rituximab, adalimumab, etanercept, infliximab or abatacept.# Clinical need and practice Rheumatoid arthritis is a chronic and progressive disabling condition characterised by inflammation of the synovial tissue of the joints. It may cause tenderness and stiffness of joints and their progressive destruction, and symptoms including pain and fatigue. It is estimated that 580,000 people in England and Wales, approximately 1% of the population, have rheumatoid arthritis. Of these, approximately 15% have severe disease. Rheumatoid arthritis affects three times as many women as men and has a peak age of onset of 40–70 years. In rheumatoid arthritis, the synovial membrane thickens because of an increased number of synovial cells, infiltration by white blood cells and formation of new blood vessels. Synovial fluid increases within the joint cavity, and bone mineral density adjacent to the joint reduces. Erosions of the bone may occur at the margin of the joint where synovial tissue meets cartilage and bone, and this can lead to irreversible damage to the structure and function of the joint. Inflammatory disease involving areas other than the joints can also occur. Dryness of the eyes and mouth and the formation of rheumatoid nodules may affect up to one third of people with rheumatoid arthritis. More severe inflammatory manifestations may lead to fibrosis in the lungs and inflammation affecting the lining of the heart, lungs and blood vessels. Ischaemic heart disease and cardiac failure are more common in people with rheumatoid arthritis than in those without this condition. Osteoporosis is also more common because of reduced mobility, inflammation and/or the side effects of drugs used to treat rheumatoid arthritis, particularly corticosteroids. Corticosteroid use can also contribute to an increased risk of infection and diabetes mellitus. Internationally agreed criteria for the diagnosis of rheumatoid arthritis (American College of Rheumatology 1987) require four of the following features: joint stiffness in the morning exceeding 1 hour physician-observed arthritis of three or more areas with soft tissue swelling arthritis involving hand joints symmetrical arthritis rheumatoid skin nodules a positive blood test for rheumatoid factor radiographic changes typical of rheumatoid disease. A diagnosis requires that, with the exception of the last criterion, all criteria must be present for a minimum of 6 weeks. However, clinicians sometimes diagnose rheumatoid arthritis without reference to these criteria. The course of rheumatoid arthritis varies, and the following factors indicate poor prognosis: the presence of antibodies to rheumatoid factor or cyclic citrullinated peptide (CCP); high erythrocyte sedimentation rate or concentrations of C-reactive protein; early radiographic evidence of erosions; and the presence of swollen and tender joints. Within 2 years of diagnosis, people with rheumatoid arthritis may experience moderate disability, and after 10 years 30% are severely disabled. Approximately one third of people with rheumatoid arthritis stop work because of the disease. Rheumatoid arthritis is associated with a reduced life expectancy; for example, a 50-year-old woman with rheumatoid arthritis is expected to die 4 years earlier than a 50-year-old woman without rheumatoid arthritis. The aim of treatment is to induce remission of disease, control pain and inflammation, and reduce or prevent joint damage, disability and loss of function, thereby improving quality of life. Treatment involves a combination of pharmacological and non-pharmacological interventions. Pharmacological treatment includes various combinations of non-steroidal anti-inflammatory drugs (NSAIDs), analgesics, corticosteroids and disease modifying anti-rheumatic drugs (DMARDs). DMARDs reduce symptoms and slow progression of structural damage. DMARDs may be classified as conventional (for example methotrexate or sulfasalazine) or biological. Biological DMARDs include, but are not limited to, the TNF inhibitors adalimumab, etanercept and infliximab, as well as rituximab and abatacept. Non-pharmacological interventions include orthopaedic surgery, physiotherapy and occupational therapy. NICE clinical guideline 79 (2009) recommends the use of a combination of conventional DMARDs (including methotrexate and at least one other conventional DMARD plus short-term glucocorticoids) as first-line treatment, beginning ideally within 3 months of the onset of persistent symptoms. When combination therapy is not appropriate (for example, in people with methotrexate intolerance), the guideline recommends monotherapy with a conventional DMARD with quick escalation to a clinically effective dose. The TNF inhibitors adalimumab, etanercept or infliximab, (NICE technology appraisal guidance 130 ) and certolizumab pegol (NICE technology appraisal guidance 186 ), each in combination with methotrexate, are recommended as options for the treatment of adults with active rheumatoid arthritis who have a disease activity score (DAS28) greater than 5.1 and whose rheumatoid arthritis has failed to respond to at least two conventional DMARDs, including methotrexate. If a patient does not tolerate methotrexate or if treatment with methotrexate is considered to be inappropriate, adalimumab, etanercept and certolizumab pegol may be given as monotherapy. Treatment should be withdrawn if response is not adequate within 6 months (as defined by an improvement in DAS28 score of more than 1.2 points) or if response is not maintained. Response to treatment should be monitored at least every 6 months. An alternative TNF inhibitor may be considered when treatment with a first TNF inhibitor is withdrawn because of an adverse event before the initial 6-month assessment. Several tools have been developed to assess the response to treatment in rheumatoid arthritis. The American College of Rheumatology (ACR) response criteria (ACR20, 50 and 70) require a specified improvement in the percentage (20%, 50% or 70% respectively) of tender joints, swollen joints, global assessments, pain, disability and circulating inflammatory markers (for example, erythrocyte sedimentation rate). The disease activity score (DAS) is an alternative scoring system developed in Europe. It is calculated using a formula that includes counts for tender and swollen joints (53 and 44 joints respectively), an evaluation of general health by the patient (on a scale of 0 to 100) and a measure of circulating inflammatory markers. DAS28 is similar to DAS but uses only 28 joints for assessment. A DAS28 score greater than 5.1 indicates high disease activity, between 3.2 and 5.1 moderate disease activity, and less than 3.2 low disease activity. A score of less than 2.6 indicates disease remission. An improvement in DAS28 score of 0.6 or less is considered a poor response, and improvements greater than 1.2 points indicate a good response. The European League Against Rheumatism (EULAR) response criteria are based on the DAS measure. The Stanford Health Assessment Questionnaire (HAQ) comprises one component of the ACR criteria and scores the ability to perform daily activities; it ranges from 0 (least disability) to 3 (most severe disability). The modified Sharp score measures joint damage as assessed radiographically, and is scored on joint-space narrowing and erosions.# The technologies # Adalimumab Adalimumab (Humira, Abbott Laboratories) is a human-sequence monoclonal antibody that binds specifically to TNF and neutralises its biological function by blocking its interaction with cell-surface TNF receptors. Adalimumab modulates biological responses induced or regulated by TNF, including changes in the concentrations of adhesion molecules responsible for the migration of leukocytes. Adalimumab has a marketing authorisation for the treatment of moderate to severe active rheumatoid arthritis in adults when the response to DMARDs, including methotrexate, has been inadequate. It is also indicated for the treatment of severe, active and progressive rheumatoid arthritis in adults not previously treated with methotrexate. The summary of product characteristics (SPC) states that adalimumab should be given in combination with methotrexate, except when methotrexate is not tolerated or is considered inappropriate. Common adverse effects of adalimumab therapy include injection-site reactions and infections. Adalimumab is contraindicated in people with moderate to severe heart failure, those with active tuberculosis or those with other severe or opportunistic infections. Before initiating therapy, physicians should evaluate people for both active and inactive (latent) tuberculosis infection. For full details of adverse effects, contraindications, special warnings and precautions for use, see the SPC. Adalimumab is administered at a dose of 40 mg every other week via subcutaneous injection. In monotherapy, if people experience a decrease in response the dose may be increased to 40 mg every week. The net price for a 40-mg prefilled syringe is £357.50 (excluding VAT; 'British National Formulary', edition 59 ). The annual cost of adalimumab for 26 doses at a dose of 40 mg every other week is £9295. Costs may vary in different settings because of negotiated procurement discounts. # Etanercept Etanercept (Enbrel, Pfizer) is a recombinant human TNF receptor fusion protein. It interferes with the inflammatory cascade by binding to TNF, thereby blocking its interaction with cell-surface receptors. Etanercept has a marketing authorisation for the treatment of moderate to severe active rheumatoid arthritis when the response to DMARDs, including methotrexate, has been inadequate. Etanercept is also indicated in the treatment of severe, active and progressive rheumatoid arthritis in adults not previously treated with methotrexate. The SPC states that etanercept should be given in combination with methotrexate, except when methotrexate is not tolerated or is considered inappropriate. Common adverse effects of etanercept therapy include injection-site reactions, infections and allergic reactions. Etanercept is contraindicated in people with sepsis or risk of sepsis, and those with other active infections. Before initiating therapy, physicians should evaluate people for both active and inactive (latent) tuberculosis infection. For the full details of adverse effects, contraindications, special warnings and precautions for use, see the SPC. Etanercept is administered by subcutaneous injection at a dose of 25 mg twice weekly. Alternatively, the SPC allows for a dose of 50 mg once weekly. The net price for a 25-mg vial is £89.38 (excluding VAT; BNF59). The annual cost of etanercept using either 52 once-weekly doses of 50 mg or 104 twice-weekly doses of 25 mg is £9295. Costs may vary in different settings because of negotiated procurement discounts. # Infliximab Infliximab (Remicade, Schering-Plough) is a chimeric monoclonal antibody that binds with high affinity to TNF, thereby neutralising its activity. Infliximab has a marketing authorisation in combination with methotrexate for the treatment of active rheumatoid arthritis when the response to DMARDs, including methotrexate, has been inadequate, and for people with severe, active and progressive disease not previously treated with methotrexate or other DMARDs. Common adverse effects of infliximab therapy include acute infusion-related reactions, infections and delayed hypersensitivity reactions. Infliximab is contraindicated in people with moderate or severe heart failure, and those with tuberculosis or other severe or opportunistic infections. For full details of adverse effects, contraindications, special warnings and precautions for use, see the SPC. Infliximab is administered at a dose of 3 mg/kg by intravenous infusion over 2 hours at an initial infusion (week 0) and then at weeks 2 and 6, and thereafter every 8 weeks. If there is an inadequate response or a loss of response after 12 weeks, physicians may consider increasing the dose of infliximab stepwise by approximately 1.5 mg/kg, up to a maximum of 7.5 mg/kg every 8 weeks. Alternatively, administration of 3 mg/kg as often as every 4 weeks may be considered. The net price for a 100-mg vial is £419.62 (excluding VAT; BNF59). The annual drug costs associated with infliximab vary according to body weight and the number of infusions required. Assuming an average weight of 70 kg and a dose of 3 mg/kg, each dose of infliximab requires three vials at a cost of £1259. The three loading doses cost £3777, with an annual cost following the loading doses of between £7553 and £8812 depending on whether six or seven doses are required. Costs may vary in different settings because of negotiated procurement discounts. # Rituximab Rituximab (MabThera, Roche Products) is a genetically engineered chimeric monoclonal antibody that depletes the B-cell population by targeting cells bearing the CD20 surface marker. Rituximab has a marketing authorisation for use in combination with methotrexate for the treatment of adults with severe active rheumatoid arthritis who have had an inadequate response or intolerance to other DMARDs including one or more TNF inhibitor therapies. Common adverse effects of rituximab therapy include infusion reactions and infections. Rituximab is contraindicated in people with severe heart failure or severe, uncontrolled cardiac disease, and those with active, severe infections. For full details of undesirable effects, contraindications, special warnings and precautions for use see the SPC. A course of rituximab consists of two 1000-mg intravenous infusions given 2 weeks apart. The SPC specifies that courses of rituximab should be given at intervals of no less than 16 weeks. The cost to the NHS of 10-ml and 50-ml vials of rituximab is £174.63 and £873.15 respectively (excluding VAT; BNF59). The cost of a single course of rituximab is £3492 (two 1000-mg intravenous infusions). Costs may vary in different settings because of negotiated procurement discounts. # Abatacept Abatacept (Orencia, Bristol-Myers Squibb) is a selective T-cell co-stimulation modulator that blocks a key co-stimulatory signal required for T-cell activation. Abatacept has a marketing authorisation for use in combination with methotrexate for the treatment of moderate to severe active rheumatoid arthritis in adults who have had an insufficient response or intolerance to other DMARDs, including at least one TNF inhibitor. Common adverse effects of abatacept therapy include infections, including sepsis and pneumonia. Abatacept is contraindicated in people with severe, uncontrolled infections, and opportunistic infections. Before initiating therapy, physicians should evaluate people for both active and inactive (latent) tuberculosis infection. For full details of undesirable effects, contraindications, special warnings and precautions for use, see the SPC. Abatacept is administered as a 30-minute intravenous infusion. After an initial infusion (week 0), it is repeated at week 2, week 4 and every 4 weeks thereafter. People require a total of 14 infusions in the first year and 13 infusions in subsequent years. Abatacept is available in 250-mg vials at a cost of £242.17 per vial (excluding VAT; BNF59). The dose of abatacept depends on body weight: people weighing less than 60 kg, 60–100 kg and over 100 kg require 500 mg, 750 mg and 1000 mg respectively. The annual drug costs associated with abatacept vary according to body weight and the number of infusions required. For a person weighing between 60 and 100 kg, the annual drug cost will be £10,171.14 in the first year and £9444.63 in subsequent years. Costs may vary in different settings because of negotiated procurement discounts.# Evidence and interpretation The Appraisal Committee (appendix A) considered evidence from a number of sources (appendix B). # Clinical effectiveness The Assessment Group completed a systematic review of the efficacy of the technologies for the treatment of rheumatoid arthritis after the failure of a TNF inhibitor. Thirty-five studies met the criteria for inclusion. Five of these were randomised controlled trials (RCTs), one was a non-randomised controlled study, and 29 were included in the Assessment Report as uncontrolled studies (including two long-term RCT extensions). Three of the RCTs were subsequently excluded from the review by the Assessment Group because the studies included regimens outside of their marketing authorisation or the comparator was not considered relevant. A sixth RCT (the SUNRISE trial) was identified but not included in the systematic review because the trial was unpublished and data from the manufacturer were not provided in time for inclusion in the analyses. The two included RCTs compared rituximab with placebo (the REFLEX trial) and abatacept with placebo (the ATTAIN trial), with all people in these two RCTs also receiving ongoing methotrexate or other conventional DMARDs. This section summarises the outcomes for clinical effectiveness in terms of ACR 20, 50 and 70 response rate and improvement in DAS28 and/or HAQ score for the studies identified in the Assessment Group's systematic review. ## Adalimumab For adalimumab, the Assessment Group identified five uncontrolled studies with durations of follow-up ranging from 3 to 12 months. Four studies had small sample sizes ranging from 24 to 41. The fifth, a multicentre study, included 899 people. The Assessment Group did not pool the results because of substantial clinical and statistical heterogeneity between studies. Three studies reported ACR 20, 50 and 70 response rates ranging from 46% to 75%, 27% to 50% and 13% to 33% respectively. Four studies reported mean improvements in DAS28 score ranging from 1.30 to 1.90 when compared with pre-treatment values. Three studies reported mean improvements in HAQ ranging from 0.21 to 0.48 when compared with pre-treatment values. None of the studies assessed joint damage or quality of life. ## Etanercept For etanercept, the Assessment Group identified seven uncontrolled studies with durations of follow-up ranging from 3 months to over 9 months. Sample sizes ranged from 25 to 201. The results were not pooled because of substantial clinical and statistical heterogeneity between studies. Four studies reported ACR 20, 50 and 70 response rates ranging from 38% to 72%, 18% to 21% and 8% to 20% respectively. Four studies reported mean improvements in DAS28 score ranging from 0.47 to 1.80 when compared with pre-treatment values. Three studies reported mean improvements in HAQ score ranging from zero to 0.45 when compared with pre-treatment values. None of the studies assessed joint damage or quality of life. ## Infliximab For infliximab, the Assessment Group identified three uncontrolled studies, each with a small sample size ranging from 20 to 24. The Assessment Group could not determine the duration of follow-up in the studies. None of the studies reported ACR response criteria or quantitative results of changes in DAS28 and HAQ scores, or assessed joint damage or quality of life. ## TNF inhibitors as a group Eight studies were identified. None provided separate outcome data for individual TNF inhibitors. One non-randomised controlled study compared TNF inhibitors with rituximab (see section 4.1.10) and seven studies had no control group. The duration of follow-up in the studies ranged from 3 months to 4 years and sample sizes ranged from 70 to 818. One study reported ACR 20, 50 and 70 response rates of 46%, 26% and 7% respectively. A different study reported a mean improvement in HAQ score of 0.11 when compared with pre-treatment values. Three studies reported mean improvements in DAS28 score ranging from 0.88 to 1.00 when compared with pre-treatment values. No studies assessed joint damage or quality of life. ## Rituximab The Assessment Group identified one RCT (REFLEX, n = 517), as well as the trial's long-term extension. The REFLEX trial compared rituximab with placebo (with ongoing methotrexate in both groups) in people who had had an inadequate response to one or more TNF inhibitors. The primary outcome in the REFLEX trial was ACR 20 response rate at 6 months. The REFLEX trial reported statistically significant differences favouring the rituximab group for ACR 20, 50 and 70 response rates. For the rituximab group the values were 51%, 27% and 12%, and for the placebo group these were 18%, 5% and 1% respectively (for all comparisons p < 0.0001). A statistically significant difference in mean improvement in DAS28 was reported (1.9 in the rituximab group compared with 0.4 in the placebo group, p < 0.0001). A statistically significant difference was also reported for mean improvement in HAQ score (0.40 in the rituximab group compared with 0.10 in the placebo group, p < 0.0001). The long-term observational extension of the REFLEX trial included people who had received up to three courses of rituximab. This reported that people receiving further courses of rituximab responded in terms of ACR comparably to patients who received rituximab in the randomised phase of the RCT. The SUNRISE trial (n = 559) compared the safety and efficacy of one course of rituximab with two courses of rituximab. This trial was not included in the Assessment Group's analysis, but the results were later submitted by consultees. The study reported that of the people who had been randomised to a second course of rituximab at week 24, 54% had an ACR 20 at 48 weeks, whereas of those who had been randomised to placebo, 45% had an ACR 20 at 48 weeks (p = 0.02). A statistically significant difference in mean improvement in DAS28 was also reported (1.9 in the rituximab retreatment group compared with 1.5 in the placebo retreatment group, p < 0.01). In addition to the REFLEX trial, the Assessment Group identified one non-randomised controlled study comparing TNF inhibitors with rituximab (see section 4.1.10), five uncontrolled studies and a pooled analysis combining data from the REFLEX trial, its long-term extension and other studies. Durations of follow-up in the uncontrolled studies ranged from 6 months to 1 year and sample sizes ranged from 20 to 158. The Assessment Group could not determine how many people the pooled analysis included. One study reported ACR 20, 50 and 70 response rates of 65%, 33% and 12% respectively. Another study reported a mean improvement in DAS of 1.61 when compared with pre-treatment values. None of the uncontrolled studies assessed improvement in HAQ score, joint damage or quality of life. The pooled analysis included people who had had up to five courses of rituximab treatment; this study showed clinical outcomes similar to those seen for rituximab in the REFLEX trial. ## Abatacept The Assessment Group identified one RCT (ATTAIN) and its long-term extension. The ATTAIN trial compared abatacept with placebo (with ongoing DMARDs in both groups) in people with an inadequate response to one or more TNF inhibitors. The co-primary outcomes in the ATTAIN trial were ACR 20 response rate and change in HAQ score at 6 months. The ATTAIN trial reported statistically significant differences in response rates for abatacept compared with placebo. The values were 50% compared with 20% (p < 0.001) for ACR 20, 20% compared with 4% (p < 0.001) for ACR 50, and 10% compared with 2% (p < 0.01) for ACR 70. The ATTAIN trial also reported a statistically significant improvement in mean DAS28 score favouring the abatacept group (1.98 compared with 0.71, p < 0.001). In addition, the ATTAIN trial reported a statistically significant difference in mean improvement in the HAQ score favouring the abatacept group (0.45 compared with 0.11, p < 0.001). The long-term extension of the ATTAIN trial followed people for up to 5 years. This analysis showed that among people continuing on abatacept, clinical outcomes in terms of ACR response rates were comparable to those seen for abatacept in the randomised phase of the RCT. Further data were provided from a large prospective uncontrolled study (ARRIVE, n = 1046); this study reported an improvement in DAS28 of 2.00 when compared with pre-treatment values. ## Comparative effectiveness The Assessment Group did not identify any randomised controlled trials directly comparing the five technologies, or trials comparing the technologies with other biological DMARDs or conventional DMARDs not previously tried by study participants. One non-randomised controlled study (n = 318) compared switching from a TNF inhibitor to rituximab with switching to an alternative TNF inhibitor. When a switch occurred because the first TNF inhibitor was not effective, the mean change in DAS28 score was reported to be significantly higher in the rituximab group (mean change -1.34) compared with the group who received an alternative TNF inhibitor (mean change -0.93) (p = 0.03). The Assessment Group conducted an adjusted indirect comparison of rituximab and abatacept using data from placebo-controlled trials that included similar populations. The analysis suggested no statistically significant differences in response rates between abatacept and rituximab for ACR 20 (relative risk 1.12, 95% confidence interval 0.68 to 1.84), ACR 50 (relative risk 1.00, 95% CI 0.33 to 2.98) and ACR 70 (relative risk 1.80, 95% CI 0.24 to 13.35). ## Subgroup analyses The Assessment Group identified evidence for adalimumab, etanercept and abatacept that compared response to treatment according to the reason for withdrawal of the first TNF inhibitor. The evidence compared primary non-responses (when the disease had never responded to treatment with a TNF inhibitor) with secondary non-responses (when there was a reduction in disease response to the first TNF inhibitor). The majority of analyses suggested no statistically significant differences in response according to reason for withdrawal of the first TNF inhibitor. However, two analyses of adalimumab showed statistically significant higher response rates for ACR 20 (pooled estimate risk difference -0.20, 95% CI -0.37 to -0.02) and ACR 50 (pooled estimate risk difference -0.12, 95% CI -0.20 to -0.04) when the first TNF inhibitor had been withdrawn because of a secondary non-response. Data for abatacept from the ATTAIN long-term extension study also suggested that in a non-intention-to-treat analysis of people who had a change in HAQ greater than 0.3 at 6 months, the proportion whose disease responded was higher among people who had experienced a secondary non-response than among those who experienced a primary non-response (risk difference -0.15, 95% CI -0.28 to -0.02). However, registry data for the TNF inhibitors as a group suggested that, when measured as EULAR response rates at 3 months, and assuming missing observations represented non-responders, there were statistically significantly higher response rates among people who stopped their first TNF inhibitor because of primary non-response (risk difference 0.30, 95% CI 0.13 to 0.46). No specific data for infliximab and rituximab were identified.Evidence for the influence of the presence of auto-antibodies (that is, rheumatoid factor and anti-CCP antibody status) on effectiveness was available only for rituximab, from the REFLEX trial. The trial reported no statistically significant differences in relative treatment effect by rheumatoid factor status. However, absolute response rates were lower in both the rituximab and the placebo groups for people who were rheumatoid factor-negative than those who were rheumatoid factor-positive. When participants were stratified according to both rheumatoid factor and anti-CCP antibody status, the data suggested a greater treatment response in people who were either rheumatoid factor-positive or anti-CCP antibody-positive than in those who were negative for both rheumatoid factor and anti-CCP. The Assessment Group noted that this retrospective analysis should be treated with caution. # Cost effectiveness ## Published literature The Assessment Group identified four published economic analyses – two of rituximab and two of abatacept – that met the criteria for inclusion in the systematic review. All four used a decision analytic model. Three of the studies carried out a cost–utility analysis and reported results in terms of costs per quality-adjusted life years (QALYs) gained. The remaining study (of abatacept) reported results in terms of costs per additional case of 'low disease activity state' gained (DAS28 less than 2.6) and costs per additional remission gained (DAS28 up to 3.2). The Assessment Group could not perform a direct comparison of the incremental cost-effectiveness ratios (ICERs) from these studies because of different specifications of the models, including treatment sequence, time horizon, perspective and country of origin. ## Manufacturers' submissions All five manufacturers provided economic analyses to support their submissions. One analysis (etanercept, Pfizer) was provided only as a narrative summary and not as a fully executable model. All submissions were based on cost–utility analyses run over a lifetime horizon and from the perspective of the healthcare provider. All but one submission (abatacept, Bristol-Myers Squibb) used conventional DMARDs as the base-case comparator. ## Abbott Laboratories (adalimumab) Abbott Laboratories developed a discrete-event simulation model and performed a cost–utility analysis of adalimumab, etanercept, infliximab, rituximab and abatacept (all of which were considered in combination with methotrexate), each in comparison with conventional DMARDs. The model also compared adalimumab with conventional DMARDs only, and the sequence of adalimumab followed by rituximab compared with each of the remaining biological DMARDs. The model simulated people with profiles based on the baseline characteristics of people in the British Society for Rheumatology Biologics Register. The model included adverse events. It also included a continuation rule using ACR 50 response to determine whether a person continued therapy after an initial trial period. Response to treatment was based on ACR response rates mapped to a change in HAQ score. The manufacturer derived the ACR response rates from a mixed treatment comparison of 34 studies and assumed that the responses were equal across all TNF inhibitors (that is, that the response to adalimumab was not different from other TNF inhibitors). To map ACR to HAQ, the change in HAQ score associated with each ACR response category was calculated from adalimumab clinical trial data in which both HAQ and ACR were measured. The model assumed that when people discontinued treatment with a TNF inhibitor, the initial effect of treatment was lost. The model assumed that disease progressed while on treatment and that it progressed at a constant annual rate to a greater degree on conventional than on biological DMARDS. This was modelled in terms of an annual increase in HAQ score of 0.030 for biological DMARDs, 0.045 for conventional DMARDs and 0.060 for rescue therapy. To convert HAQ scores to EuroQol (EQ-5D) scores, the manufacturer used a non-linear mapping mechanism estimated using EQ-5D data collected in trials of tocilizumab (another biological DMARD). Costs included drug acquisition, administration, monitoring and hospitalisation (including joint replacement surgery). The cost of administering intravenous drugs was estimated to be £462 for each infusion, based on the Healthcare Resource Group 2007/08 tariff. The manufacturer of adalimumab assumed that administering subcutaneous drugs would require 3 hours of nurse training incurring a one-off cost of £129. The manufacturer assumed retreatment with rituximab would occur every 9 months. This assumption was tested in a sensitivity analysis using a retreatment schedule of every 6 months. The base-case analysis showed that for rituximab in comparison with conventional DMARDs, the incremental QALY gain was 1.375 at an incremental cost of £15,100, giving an ICER of £10,986 per QALY gained. When it was assumed that treatment with rituximab was repeated every 6 months instead of every 9 months, the ICER increased from £10,986 per QALY gained in the base case to £15,856 per QALY gained. The base-case analysis showed that for adalimumab or etanercept in comparison with conventional DMARDs, the QALY gain was 1.467 at an incremental cost of £23,423, giving an ICER of £15,962 per QALY gained. For infliximab and abatacept (each in comparison with conventional DMARDs), the QALY gains were 1.451 and 1.136 respectively. The incremental costs were £31,241 and £34,188 respectively, giving ICERs of £21,529 and £30,104 per QALY gained. From the data presented, the ICER for adalimumab or etanercept compared with rituximab, given every 9 months, could be calculated to be £83,230 per QALY gained. Infliximab was dominated by adalimumab and etanercept, and abatacept was dominated by rituximab. From the data presented, the ICER for adalimumab or etanercept in comparison with rituximab given every 6 months could be calculated to be £16,280 per QALY gained. Infliximab was dominated by adalimumab and etanercept, and abatacept was dominated by rituximab. Univariate sensitivity analyses (altering one variable at a time) suggested that the model was most sensitive to the HAQ score at the start of treatment, change in HAQ score while on treatment (that is, underlying disease progression), assumptions regarding the loss or maintenance of initial treatment effect upon stopping treatment, the way in which HAQ was mapped to EQ-5D and the dosing schedule of rituximab. ## Pfizer (etanercept) Pfizer presented the results of a Markov model with a 6-month cycle. The model compared three strategies: treatment with two sequential TNF inhibitors, treatment with a TNF inhibitor followed by a conventional DMARD and treatment with a TNF inhibitor followed by rituximab. The manufacturer did not include abatacept in the economic analyses. Baseline patient characteristics reflected those of the patients in the TEMPO trial (an RCT of etanercept in people whose rheumatoid arthritis had had an inadequate response to conventional DMARDs). The model included serious adverse events. The base-case model included a continuation rule using HAQ score mapped from DAS28 to determine whether a person continued therapy after an initial trial period. The manufacturer defined response to treatment in terms of mean change in HAQ score in people treated with a second TNF inhibitor after primary non-response, secondary loss of response or intolerance of their first TNF inhibitor. The data were taken from a trial of adalimumab; the values used were -0.44, -0.51 and -0.55 respectively. The manufacturer estimated the mean changes in HAQ score for those treated with rituximab (-0.40) from the REFLEX trial; all were unadjusted estimates of absolute treatment effect observed in the trial. The effect of conventional DMARDs following failure of a TNF inhibitor was assumed to be zero, based on data from the British Society for Rheumatology Biologics Register. The model included underlying disease progression while on treatment, modelled in terms of worsening HAQ score over time. The manufacturer assumed that while on treatment with biological DMARDs the HAQ score remained unchanged (that is, disease did not progress/worsen) but that while on conventional DMARDs the HAQ score changed at a rate of 0.075 per 6-month cycle from the first 6 months up to 3 years, and then 0.10 per 6-month cycle from year 3 onwards. The manufacturer used a linear mapping mechanism to convert HAQ scores to EQ-5D scores during each model cycle. Costs included drug acquisition and administration, and costs associated with hospitalisation, outpatient visits, primary care visits, investigations and monitoring. The cost of administration was unclear. Rituximab was assumed to be provided once every 6 months. The manufacturer presented the base-case results for a range of assumptions regarding changes in HAQ score for both TNF inhibitors and conventional DMARDs. Total differences in costs and QALYs were presented only for people who had switched from one TNF inhibitor to another because of an adverse event. The ICER for TNF inhibitors compared with conventional DMARDs was £15,294 per QALY gained when switching as a result of primary non-response and £14,501 per QALY gained when switching as a result of secondary loss of response. The ICER for TNF inhibitors compared with rituximab was £19,077 per QALY gained and £16,225 per QALY gained following switching for primary non-response and secondary loss of response respectively. The manufacturer presented no probabilistic sensitivity analysis results in the submission. ## Schering-Plough (infliximab) Schering-Plough developed a patient-level simulation model and performed a cost–utility analysis of infliximab compared with adalimumab, etanercept, rituximab, and abatacept, all of which were considered in combination with methotrexate. Comparisons were also made with conventional DMARDs only, and of the TNF inhibitors followed by rituximab. The model simulated people based on the characteristics at baseline of participants in the GO-AFTER trial (a trial of the TNF inhibitor golimumab in people with an inadequate response to a previous TNF inhibitor). The model did not include adverse events. The base-case model included a continuation rule using EULAR response to determine whether a person continued therapy after an initial trial period. The manufacturer determined response to treatment by a multi-step process. First, baseline EULAR response rates from the British Society for Rheumatology Biologics Register were converted to baseline ACR response rates using an algorithm derived from the GO-AFTER trial. Treatment-specific ACR response rates were generated from the results of a mixed treatment comparison of RCTs of biological DMARDs. These ACR response rates were then converted back to EULAR response rates using the GO-AFTER algorithm. The EULAR response categories were then mapped to EQ-5D using algorithms derived from British Society for Rheumatology Biologics Register data that indirectly calculated EQ-5D from HAQ. In addition to the initial response to treatment, the model included underlying disease progression while on treatment, modelled using change in HAQ score over time. The manufacturer assumed that people treated with biological DMARDs experienced no progression in their disease whereas the condition deteriorated at a rate of 0.042 per year in people treated with conventional DMARDs. Costs included drug acquisition and administration, monitoring and hospitalisation. It was assumed that in 63% of cases sharing of vials resulted in no wastage of unused infliximab. The cost of administering infused drugs was assumed to be £162.12, based on the cost given in the assessment report for NICE technology appraisal guidance 130 and adjusted for inflation. The manufacturer presented two analyses for rituximab: one assuming retreatment every 6 months and the other every 9 months. The base-case analysis showed that for rituximab in comparison with conventional DMARDs, the incremental QALY gain was 0.65 at an incremental cost of £11,325, giving an ICER of £17,422 per QALY gained (assuming 9-month retreatment intervals). Assuming retreatment with rituximab every 6 months, the ICER for rituximab compared with conventional DMARDs was £27,161 per QALY gained. The QALY gains for adalimumab, etanercept and infliximab were 0.66, 0.62 and 0.65 respectively. The respective incremental costs were £23,129, £22,257 and £18,628, giving ICERs of £35,138, £35,898 and £28,661 per QALY gained compared with conventional DMARDs. The strategy comparing abatacept with conventional DMARDs resulted in an incremental QALY gain of 0.63 for an incremental cost of £28,205, producing an ICER of £44,795 per QALY gained. From the data presented, the ICER for adalimumab in comparison with rituximab given every 9 months could be calculated to be £1,186,230 per QALY gained. Etanercept and abatacept were dominated by rituximab, and infliximab was extendedly dominated by rituximab. When rituximab was assumed to be given every 6 months, the ICER for adalimumab compared with rituximab could be calculated to be £553,700 per QALY gained. Etanercept and abatacept were dominated by rituximab, and infliximab was extendedly dominated by rituximab. ## Roche Products (rituximab) Roche Products developed a patient-level simulation model and performed a cost–utility analysis of rituximab compared with adalimumab, etanercept, infliximab and abatacept, all of which were followed by a sequence of conventional DMARDs. The manufacturer also compared rituximab with conventional DMARDs alone. The model simulated people whose profiles were based on baseline characteristics of participants in the REFLEX trial. The manufacturer did not include adverse events. Response to treatment was defined in terms of ACR response rates mapped to a change in HAQ score. ACR response rates were derived from two sources: a mixed treatment comparison of RCTs of TNF inhibitors in people whose rheumatoid arthritis had had an inadequate response to conventional DMARDs, and an indirect comparison of the abatacept ATTAIN trial and the rituximab REFLEX trial. The manufacturer then adjusted (reduced by 30%) the results of the mixed treatment comparison to reflect a lower response to treatment observed in people who had had an inadequate response to a first TNF inhibitor. The manufacturer converted ACR to HAQ using an algorithm from data in the REFLEX trial. When people discontinued treatment, the manufacturer assumed that the initial effect of treatment was lost. The model included both initial response to treatment and underlying disease progression while on treatment, each modelled as changes in HAQ score. It was assumed that while a person was on a biological DMARD there was no change in HAQ score. People on conventional DMARDs experienced an increase (worsening) in HAQ score of 0.0225 per 6-month cycle and people receiving palliative care experienced an increase in HAQ score of 0.03 per 6-month cycle. The manufacturer mapped HAQ scores to EQ-5D scores using a non-linear mapping mechanism derived from data from the tocilizumab trials. The costs included drug acquisition and administration, monitoring and hospitalisation. The cost of administration was assumed to be £162 per infusion and this included all premedication and monitoring costs. Subcutaneous drugs incurred monitoring and premedication costs of £1268 per year and administration costs (£136 for etanercept and £68 for adalimumab) to allow for the 10% of people who will receive injections from a district nurse. Retreatment with rituximab was assumed to occur every 8.7 months. This assumption was tested in sensitivity analysis. The base-case analysis showed that for rituximab compared with conventional DMARDs, the incremental QALY gain was 1.071 with an incremental cost of £5,685, giving an ICER of £5,311 per QALY gained. Assuming retreatment with rituximab every 6 months, the ICER for rituximab compared with conventional DMARDs increased from £5,311 to £10,876 per QALY gained. The strategies comparing rituximab with etanercept, infliximab or abatacept showed rituximab to be both more effective and less costly. The strategy comparing rituximab with adalimumab showed rituximab to be less effective and less costly, with a QALY loss of 0.044 and an incremental reduction in cost of £13,551, resulting in an ICER for adalimumab compared with rituximab of £310,771 per QALY gained. ## Bristol-Myers Squibb (abatacept) Bristol-Myers Squibb developed a patient-level simulation model and performed a cost–utility analysis of abatacept compared with rituximab, both followed by infliximab. They also modelled abatacept compared with a basket of TNF inhibitors (reflecting the proportion of each drug's market share), both followed by another basket of TNF inhibitors. The model simulated people whose profiles were based on the baseline characteristics of participants in the ATTAIN trial. The model included adverse events for the first 6 months of treatment. The manufacturer defined response to treatment in terms of mean change in HAQ score. Estimates for rituximab (0.38) and abatacept (0.42) were based on a mixed treatment comparison of the ATTAIN and REFLEX trials. Estimates for TNF inhibitors (0.21) were taken from an analysis of data from the British Society for Rheumatology Biologics Register completed by NICE's Decision Support Unit for NICE technology appraisal guidance 130. The manufacturer assumed that people who discontinued treatment lost the initial effect of treatment. Underlying progression of disease while on treatment was modelled using HAQ score. For people treated with abatacept, disease was assumed to improve over time, with an annual improvement (HAQ score decrease) of 0.0729 in analyses compared with rituximab, and of 0.013 in analyses compared with TNF inhibitors. For the other biological treatments, the manufacturer assumed that disease worsened at an annual HAQ score increase of 0.012. A linear mapping mechanism was used to convert HAQ scores to Health Utilities Index Mark 3 scores during each model cycle. Costs included drug acquisition and administration, monitoring, hospitalisation (including that for joint replacement surgery), outpatient visits and costs associated with adverse events. Different administration costs were used for the different drugs requiring intravenous infusion. For abatacept the cost per infusion was £141.83 based on the assessment report for NICE technology appraisal guidance 130 and adjusted for inflation to 2007/2008; for rituximab and infliximab the cost was £284.73 based on NHS reference costs. For subcutaneous treatments a one-off cost of £25.66 was incurred for training. Retreatment with rituximab occurred once every 6 months. The base-case analysis showed that in comparison with the basket of TNF inhibitors, the QALY gain for abatacept was 0.47 at an incremental cost of £10,888, giving an ICER of £23,019 per QALY gained. The strategy comparing abatacept with rituximab resulted in an incremental QALY gain of 0.45 for an incremental cost of £9238, producing an ICER of £20,438 per QALY gained. Sensitivity analyses showed that when it was assumed that there were no differences in the underlying progression of disease between the biological DMARDs (that is, a worsening of HAQ score of 0.012 per year was assumed for each biological treatment), the ICER for abatacept was £40,534 per QALY gained compared with rituximab, and £27,871 per QALY gained compared with TNF inhibitors. ## The Birmingham Rheumatoid Arthritis Model The Assessment Group carried out an independent economic analysis using the Birmingham Rheumatoid Arthritis Model. The model simulated people with rheumatoid arthritis based on the baseline characteristics of people in the British Society for Rheumatology Biologics Register. The model sampled people individually and compared each of the technologies (followed by a sequence of conventional DMARDs) with one another or with conventional DMARDs alone. It allowed for two stages of stopping treatment early. The first stage represented the possibility of stopping treatment after 6 weeks (assumed to be because of toxicity) and the second stage represented stopping treatment at between 6 and 24 weeks (assumed to be because of either toxicity or lack of efficacy). The model did not allow for stopping rituximab early because it was necessary to model the full costs of each cycle of treatment. The Assessment Group modelled response to treatment using HAQ, with changes in HAQ scores calculated using a multiplier that represents a proportional change from a given baseline HAQ score. The respective HAQ multipliers for rituximab and abatacept were derived from the REFLEX and ATTAIN trials. The HAQ multipliers for adalimumab and etanercept were derived from uncontrolled studies. In the absence of data, the HAQ multiplier for infliximab was assumed to be the same as for etanercept. The Assessment Group assumed that when people discontinue treatment, they lose the initial effect of treatment. In addition to the initial response to treatment, the model assumed that underlying disease progresses during treatment. This was modelled by increases in HAQ score. In the base-case analysis, it was assumed that HAQ score remains constant for a person treated with a biological DMARD, but increases (worsens) for people treated with conventional DMARDs or palliative care. The annual HAQ score increase was 0.045 for conventional DMARDs and 0.06 for palliative care. The Assessment Group used a non-linear equation to convert HAQ scores to EQ-5D scores. Costs included drug acquisition and administration plus monitoring. The administration cost for drugs requiring infusion was assumed to be £141.83. Costs for hospitalisation and joint replacement were estimated using a cost per unit HAQ score. Retreatment with rituximab was assumed to occur every 8.7 months. The base-case analysis showed that for rituximab compared with conventional DMARDs, the incremental QALY gain was 0.96 with an incremental cost of £20,400, giving an ICER of £21,100 per QALY gained. The QALY gains for adalimumab, etanercept and infliximab were 0.75, 0.67 and 0.67 respectively. The respective incremental costs were £25,800, £26,100 and £24,000, giving ICERs (rounded to the nearest £100) of £34,300, £38,900 and £36,100 per QALY gained. The strategy comparing abatacept with conventional DMARDs resulted in an incremental QALY gain of 1.15 for an incremental cost of £44,000, producing an ICER of £38,400 per QALY gained. Compared with the TNF inhibitors, rituximab was shown to be both less costly and more effective. The ICER for abatacept in comparison with rituximab was £130,600 per QALY gained. The strategies comparing abatacept with adalimumab, etanercept and infliximab resulted in ICERs of £46,400 per QALY gained, £37,800 per QALY gained and £41,700 per QALY gained respectively. Scenario analyses were undertaken to explore the impact of varying single assumptions within the model. These included: the time on treatment with the various therapies; the rituximab treatment interval; the efficacy of conventional DMARDs after the failure of a TNF inhibitor; the change in HAQ score while on biological DMARDs; the proportion of people stopping treatment early; the inclusion of costs of adverse events and palliation; and assumptions related to the equation used to map HAQ score to EQ-5D scores. These analyses indicated that the results are subject to considerable uncertainty. Assuming that there was underlying progression of disease modelled as an increase in HAQ score of 0.03 per year while on biological DMARDs increased the ICERs for the comparison with conventional DMARDs. The ICERs were £61,300 per QALY gained for adalimumab, £76,300 per QALY gained for etanercept, £68,900 per QALY gained for infliximab, £46,000 per QALY gained for rituximab and £63,300 per QALY gained for abatacept. Assuming conventional DMARDs were no more effective than placebo reduced the base-case ICERs for the comparison with conventional DMARDs to £28,100 per QALY gained for adalimumab, £31,100 per QALY gained for etanercept, £28,800 per QALY gained for infliximab, £16,300 per QALY gained for rituximab and £32,100 per QALY gained for abatacept. An incremental analysis demonstrated that rituximab was shown to be both less costly and more effective than each of the TNF inhibitors. The ICER for abatacept in comparison with rituximab was £158,000 per QALY gained. Using the same proportion of people stopping early as was used in the Roche model (based on failure to achieve an ACR 20 response) reduced the base-case ICERs for the comparison with conventional DMARDs to £22,200 per QALY gained for adalimumab, £23,400 per QALY gained for etanercept, £26,200 per QALY gained for infliximab, £19,500 per QALY gained for rituximab, and £24,100 per QALY gained for abatacept. A detailed analysis of the costs and QALYs provided as an addendum by the Assessment Group showed that abatacept (with costs of £70,500 and 2.82 QALYs) was dominated by rituximab (with costs of £62,300 and 2.91 QALYs). Adalimumab, etanercept and infliximab were associated with lower costs than rituximab (£61,700, £60,300, and £62,300, respectively). However, they were also associated with fewer QALYs (2.56, 2.47 and 2.49, respectively). In an incremental analysis, rituximab had the lowest ICER, with the other treatments being either dominated or extendedly dominated. Results suggested that the model was sensitive to changes in the equation converting HAQ to health-related quality of life; and the assumed time between treatments for comparisons involving rituximab. Assuming retreatment with rituximab every 6 months instead of every 8.7 months, the ICER for rituximab in comparison with conventional DMARDs increased from £21,100 to £32,600 per QALY gained. Results suggested that the model was not sensitive to changes in the cost parameters, including those associated with hospitalisation and joint replacement, palliative care, and adverse events. The base-case analysis assumed a cost of joint replacement and hospitalisation of £1120 per HAQ score unit. The exclusion of these costs increased the ICER in comparison with conventional DMARDs by approximately £2500 per QALY gained. The inclusion of additional drug costs of palliation (that is, a £420 start-up cost and a subsequent annual cost of approximately £1000) reduced the ICERs in comparison with conventional DMARDs by approximately £1000 per QALY gained. # Consideration of the evidence The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of adalimumab, etanercept, infliximab, rituximab and abatacept after the failure of a TNF inhibitor. The Committee considered evidence on the nature of rheumatoid arthritis and the value placed on the benefits of adalimumab, etanercept, infliximab, rituximab and abatacept by people with the condition, those who represent them and clinical specialists. It also took into account the effective use of NHS resources. ## Clinical effectiveness The Committee considered the current clinical management of people with rheumatoid arthritis. The Committee heard from clinical specialists that the pathway of care following the failure of treatment with a TNF inhibitor depends on the individual person's responses to therapies, the clinical experience of the physician and the person's preference. The Committee heard from patient experts that rheumatoid arthritis can have a severe impact on quality of life, and that fatigue, pain and depression are common among people with the disease. Patient experts reported that rheumatoid arthritis frequently affects people's ability to work, noting the considerable burden placed on the carers of people with the disease. The Committee heard that rheumatoid arthritis may not respond to a given treatment, or there may be a decline in response over time that requires a change in treatment. Clinical specialists and patient experts emphasised the importance of having the option of multiple treatments for people whose disease has not responded adequately to initial treatment with a TNF inhibitor. The Committee heard from clinical specialists that rheumatoid arthritis is heterogeneous and that different people may respond differently to a given treatment. In addition, it is difficult to predict whether an individual's disease will respond to a given treatment. Experts stated that people for whom a TNF inhibitor had never produced a response may be less suitable for a second TNF inhibitor than people whose rheumatoid arthritis had previously responded, and that people with seronegative antibody status may be less suitable for treatment with rituximab, than people with seropositive antibody status, although uncertainty surrounds this. The Committee therefore understood that response to treatments varies, and that it is not currently possible to target specific treatments to individuals because the response to any particular treatment cannot be predicted. The Committee heard that the management of rheumatoid arthritis was changing in line with NICE guidelines for rheumatoid arthritis, and that more clinicians start DMARDs early and increase the dose of DMARDs quickly as required. The Committee heard from clinical specialists that, as a consequence of this accelerated approach to the use of DMARDs, physicians initiate treatment with TNF inhibitors sooner after diagnosis than they had done previously and therefore the characteristics of the people being treated with TNF inhibitors have changed over time. The Committee also heard from the clinical specialists that initiating treatment with TNF inhibitors earlier in the treatment pathway may increase people's potential to benefit from such treatment because of the reduced accumulation of irreversible joint damage. The Committee understood that these changes in the management of rheumatoid arthritis limited the generalisability of data from the British Society for Rheumatology Biologics Register, as it represents a cohort of people whose characteristics (including disease duration and number of previously received treatments) may not reflect those of the people currently seen in clinical practice for whom the first biological DMARD has failed. The Committee considered the decision problem in the scope, noting comments from consultees that three technologies (certolizumab pegol, golimumab and tocilizumab) defined as comparators in the scope had not been included in the Assessment Report because marketing authorisations had not been obtained at the point at which the protocol was finalised. The Committee noted that golimumab and tocilizumab were subject to separate ongoing appraisals and were not yet in routine clinical use. It recognised that NICE technology appraisal guidance 186 on certolizumab pegol for the treatment of rheumatoid arthritis did not include guidance on its use after the failure of a TNF inhibitor. The Committee heard that in the absence of NICE guidance, the use of certolizumab pegol in this patient group would be subject to local decision making. The Committee concluded that excluding certolizumab pegol, golimumab and tocilizumab from the Assessment Report was appropriate. The Committee noted, however, the availability of RCT data for golimumab (an alternative TNF inhibitor) after the failure of a TNF inhibitor, and agreed that consideration of this data would be relevant to the decision problem in the appraisal (section 4.3.7). The Committee considered whether the TNF inhibitors could be considered as a group with respect to clinical effectiveness. The Committee was aware that each of the TNF inhibitors has a different mechanism of action. The Committee heard from clinical specialists that variations in the underlying mechanism of disease across people coupled with different mechanisms of action of the individual drugs can result in a variety of responses to treatment with TNF inhibitors. The Committee heard from patient experts that the technologies should be considered separately. The Committee heard from clinical specialists that data from the British Society for Rheumatology Biologics Register show no statistically significant difference in effect between TNF inhibitors, but that these data reflect the effectiveness of the first use of TNF inhibitors and not the effectiveness after the failure of a previous TNF inhibitor. Based on advice from the clinical specialists and patient experts that disease can respond differently to different TNF inhibitors, the Committee concluded that it may not be appropriate to assume that the TNF inhibitors form a homogeneous group with regard to clinical effectiveness. However, in the absence of evidence either way, it was not currently possible to distinguish with certainty between the TNF inhibitors in terms of their clinical effectiveness. The Committee discussed the clinical effectiveness of a second TNF inhibitor after the failure of a first. It noted that the review of the evidence by the Assessment Group had identified no RCTs and that the majority of other studies were uncontrolled observational or registry datasets, some of which had examined the TNF inhibitors as a group. The Committee heard from clinical specialists that for conventional DMARDs, the proportion of people whose condition responded to each successive treatment was reduced as the number of treatments increased, and that the same was considered to hold true for biological DMARDs. The clinical specialists noted that failure of a first TNF inhibitor was associated with an increased risk of failure of a second TNF inhibitor, but that the proportion of people with a good response was comparable. The clinical specialists therefore considered that a second TNF inhibitor was clinically effective. The Committee noted the comment made in consultation that the GO-AFTER trial data for a different TNF inhibitor (golimumab) could be used to inform the relative treatment effect of the TNF inhibitors in comparison with placebo. It discussed data from this trial that showed a statistically significant benefit from treatment with the TNF inhibitor golimumab after the failure of a different TNF inhibitor when compared with placebo. However, while noting the availability of these data, the Committee were mindful of comments from the clinical specialists and patient experts that the TNF inhibitors should be considered separately (see section 4.3.6). Furthermore, the Committee agreed that it would not be appropriate to apply the results from a treatment not included in the appraisal to the drugs in the appraisal, but concluded that the results for golimumab could be seen as confirming a beneficial effect of TNF inhibitor treatment following failure of a first TNF inhibitor. The Committee specifically considered the data from the British Society for Rheumatology Biologics Register. It heard from clinical specialists that the register reported an improvement in HAQ score of 0.11 among people receiving a second TNF inhibitor. The Committee also heard that this change did not differ from the average change in HAQ score (0.10) among people whose first TNF inhibitor had failed but who had continued to take it. The Committee heard from the clinical specialists that this change was smaller than the minimum value that is considered a clinically important difference within the context of a clinical trial (0.22) and within the context of an observational study (0.14). The Committee noted the limitations of the British Society for Rheumatology Biologics Register data. Considering these data in conjunction with the evidence discussed in section 4.3.7, the Committee concluded that although the studies suggest that a second TNF inhibitor is effective after the failure of a first, the absence of any rigorously controlled data meant that it could not quantify with certainty the relative effects of adalimumab, etanercept or infliximab in comparison with either conventional DMARDs or alternative biological DMARDs. The Committee considered the evidence from the randomised controlled trials of rituximab (REFLEX trial) and of abatacept (ATTAIN trial). The Committee noted the results of the Assessment Group's indirect comparison of rituximab and abatacept based on these trials, which did not show statistically significant differences between the two treatments, and that the conclusions were similar to those from the indirect comparisons carried out by Roche and Bristol Myers Squibb. The Committee concluded that both treatments had been shown to be clinically effective in comparison with placebo, but that one treatment had not been shown to be more effective than the other. The Committee concluded that the data for TNF inhibitors were insufficient to quantify with certainty the relative effect of rituximab and abatacept in comparison with adalimumab, etanercept or infliximab when used after the failure of the first TNF inhibitor. The Committee considered specifically the evidence of clinical effectiveness for the subgroup of people defined by reason for withdrawal of the first TNF inhibitor. It heard from clinical specialists that they considered that people whose disease had not responded to the first TNF inhibitor (primary non-response) would be less likely to experience a response to a second TNF inhibitor in comparison with those whose disease had initially responded but who had later experienced diminishing benefit (secondary non-response). However, the Committee considered that the studies identified by the Assessment Group did not show a consistent difference in response (including less response, similar response and better response) between secondary non-response and primary non-response. The Committee concluded that although some evidence and clinical testimony suggested a difference in response by reason for withdrawal, there was currently insufficient evidence for the Committee to use this as a basis for making recommendations for this specific subgroup. The Committee also considered subgroups based on the presence of auto-antibodies (rheumatoid factor and anti-CCP antibody status) and the impact of the presence of auto-antibodies on the clinical and cost effectiveness of rituximab. The Committee heard from the clinical specialists that the presence of auto-antibodies is not a consistent measure in that the same person may have a positive test for auto-antibodies in one instance and a negative test in another. The Committee was aware that a post-hoc analysis of the REFLEX study showed no statistically significant differences in relative effectiveness between subgroups defined by auto-antibody status. The Committee recognised that the REFLEX study and several other studies highlighted by consultees showed a lower absolute response rate in people who test seronegative compared with those who test seropositive. The Committee heard from clinical specialists that draft guidelines from the British Society for Rheumatology advise that people who test seropositive for either rheumatoid factor or anti-CCP may be more likely to respond than people who test seronegative for the two antibodies, and that this should be taken into account when considering rituximab. However, the clinical specialists considered that people who test seronegative may still respond to rituximab treatment. The Committee was not aware of data showing with certainty that adalimumab, etanercept, infliximab or abatacept would be more clinically effective than rituximab in this situation and that people who test seronegative are not excluded from the current marketing authorisation for rituximab. On balance, the Committee was not persuaded that there was currently sufficient evidence to conclude that rituximab treatment was inappropriate for people who test seronegative. Therefore, the Committee agreed not to make differential recommendations for a subgroup based on auto-antibody status. The Committee noted that no studies had been identified that compared the biological DMARDs with a newly initiated conventional DMARD after the failure of a first TNF inhibitor. The Committee heard from clinical specialists that they considered that any treatment effect for conventional DMARDs in this situation would be very limited. The Committee was aware of evidence from the Behandel Strategieen (BeST) study, which investigated the effectiveness of different treatment sequences of biological and conventional DMARDs in people with early rheumatoid arthritis. The Committee heard from the Assessment Group that evidence from the BeST study was not appropriate in this instance, as it did not address the clinical effectiveness of individual DMARDs and the study population did not represent people with established rheumatoid arthritis. The Committee noted comments received in consultation stating that it would be appropriate to assume no effect of conventional DMARDs after failure of a TNF inhibitor, because data from the British Society for Rheumatology Biologics Register reported that people who stopped treatment with a TNF inhibitor showed no average change in HAQ score 12 months later. However, the Committee was mindful that these data were for people stopping treatment with a TNF inhibitor only and did not specifically measure the effect of treatment for people starting conventional DMARDs at that point. Overall, the Committee concluded that, on the basis of clinical opinion, the effect of conventional DMARDs in people for whom a TNF inhibitor had failed was likely to be small, but it did not accept that there would be no effect at all associated with therapy. In addition, the Committee agreed that the uncertainty about the effectiveness of DMARDs contributed to the difficulty in quantifying with certainty the relative effect of biological treatments compared with DMARDs. In summary, the Committee noted that, apart from the randomised controlled trials of rituximab and abatacept, the available evidence on the effectiveness of treatment with the considered technologies after the failure of a TNF inhibitor was mainly derived from observational studies with short follow-up periods that included relatively small numbers of participants. The Committee noted that many of the studies lacked a comparison group, so it was not clear what would have happened had participants not received therapy. The Committee considered that shortcomings in the design of studies of the sequential use of TNF inhibitors could affect the validity of the results. It also considered that characteristics of the study participants, changes in clinical practice, and, in some instances, small participant numbers could affect the generalisability of the results. The Committee considered that there are significant limitations in the evidence base available for this appraisal and that the relative clinical effectiveness of TNF inhibitors after the failure of a first TNF inhibitor remains uncertain. The Committee acknowledged that some of the manufacturers had carried out mixed treatment or indirect comparisons. It noted the concerns of the Assessment Group that these comparisons did not increase the robustness of the results because of the inclusion of populations outside the scope, and because of the possible shortcomings related to dealing with heterogeneity between the included studies. The Committee was aware that the analyses did not consistently demonstrate a similar pattern of effect between the technologies. On balance, the Committee was not persuaded that for this appraisal the nature of the evidence available would allow mixed treatment or indirect comparisons to adequately address the underlying uncertainty in the effectiveness of these technologies. The Committee further noted that more research is needed, specifically using the DAS28 outcome measure (which forms the basis for the rules for continuing treatment in current NICE guidance on treatments for rheumatoid arthritis). The Committee heard from clinical specialists and manufacturers about ongoing research on the treatment of rheumatoid arthritis after the failure of a TNF inhibitor. The Committee heard that a current clinical trial of infliximab (RESTART) is being undertaken in patients with active rheumatoid arthritis in whom treatment with etanercept or adalimumab has failed. It noted that a preliminary analysis from this trial had been provided by the manufacturer of infliximab as commercial in confidence. ## Cost effectiveness The Committee examined the cost-effectiveness analysis of sequential use of TNF inhibitors performed by the Assessment Group and the manufacturers of the technologies. The Committee noted that all analyses modelled a sequence of treatments, which it considered appropriate for rheumatoid arthritis. The Committee noted, however, that there were differences in the sequences modelled. The Committee was aware that one of the models (from Pfizer) had not been provided as an executable file, and had not included abatacept. This limited the Committee's ability to use the model to inform decision making. The Committee recognised that one of the models (from Bristol-Myers Squibb) had not included a comparison with conventional DMARDs, which limited the comparability of the model with those of the other manufacturers and of the Assessment Group. The Committee was presented with information about the costs used in the economic models. The Committee recognised that the costs of hospitalisation and joint replacement had been included in all of the manufacturers' models, and that these costs were derived from a range of data sources including the British Society for Rheumatology Biologics Register and the Norfolk Arthritis Register. The Committee was aware that the Birmingham Rheumatoid Arthritis Model included an assumed cost for joint replacement and hospitalisation. The Committee noted comments received during consultation that the costs of palliative care had been underestimated in the Birmingham Rheumatoid Arthritis Model. The Committee recognised that the Assessment Group had carried out a series of analyses examining the sensitivity of the ICERs to changes in the cost parameters, including the removal of joint replacement and hospitalisation costs, the addition of extra costs of palliation and inclusion of the costs of adverse events. These analyses showed that the ICERs were not very sensitive to changes in these costs, and that the ICERs were most sensitive to changes in the assumptions about the natural history of the disease, the efficacy of the treatments and the proportion of people stopping treatment early. The Committee discussed the different sources of estimates of clinical effectiveness for the biological DMARDs that had been used in the economic modelling. The Committee noted that all models had used the REFLEX and ATTAIN trials to inform the estimates of rituximab and abatacept, but that sources varied for the estimates for TNF inhibitors and conventional DMARDs. It noted that some had included RCT data from populations outside the scope of the appraisal, uncontrolled observational studies or registry data. The Committee was aware that no head-to-head evidence existed that compared all the biological DMARDs, and as a result some models derived relative treatment effect from indirect comparisons. The Committee noted that these had included evidence from studies in which participants had not previously been treated with a TNF inhibitor. The Assessment Group reported that it considered the use of data from populations beyond the scope of the appraisal to complete an indirect comparison inappropriate because of the heterogeneity of the studies from which the data were taken. The Committee heard from the Assessment Group that it had modelled the rates of effectiveness for biological and conventional DMARDs as absolute rather than relative changes, even if from placebo-controlled randomised trials, because it considered that evidence did not allow for the completion of a mixed treatment or indirect comparison. The Committee noted that the use of non-randomised comparisons could affect the robustness of the results, but it accepted that the evidence base available for the sequential use of adalimumab, etanercept and infliximab did not currently allow for a robust analysis of the relative treatment effects. The Committee considered the value of HAQ score as a measure of functional assessment. The Committee heard from clinical specialists that HAQ score was affected by both reversible and irreversible components of the disease process, and that longstanding disease lessens the potential for improvements in HAQ score because of irreversible damage. For this reason the Committee considered that HAQ score may not be an appropriate measure of clinical benefit in established disease. The clinical specialists and patient experts considered that treatment might benefit individuals in ways not captured by HAQ score (such as a reduction in inflammation). The Committee recognised that the HAQ may be subject to 'ceiling effects' (in certain circumstances, the score cannot worsen), and that it does not incorporate symptoms such as pain, fatigue and sleep disturbance. The Committee concluded that patients may derive benefits from the treatment that are not reflected in HAQ score because of irreversible joint damage. The Committee discussed the range of methods used to model efficacy of the treatments, including responses in ACR categories mapped to changes in HAQ score, ACR response categories mapped to EULAR response and mean HAQ score change without the use of ACR response categories. The Committee was aware of the limitations of the HAQ score, including its insensitivity to small changes within the higher range of scores and its inability to capture meaningful improvements in pain and fatigue (see section 4.3.17). Following explanation from the Assessment Group, the Committee understood that HAQ multipliers represent a proportional change from a given baseline HAQ score. This means that for a baseline HAQ score of 2.00, the use of a HAQ multiplier of 0.25 translates into an HAQ improvement of 0.50, which results in a post-treatment HAQ score of 1.50. The Committee considered that the use of a multiplier to model changes in HAQ meant that absolute changes in the upper range of the HAQ scores were larger than those in the lower range, and that, using a HAQ multiplier, people with more severe disease would have larger absolute HAQ improvements than if the changes in HAQ score observed from the clinical studies were used directly. The Committee discussed comments received in consultation that the HAQ multiplier lacked face validity because the distribution of simulated changes in treatment-related HAQ score did not reflect the ranges observed in clinical trials. Bearing in mind these considerations, the Committee was not persuaded that the use of a HAQ multiplier was an unreasonable way to model changes in HAQ score. However, it agreed that alternative approaches should not be discounted and that it was appropriate to consider the cost-effectiveness analyses of the manufacturers who used alternative methods to calculate clinical effectiveness inputs. The Committee discussed how the models had incorporated underlying progression of disease during treatment. The Committee noted that all but two analyses had been carried out assuming that disease did not progress in people receiving TNF inhibitors, rituximab and abatacept, but that disease did progress in people taking conventional DMARDs. The Committee was aware that for the biological DMARDs, the use of no progression assumed both no underlying deterioration of physical function and no reduction in response to treatment. The Committee noted that one of the analyses (from Bristol-Myers Squibb) had assumed that abatacept delayed progression more than the other biological DMARDs. It recognised that the values used came from two different sources: clinical trial data on abatacept and an analysis of natural history data not specific to biological DMARDs. The Committee was not persuaded that the evidence was sufficient to support an assumption that the different biological treatments differentially altered progression of disease. In conclusion, the Committee was persuaded that it was appropriate to assume that biological DMARDs delayed disease more than conventional DMARDs. However, the Committee was aware that people with rheumatoid arthritis normally experience a reduction in the response to treatment before stopping it (secondary loss of response). The Committee agreed to base its discussions on the ICERs that assumed no progression of disease for patients during treatment with the biological DMARDs, but was not persuaded that this assumption fully reflects the disease process. This is because people could experience some worsening of HAQ while on treatment, particularly in the period of time prior to stopping treatment because of secondary loss of response, in which case the ICERs assuming no progression of disease may overestimate the benefits of treatment. The Committee noted that none of the economic models included health-related quality of life measured using a generic preference-based measure, but had mapped a disease-specific measure (HAQ or DAS) to a generic measure (EQ-5D). The Committee understood that in the case where DAS was mapped to EQ-5D, the algorithm used had been developed from EQ-5D data itself derived indirectly from HAQ data. The Committee noted that the mapping of HAQ to EQ-5D allowed for the symptoms of rheumatoid arthritis to cover a broad range of values on the quality-of-life scale, from excellent health to states worse than death. The Committee noted that mapping utilities was outside the reference case, but recognised it had been used in previous NICE technology appraisals of treatments for rheumatoid arthritis in the absence of directly-elicited EQ-5D data. The Committee heard from the Assessment Group that the Birmingham Rheumatoid Arthritis Model incorporated HAQ because it did not consider that DAS captured all aspects of disability that one would expect to correlate with health-related quality of life. The Committee heard from clinical specialists that evidence from the British Society for Rheumatology Biologics Register suggested that for more severe HAQ scores, mapping may underestimate the change in EQ-5D. However, the Committee was mindful that none of the models incorporated directly elicited EQ-5D data and all relied on mapping to inform estimates. The Committee noted that some of the manufacturers had mapped HAQ to EQ-5D using a linear function, while others had used a non-linear function. It heard from the Assessment Group that the use of a non-linear function places a greater value on changes at the lower end of the HAQ scale than at the upper end, but that this did not significantly change the estimated ICERs. The Committee concluded that mapping to EQ-5D had shortcomings, but in the absence of an alternative was an acceptable way to derive estimates of utility, and that the use of a non-linear function was not unreasonable. The Committee discussed the time intervals between treatments with rituximab. The Committee was aware of the results of the REFLEX trial, in which the average time interval between treatments was 307 days, and the SPC for rituximab, which indicates treatment intervals of no less than 16 weeks. It heard from clinical specialists that they would offer to retreat a patient with rituximab before disease flared, that there was wide variation in time to retreatment with rituximab and that it would be reasonable to assume that treatment with rituximab would occur, on average, less frequently than every 6 months, with some people requiring an infusion less often than once a year. The Committee noted that the Birmingham Rheumatoid Arthritis Model modelled time to repeat treatment as 8.7 months in the base case, basing this estimate on Roche's submission. It noted that similar time to re-treatment had been assumed in a number of the other manufacturers' submissions. The Committee understood that recently published data from the SUNRISE trial indicate that two courses of rituximab given 6-monthly result in a statistically significantly higher ACR 20 response rate at 1 year than one course given per year. It noted the comments received in consultation from some of the manufacturers who, because of the newly available data from the SUNRISE trial, considered that their base-case analyses may overestimate the duration of time between rituximab retreatments. The Committee noted that in the Assessment Group's scenario analysis, the ICER for rituximab compared with conventional DMARDs was from £21,100 per QALY gained when time to retreatment was 8.7 months, and that this increased to £32,600 per QALY gained when time to retreatment was 6 months. The Committee concluded that an 8.7-month retreatment interval is likely to overestimate the time between consecutive courses of rituximab. However, on the basis of the clinical specialists' advice, the Committee considered that it was unlikely to be as frequent as every 6 months for every person receiving rituximab. The Committee considered the use of stopping and continuation rules in the economic models. The Committee noted that current NICE guidance on the first use of TNF inhibitors (NICE technology appraisal guidance 130) recommends that TNF inhibitors should be not be continued unless there is an adequate response at 6 months following initiation of therapy. An adequate response is defined as an improvement in DAS28 of 1.2 points or more. The Committee heard from the clinical specialists that data from the British Society for Rheumatology Biologics Register indicate that a number of people will continue treatment with a TNF inhibitor in the absence of such a response, indicating that clinicians currently do not adhere strictly to continuation rules. However, it also heard from the clinical specialists that although implementing continuation rules could be difficult, clinicians were increasingly following guidance on continuation rules. The Committee was aware that four of the manufacturers had submitted models that included continuation rules, each based on a different response criterion (that is HAQ score, EULAR response, ACR 20 and ACR 50). The Committee understood that the Birmingham Rheumatoid Arthritis Model was not designed in a way that could incorporate continuation rules based on response. The Committee noted, however, the scenario analyses that included the proportions of people stopping treatment early that were used in the manufacturers' response-based models. These analyses lowered the ICERs for the TNF inhibitors and abatacept compared with conventional DMARDs by approximately £10,000 per QALY gained, to between £23,800 per QALY gained for adalimumab and £27,400 per QALY gained for infliximab. The Assessment Group explained that ICERs for rituximab did not change because the cost of rituximab treatment occurred at the start of each course of treatment. The Committee understood that consultees considered the modelling of continuation rules appropriate, as it reflects existing NICE guidance for the treatment of rheumatoid arthritis. The Committee concluded that continuation rules should be considered in the estimation of cost effectiveness. The Committee discussed the different ways in which the manufacturers and the Assessment Group had modelled the efficacy of conventional DMARDs. The Committee noted that the Birmingham Rheumatoid Arthritis Model assumed that the conventional DMARDs used after the failure of a TNF inhibitor were 50% as effective as when used in early rheumatoid arthritis. The Committee heard from the clinical specialists and from comments received in consultation that the assumption that conventional DMARDs used after the failure of a TNF inhibitor were 50% as effective as when used in early rheumatoid arthritis overestimated their effectiveness at this point in the treatment pathway. The Committee noted that the Assessment Group had completed a scenario analysis that assumed an efficacy of conventional DMARDs equal to that of placebo (reflecting the assumption used in the submission from Roche). This resulted in ICERs of approximately £16,000 per QALY gained for rituximab compared with conventional DMARDs, and between £28,000 and £32,000 per QALY gained for the other technologies compared with conventional DMARDs. The Assessment Group explained that the differences between the ICERs using different assumptions about DMARD efficacy were not larger because the Birmingham Rheumatoid Arthritis Model assumes that TNF inhibitors are added to a sequence rather than used as an alternative treatment. Therefore, the effects of the conventional DMARDs were observed in both the intervention and comparator sequences. The Committee discussed comments received on the effectiveness of conventional DMARDs. The Committee concluded that an analysis that assumed the effect of conventional DMARDs to be no more than that of placebo was not plausible, but accepted that the base-case assumption of a reduction of 50% was an underestimate of the reduction in effect of conventional DMARDs, and therefore overestimated the ICERs in the Assessment Group's base-case analysis. The Committee considered the estimates of cost effectiveness for the use of rituximab after the failure of a TNF inhibitor. It recognised that in all but one of the economic models, rituximab had been associated with the lowest ICERs of the biological DMARDs compared with conventional DMARDs. Rituximab was also associated with the lowest ICERs of the biological DMARDs in the Assessment Group's scenario analysis that assumed a poorer response to conventional DMARDs than was assumed in the base case. In addition, the Committee considered it was appropriate to incorporate continuation rules, and noted the ICERs from a sensitivity analysis carried out by the Assessment Group that included the assumptions regarding continuation rule from the model submitted by Roche. This analysis also showed that rituximab had the most favourable ICER among the technologies, with the other drugs being either dominated or extendedly dominated. Taking these results into account, as well as the estimates from the manufacturers' economic models, the Committee considered that the most plausible ICER for rituximab compared with DMARDs would be in the lower end of the range of £20,000 to £30,000 per QALY gained. The Committee concluded that rituximab could be considered a cost-effective use of NHS resources. The Committee recognised that rituximab treatment was not provided at regular intervals, but instead that people were retreated when treatment was required, which could mean some loss of response between infusions. However, the Committee noted the testimony from clinical specialists that they would aim to treat before disease flared. The Committee concluded that treatment could only be considered cost effective if an adequate response could be maintained following retreatment with a dosing interval of at least 6 months. The Committee discussed the cost effectiveness of the TNF inhibitors. The Committee understood that that in the absence of robust data on the clinical effectiveness of the TNF inhibitors, the ICERs were uncertain. The Committee noted that the analyses by Pfizer comparing the TNF inhibitors with rituximab produced ICERs of £19,077 per QALY gained (with primary non-response to the first TNF inhibitor) and £16,225 per QALY gained (with secondary loss of response). However, as Pfizer did not include an economic model in their submission, these results could not be validated. The Committee noted that most of the other models, including the Assessment Group's model, showed that in comparison with rituximab, either the ICERs for the TNF inhibitors were very high (above £80,000 per QALY gained) or the TNF inhibitors were dominated by rituximab (that is, rituximab was both more effective and less costly). In the Abbott model the ICER for TNF inhibitors compared with rituximab was £16,000 when rituximab was given every 6 months. However, the Committee did not accept that the re-treatment interval with rituximab would on average be 6 months. The Committee was mindful of the differences in the analyses of clinical effectiveness used in the different economic models, and considered the comments from consultees on the Birmingham Rheumatoid Arthritis Model. The Committee considered the manufacturer's models and agreed that taking into account all data together did not alter the conclusion drawn from the Birmingham Rheumatoid Arthritis Model. The Committee was not persuaded that the current evidence available and the cost-effectiveness analyses presented could support a decision to recommend adalimumab, etanercept or infliximab as an alternative to rituximab after the failure of a previous TNF inhibitor as an appropriate use of NHS resources. The Committee discussed the cost effectiveness of abatacept. The Committee considered that most of the economic models showed that in comparison with rituximab, the ICERs for abatacept were either very high (above £100,000 per QALY gained in the Assessment Group base case) or abatacept was dominated by rituximab (that is, rituximab was both more effective and less costly). The analysis by Bristol-Myers Squibb that produced an ICER of £20,438 per QALY gained assumed an improvement in HAQ of 0.013 per year during treatment with abatacept. When the same rate of HAQ score increase was assumed for abatacept as for the other biological DMARDs in the base case (a worsening of 0.012 per year), the ICER increased to £40,534 per QALY gained. The Committee therefore concluded that abatacept when used as an alternative to rituximab after the failure of a previous TNF inhibitor would not be a cost-effective use of NHS resources. The Committee was aware that for some people rituximab treatment may not be suitable because of a contraindication to rituximab or methotrexate, or that rituximab or methotrexate may need to be withdrawn because of an adverse event. The Committee was mindful that it had not been presented with any clinical evidence regarding the use of adalimumab, etanercept, infliximab or abatacept for patients for whom rituximab was contraindicated or not tolerated, and that any estimates of their effectiveness in this population were subject to additional uncertainty. However, it acknowledged that for people unable to take rituximab or methotrexate because of adverse events or contraindications, the appropriate comparator was conventional DMARDs. It considered the ICERs in the Birmingham Rheumatoid Arthritis Model that compared the TNF inhibitors with conventional DMARDs, noting that with the addition of continuation rules, the ICERs were between £23,800 and £27,400 per QALY gained, and would be lower if a lower effect of conventional DMARDs was assumed. The Committee considered these ICERs in light of the respective ICERs from the manufacturers' models, which lay between £14,500 and £35,900 per QALY gained. The Committee concluded that, on balance, these ICERs were sufficiently low to compensate for the uncertainty about the effectiveness of these treatments to be accepted. The Committee considered the Assessment Group's ICER for abatacept (including the continuation rule) of £26,200 per QALY gained compared with conventional DMARDs and agreed that this would be lower if the model assumed a lower effect of conventional DMARDs. The Committee considered these ICERs and the respective ICERs for abatacept from the manufacturer's model. It noted that these lay between £21,500 and £44,700 per QALY gained. The Committee was persuaded that these data taken together could support a decision to recommend adalimumab, etanercept, infliximab or abatacept as treatment options to be used after the failure of a first TNF inhibitor for the treatment of people who cannot receive rituximab therapy because have a contraindication to rituximab or who have had an adverse event on treatment with rituximab, as an appropriate use of NHS resources. The Committee recognised that for people who cannot receive rituximab therapy because they have a contraindication to methotrexate or where methotrexate is withdrawn because of an adverse event, this choice would be limited to adalimumab and etanercept, because infliximab and abatacept have marketing authorisations for use in combination with methotrexate. The Committee was aware that for some people rituximab treatment may fail to provide an adequate response. The Committee was mindful that it had not been presented with any clinical or cost-effectiveness evidence regarding the use of adalimumab, etanercept, infliximab or abatacept for this group of people. The Committee considered that all estimates of relative clinical effectiveness were subject to uncertainty, and that in this group of patients the estimates were subject to further uncertainty because factors such as disease duration and prior treatment exposure may affect response to treatment (see section 4.3.7). Therefore, while accepting that the evidence submitted could be considered reflective of the group who had not received rituximab because of contraindications, or had not had an adequate trial because rituximab treatment was withdrawn because of an adverse event, the Committee was not persuaded that this evidence could be applied to the group of people for whom rituximab had failed to provide an adequate response. The Committee was therefore unable to make recommendations about the use of adalimumab, etanercept, infliximab or abatacept in people for whom rituximab has failed to provide an adequate response. The Committee considered whether its recommendations were associated with any potential issues related to equality. The Committee was made aware that the use of the DAS28 would not be an appropriate tool for people with specific disabilities of the lower limbs and that the DAS44 would be a better tool to use for people with greater lower limb disease burden. The Committee agreed that it was important to allow clinicians to adjust the assessment of disease severity depending on the characteristics of the disease, and that the recommendations should reflect this. The Committee explored whether there were people, other than those who for whom rituximab or methotrexate was contraindicated or who had an adverse event on treatment with rituximab or methotrexate, who were unable to have rituximab because of a specific additional disability or comorbidity. The Committee noted that no such group of people had been identified during scoping or in consultation. The Committee was aware that people with mobility problems or visual impairment may find travel to hospital onerous or inconvenient. However, the Committee concluded that it was not clear that travel to receive infusions one or two times per year was necessarily more onerous or inconvenient than the alternative of much more frequent injections. In any event, the Committee did not consider that the need to travel would make it impossible or unreasonably difficult for these people to obtain treatment with rituximab, and noted that they would need to travel to other hospital or healthcare appointments in relation to their condition. The Committee concluded that rituximab would still be the most appropriate treatment option, taking into account its cost-effectiveness data and the infrequent dosing interval, but that all reasonable steps should be taken to provide practical support and assistance to ensure access to treatment for this group of people. The Committee noted a consultee's concerns about equity of access with other countries, but concluded that this concern did not pertain to any group protected by the equalities legislation, and that it would not be appropriate to address this as part of a technology appraisal. The Committee also noted a consultee's comment stating that the guidance may have a disproportional impact on patients who test seronegative, but agreed that its recommendations, not differentiating between groups of people, did not affect any group protected by the equalities legislation and that the issue of auto-antibody status had been addressed in detail. # Summary of Appraisal Committee's key conclusions TA195 (MTA) Appraisal title: Adalimumab, etanercept, infliximab, rituximab and abatacept for the treatment of rheumatoid arthritis after the failure of a TNF inhibitor (part review of NICE technology appraisal guidance 36, review of NICE technology appraisal guidance 126 and 141) FAD section Key conclusions Rituximab in combination with methotrexate is recommended as an option for the treatment of adults with severe active rheumatoid arthritis who have had an inadequate response to, or have an intolerance of, other disease-modifying anti-rheumatic drugs (DMARDs), including at least one tumour necrosis factor (TNF) inhibitor. Reason for recommendation Rituximab was considered to be a cost-effective option, based on data from most of the models available for this appraisal. Adalimumab, etanercept, infliximab and abatacept, each in combination with methotrexate) are recommended as treatment options only for adults with severe active rheumatoid arthritis who have had an inadequate response to, or have an intolerance of, other DMARDs, including at least one TNF inhibitor, and who cannot receive rituximab therapy because they have a contraindication to rituximab, or when rituximab is withdrawn because of an adverse event. Adalimumab monotherapy and etanercept monotherapy are recommended as treatment options for adults with severe active rheumatoid arthritis who have had an inadequate response to, or have an intolerance of, other DMARDs, including at least one TNF inhibitor, and who cannot receive rituximab therapy because have a contraindication to methotrexate, or when methotrexate is withdrawn because of an adverse event. Reasons for recommendations Based on the evidence available, the ICERs for adalimumab, etanercept, infliximab and abatacept compared with rituximab were either very high, or these drugs were dominated by rituximab (that is, rituximab was both more effective and less costly). For people who are unable to take rituximab or methotrexate, the appropriate comparator was conventional DMARDs. Based on the evidence available, adalimumab, etanercept, infliximab and abatacept compared with conventional DMARDs were considered cost-effective options based on data from most of the models available for this appraisal. Current practice Clinical need of patients Rheumatoid arthritis has a severe impact on quality of life, with fatigue, pain and depression being common among people with the disease. In addition, rheumatoid arthritis frequently affects patients' abilities to work, and there is considerable burden placed on the carers of patients with the disease. Patients may not respond to a treatment, or may experience a decline in initial response over time, and therefore need to change treatments. Availability of alternative treatments The pathway of care following the failure of treatment with a TNF inhibitor depends on the individual person's responses to therapies, the clinical experience of the physician and the person's preference. It is not currently possible to target specific treatments to individual patients because the response to any particular treatment cannot be predicted. The technology Proposed benefits of the technology from the manufacturer, clinician and patient perspective Clinical specialists and patient experts emphasised the importance of having the option of multiple treatments for people whose disease has not responded adequately to initial treatment with a TNF inhibitor. How innovative is the technology? This is a review of established technologies. N/A Adverse events This is a review of established technologies with known adverse events. Adverse events were not considered a key factor in distinguishing between the technologies. N/A Evidence for clinical effectiveness Quality of the evidence The evidence review identified no randomised controlled trials (RCTs) on the effectiveness of the TNF inhibitors. The majority of studies were uncontrolled observational or registry datasets. Data from RCTs were available only for rituximab and abatacept. Subgroup analyses based on rheumatoid factor and anti-CCP antibody status were post hoc. Availability and nature of evidence Studies suggested that a second TNF inhibitor is effective after the failure of a first, but the absence of any rigorously controlled data meant that the relative effects of adalimumab, etanercept, or infliximab in comparison with either conventional DMARDs or alternative biological DMARDs could not be quantified with certainty. There was insufficient evidence suggesting a difference in response based on the reason for withdrawal of the first TNF inhibitor. There was insufficient evidence to make differential recommendations for subgroups based on the presence of auto-antibodies (rheumatoid factor and anti-CCP antibody). No studies were identified that compared biological DMARDs with newly-initiated conventional DMARDs after the failure of a first TNF inhibitor. The Committee concluded that, on the basis of clinical opinion, the effect of conventional DMARDs in people for whom a TNF inhibitor had failed was likely to be small, but it did not accept that there would be no effect at all associated with therapy. In addition, the Committee agreed that the uncertainty about the effectiveness of DMARDs contributed to the difficulty in quantifying with certainty the relative effect of biological treatments compared with DMARDs. Relevance to general clinical practice in the NHS Changes in clinical management, including starting DMARDs earlier, increasing DMARD dosage more quickly and starting treatment with TNF inhibitors sooner than in the past limit the generalisability of some of the registry data presented. Patients may derive benefits from the treatment that would not be reflected in Stanford Health Assessment Questionnaire (HAQ) score because of the inclusion of irreversible joint damage in the score. Uncertainties generated by the evidence Based on advice from the clinical specialists and patient experts, it may not be appropriate to assume that TNF inhibitors form a homogeneous group with regard to clinical effectiveness. However, evidence was not available to enable any distinction to be made. (See also Availability and nature of evidence above.) Evidence for cost effectiveness Availability and nature of evidence One of the models was not provided as an executable file, limiting the ability to validate the modelling and ICERs. Another model did not include a comparison with conventional DMARDs, limiting the ability to compare it with other models. The model from the Assessment Group was not sensitive to assumptions about costs and was sensitive to assumptions about natural history, clinical effectiveness and number of people stopping treatment early. The sources of effectiveness evidence varied for the estimates of the TNF inhibitors and conventional DMARDs. Some included RCT data from populations outside the scope of the appraisal and/or uncontrolled observational studies or registry data. The Assessment Group modelled rates of effectiveness for biological DMARDs and conventional DMARDs as absolute (rather than relative) changes in disease measures, which could affect the robustness of the results. A range of methods were used to model efficacy of treatments, including mapping response criteria to HAQ change and use of HAQ change on its own. The Committee was not persuaded that the use of a HAQ multiplier was an unreasonable way to model changes in HAQ score. However, it agreed that alternative approaches should not be discounted and that it was appropriate to consider the cost-effectiveness analyses of the manufacturers who used alternative methods to calculate clinical effectiveness inputs. A variety of assumptions were made about progression of disease while on treatment with biological DMARDs including no progression, worsening disease and continuing improvement. All models except one assumed no progression for all biological DMARDs. The Committee did not consider that the evidence supported an assumption that the biological DMARDs differentially affected underlying disease progression. Uncertainties around and plausibility of assumptions and inputs in the economic model The Committee considered estimates of cost effectiveness using an assumption of no progression of disease while on treatment with biological DMARDs, but was not persuaded that this fully reflects the disease process. Based on evidence from patient experts and clinical specialists, the Committee considered an assumed 50% reduction in the efficacy of conventional DMARDs to be an underestimate of the reduction in effect of conventional DMARDs, although the assumption that they are no more effective than placebo was also considered implausible. The Committee recognised that incorporating response-based continuation rules into the models lowered the ICERs for the TNF inhibitors and abatacept in comparison with conventional DMARDs. It concluded that the modelling of continuation rules should be considered when examining estimates of cost effectiveness. On the basis of the clinical specialists' advice, the Committee considered that treatment with rituximab would occur less frequently than every 6 months, but accepted that 8.7 months may be an overestimate. Incorporation of health-related quality of life benefits and utility values All models presented EuroQol (EQ-5D) data derived from a disease-specific measure. Mapping to EQ-5D has shortcomings but, in the absence of an alternative approach, was considered an acceptable way to derive estimates of utility. Use of a non-linear mapping function was not unreasonable. Most likely cost-effectiveness estimate (given as an ICER) For rituximab, the most plausible estimated ICER would be in the lower range of £20,000 to £30,000 per QALY gained. In the absence of robust data on the clinical effectiveness of the TNF inhibitors, the estimates of cost effectiveness were uncertain. Most models showed that, when compared with rituximab, the ICERs for the TNF inhibitors were either very high (above £80,000 per QALY gained) or that rituximab dominated the TNF inhibitors (that is, rituximab was both more effective and less costly than the TNF inhibitors). In the Abbott model the ICER for TNF inhibitors compared with rituximab was £16,000 when rituximab was given every 6 months. However, the Committee did not accept that the re-treatment interval with rituximab would on average be 6 months. The Committee considered that most of the economic models showed that in comparison with rituximab, the ICERs for abatacept were either very high (above £100,000 per QALY gained in the Assessment Group base case) or abatacept was dominated by rituximab. The only exception was the analysis from the manufacturer of abatacept, which assumed an HAQ improvement while on abatacept (an assumption that the Committee did not accept). For people who are unable to have rituximab treatment because of a contraindication to rituximab or methotrexate, or for whom rituximab or methotrexate may need to be withdrawn because of an adverse event, the ICERs were based on a comparison with conventional DMARDs. The Assessment Group reported ICERs for adalimumab, etanercept, infliximab and abatacept of between £23,800 and £27,400 per QALY gained, including the addition of continuation rules, which would be lower if the model assumed a lower effect of conventional DMARDs. Additional factors taken into account Equalities considerations, social value judgements The Committee was made aware that the use of the DAS28 would not be an appropriate tool for people with specific disabilities of the lower limbs and that the DAS44 would be a better tool to use for people with greater lower limb disease burden. The Committee agreed that it was important to allow clinicians to adjust the assessment of disease severity depending on the characteristics of the disease, and that the recommendations should reflect this. The Committee was aware that people with mobility problems or visual impairment may find travel to hospital onerous or inconvenient. The Committee concluded that rituximab would still be the most appropriate treatment option, taking into account its cost-effectiveness data and the infrequent dosing interval, but that all reasonable steps should be taken to provide practical support and assistance to ensure access to treatment for this group of people. The Committee concluded that concerns about equity of access with other countries did not pertain to any group protected by the equalities legislation, and that it would not be appropriate to address this as part of a technology appraisal. The Committee also noted a consultee's comment stating that the guidance may have a disproportional impact on patients who test seronegative, but agreed that its recommendations, not differentiating between groups of people, did not affect any group protected by the equalities legislation. # Recommendations for further research Further clinical trials should be undertaken to compare the clinical effectiveness of adalimumab, etanercept and infliximab used sequentially after the failure of a TNF inhibitor with the clinical effectiveness of management strategies that do not include TNF inhibitors, including strategies that use untried DMARDs or biological DMARDs such as rituximab. This is important because there is currently no evidence on the clinical effectiveness of the TNF inhibitors at this stage in the treatment pathway compared with alternative treatment options (see section 4.3.6). Further research should be undertaken to estimate utilities using directly observed health-related quality of life values (such as EQ−5D scores) in people with rheumatoid arthritis. This is important because current methods of establishing utility values do not allow for links to be made between utilities and common clinical measures such as DAS.# Related NICE guidance Tocilizumab for the treatment of rheumatoid arthritis. NICE technology appraisal guidance 198 (2010). Certolizumab pegol for the treatment of rheumatoid arthritis. NICE technology appraisal guidance 186 (2010). Rheumatoid arthritis: the management of rheumatoid arthritis in adults. NICE clinical guideline 79 (2009). Adalimumab, etanercept and infliximab for the treatment of rheumatoid arthritis.NICE technology appraisal guidance 130 (2007). Golimumab for the treatment of rheumatoid arthritis after the failure of previous disease-modifying anti-rheumatic drugs. NICE technology appraisal 225 (2011).# Review of guidance The guidance on these technologies will be considered for review by the Guidance Executive in June 2013. The Guidance Executive will decide whether the technology should be reviewed based on information gathered by NICE, and in consultation with consultees and commentators. Andrew DillonChief ExecutiveAugust 2010# Changes after publication February 2014: implementation section updated to clarify adalimumab, etanercept, infliximab, rituximab and abatacept are recommended as options for treating rheumatoid arthritis after the failure of a TNF inhibitor. Additional minor maintenance update also carried out. March 2012: minor maintenance# About this guidance NICE technology appraisal guidance is about the use of new and existing medicines and treatments in the NHS in England and Wales. This guidance was developed using the NICE multiple technology appraisal process. It replaces NICE technology appraisal guidance 126 and 141 issued in August 2007 and April 2008 respectively. It also replaces the remaining recommendations in NICE technology appraisal guidance 36 issued in March 2002. The appraisal of adalimumab and the review of the appraisals of etanercept, infliximab, rituximab and abatacept for the treatment of rheumatoid arthritis have resulted in changes in the guidance. Rituximab in combination with methotrexate is still recommended as an option for the treatment of adults with severe active rheumatoid arthritis who have had an inadequate response to, or have an intolerance of, other DMARDs, including at least one TNF inhibitor. Additional treatment options are now recommended for these adults if rituximab therapy is contraindicated or withdrawn because of an adverse event, specifically: If rituximab is contraindicated or withdrawn, adalimumab, etanercept, infliximab and abatacept, each in combination with methotrexate, are now recommended as treatment options. If rituximab therapy cannot be given because methotrexate is contraindicated or withdrawn because of an adverse event, adalimumab and etanercept, each as monotherapy, are now recommended as treatment options. The price of abatacept has recently increased to £302.40 (excluding VAT) for a 250-mg vial. The manufacturer of abatacept has agreed a simple discount with the Department of Health as part of PPRS modulation with the result that the acquisition cost to the NHS remains the same as considered in the development of TA195 at £242.17 (excluding VAT) per 250-mg vial, until NICE next reviews the guidance on abatacept for this indication. This change therefore does not affect the recommendations in TA195. We have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available. Your responsibility This guidance represents the views of NICE and was arrived at after careful consideration of the evidence available. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. However, the guidance does not override the individual responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or guardian or carer. Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties. Copyright © National Institute for Health and Clinical Excellence 2010. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.	{'Guidance': "This guidance replaces NICE technology appraisal guidance 126 and 141 issued in August 2007 and April 2008 respectively. It also replaces the remaining recommendations in NICE technology appraisal guidance 36 issued in March 2002.\n\nFor details, see 'About this guidance'.\n\nRituximab in combination with methotrexate is recommended as an option for the treatment of adults with severe active rheumatoid arthritis who have had an inadequate response to, or are intolerant of, other disease-modifying anti-rheumatic drugs (DMARDs), including at least one tumour necrosis factor (TNF) inhibitor. Treatment with rituximab should be given no more frequently than every 6\xa0months.\n\nTreatment with rituximab in combination with methotrexate should be continued only if there is an adequate response following initiation of therapy and if an adequate response is maintained following retreatment with a dosing interval of at least 6\xa0months. An adequate response is defined as an improvement in disease activity score (DAS28) of 1.2\xa0points or more.\n\nAdalimumab, etanercept, infliximab and abatacept, each in combination with methotrexate, are recommended as treatment options only for adults with severe active rheumatoid arthritis who have had an inadequate response to, or have an intolerance of, other DMARDs, including at least one TNF inhibitor, and who cannot receive rituximab therapy because they have a contraindication to rituximab, or when rituximab is withdrawn because of an adverse event.\n\nAdalimumab monotherapy and etanercept monotherapy are recommended as treatment options for adults with severe active rheumatoid arthritis who have had an inadequate response to, or have an intolerance of, other DMARDs, including at least one TNF inhibitor, and who cannot receive rituximab therapy because they have a contraindication to methotrexate, or when methotrexate is withdrawn because of an adverse event.\n\nTreatment with adalimumab, etanercept, infliximab and abatacept should be continued only if there is an adequate response (as defined in 1.2) 6\xa0months after initiation of therapy. Treatment should be monitored, with assessment of DAS28, at least every 6\xa0months and continued only if an adequate response is maintained.\n\nWhen using DAS28, healthcare professionals should take into account any physical, sensory or learning disabilities, communication difficulties, or disease characteristics that could adversely affect patient assessment and make any adjustments they consider appropriate.\n\nA team experienced in the diagnosis and treatment of rheumatoid arthritis and working under the supervision of a rheumatologist should initiate, supervise and assess response to treatment with rituximab, adalimumab, etanercept, infliximab or abatacept.", 'Clinical need and practice': 'Rheumatoid arthritis is a chronic and progressive disabling condition characterised by inflammation of the synovial tissue of the joints. It may cause tenderness and stiffness of joints and their progressive destruction, and symptoms including pain and fatigue. It is estimated that 580,000\xa0people in England and Wales, approximately 1% of the population, have rheumatoid arthritis. Of these, approximately 15% have severe disease. Rheumatoid arthritis affects three times as many women as men and has a peak age of onset of 40–70\xa0years.\n\nIn rheumatoid arthritis, the synovial membrane thickens because of an increased number of synovial cells, infiltration by white blood cells and formation of new blood vessels. Synovial fluid increases within the joint cavity, and bone mineral density adjacent to the joint reduces. Erosions of the bone may occur at the margin of the joint where synovial tissue meets cartilage and bone, and this can lead to irreversible damage to the structure and function of the joint.\n\nInflammatory disease involving areas other than the joints can also occur. Dryness of the eyes and mouth and the formation of rheumatoid nodules may affect up to one third of people with rheumatoid arthritis. More severe inflammatory manifestations may lead to fibrosis in the lungs and inflammation affecting the lining of the heart, lungs and blood vessels. Ischaemic heart disease and cardiac failure are more common in people with rheumatoid arthritis than in those without this condition. Osteoporosis is also more common because of reduced mobility, inflammation and/or the side effects of drugs used to treat rheumatoid arthritis, particularly corticosteroids. Corticosteroid use can also contribute to an increased risk of infection and diabetes mellitus.\n\nInternationally agreed criteria for the diagnosis of rheumatoid arthritis (American College of Rheumatology [ACR] 1987) require four of the following features:\n\njoint stiffness in the morning exceeding 1\xa0hour\n\nphysician-observed arthritis of three or more areas with soft tissue swelling\n\narthritis involving hand joints\n\nsymmetrical arthritis\n\nrheumatoid skin nodules\n\na positive blood test for rheumatoid factor\n\nradiographic changes typical of rheumatoid disease.\n\nA diagnosis requires that, with the exception of the last criterion, all criteria must be present for a minimum of 6\xa0weeks. However, clinicians sometimes diagnose rheumatoid arthritis without reference to these criteria.\n\nThe course of rheumatoid arthritis varies, and the following factors indicate poor prognosis: the presence of antibodies to rheumatoid factor or cyclic citrullinated peptide (CCP); high erythrocyte sedimentation rate or concentrations of C-reactive protein; early radiographic evidence of erosions; and the presence of swollen and tender joints. Within 2\xa0years of diagnosis, people with rheumatoid arthritis may experience moderate disability, and after 10\xa0years 30% are severely disabled. Approximately one third of people with rheumatoid arthritis stop work because of the disease. Rheumatoid arthritis is associated with a reduced life expectancy; for example, a 50-year-old woman with rheumatoid arthritis is expected to die 4\xa0years earlier than a 50-year-old woman without rheumatoid arthritis.\n\nThe aim of treatment is to induce remission of disease, control pain and inflammation, and reduce or prevent joint damage, disability and loss of function, thereby improving quality of life. Treatment involves a combination of pharmacological and non-pharmacological interventions. Pharmacological treatment includes various combinations of non-steroidal anti-inflammatory drugs (NSAIDs), analgesics, corticosteroids and disease modifying anti-rheumatic drugs (DMARDs). DMARDs reduce symptoms and slow progression of structural damage. DMARDs may be classified as conventional (for example methotrexate or sulfasalazine) or biological. Biological DMARDs include, but are not limited to, the TNF inhibitors adalimumab, etanercept and infliximab, as well as rituximab and abatacept. Non-pharmacological interventions include orthopaedic surgery, physiotherapy and occupational therapy.\n\nNICE clinical guideline 79 (2009) recommends the use of a combination of conventional DMARDs (including methotrexate and at least one other conventional DMARD plus short-term glucocorticoids) as first-line treatment, beginning ideally within 3\xa0months of the onset of persistent symptoms. When combination therapy is not appropriate (for example, in people with methotrexate intolerance), the guideline recommends monotherapy with a conventional DMARD with quick escalation to a clinically effective dose.\n\nThe TNF inhibitors adalimumab, etanercept or infliximab, (NICE technology appraisal guidance 130 ) and certolizumab pegol (NICE technology appraisal guidance 186 ), each in combination with methotrexate, are recommended as options for the treatment of adults with active rheumatoid arthritis who have a disease activity score (DAS28) greater than 5.1 and whose rheumatoid arthritis has failed to respond to at least two conventional DMARDs, including methotrexate. If a patient does not tolerate methotrexate or if treatment with methotrexate is considered to be inappropriate, adalimumab, etanercept and certolizumab pegol may be given as monotherapy. Treatment should be withdrawn if response is not adequate within 6\xa0months (as defined by an improvement in DAS28 score of more than 1.2\xa0points) or if response is not maintained. Response to treatment should be monitored at least every 6\xa0months. An alternative TNF inhibitor may be considered when treatment with a first TNF inhibitor is withdrawn because of an adverse event before the initial 6-month assessment.\n\nSeveral tools have been developed to assess the response to treatment in rheumatoid arthritis. The American College of Rheumatology (ACR) response criteria (ACR20, 50 and 70) require a specified improvement in the percentage (20%, 50% or 70% respectively) of tender joints, swollen joints, global assessments, pain, disability and circulating inflammatory markers (for example, erythrocyte sedimentation rate). The disease activity score (DAS) is an alternative scoring system developed in Europe. It is calculated using a formula that includes counts for tender and swollen joints (53 and 44\xa0joints respectively), an evaluation of general health by the patient (on a scale of 0 to 100) and a measure of circulating inflammatory markers. DAS28 is similar to DAS but uses only 28\xa0joints for assessment. A DAS28 score greater than 5.1 indicates high disease activity, between 3.2 and 5.1 moderate disease activity, and less than 3.2 low disease activity. A score of less than 2.6\xa0indicates disease remission. An improvement in DAS28 score of 0.6 or less is considered a poor response, and improvements greater than 1.2\xa0points indicate a good response. The European League Against Rheumatism (EULAR) response criteria are based on the DAS measure. The Stanford Health Assessment Questionnaire (HAQ) comprises one component of the ACR criteria and scores the ability to perform daily activities; it ranges from 0 (least disability) to 3 (most severe disability). The modified Sharp score measures joint damage as assessed radiographically, and is scored on joint-space narrowing and erosions.', 'The technologies ': "# Adalimumab\n\nAdalimumab (Humira, Abbott Laboratories) is a human-sequence monoclonal antibody that binds specifically to TNF and neutralises its biological function by blocking its interaction with cell-surface TNF receptors. Adalimumab modulates biological responses induced or regulated by TNF, including changes in the concentrations of adhesion molecules responsible for the migration of leukocytes. Adalimumab has a marketing authorisation for the treatment of moderate to severe active rheumatoid arthritis in adults when the response to DMARDs, including methotrexate, has been inadequate. It is also indicated for the treatment of severe, active and progressive rheumatoid arthritis in adults not previously treated with methotrexate. The summary of product characteristics (SPC) states that adalimumab should be given in combination with methotrexate, except when methotrexate is not tolerated or is considered inappropriate.\n\nCommon adverse effects of adalimumab therapy include injection-site reactions and infections. Adalimumab is contraindicated in people with moderate to severe heart failure, those with active tuberculosis or those with other severe or opportunistic infections. Before initiating therapy, physicians should evaluate people for both active and inactive (latent) tuberculosis infection. For full details of adverse effects, contraindications, special warnings and precautions for use, see the SPC.\n\nAdalimumab is administered at a dose of 40\xa0mg every other week via subcutaneous injection. In monotherapy, if people experience a decrease in response the dose may be increased to 40\xa0mg every week. The net price for a 40-mg prefilled syringe is £357.50 (excluding VAT; 'British National Formulary', edition 59 [BNF59]). The annual cost of adalimumab for 26\xa0doses at a dose of 40\xa0mg every other week is £9295. Costs may vary in different settings because of negotiated procurement discounts.\n\n# Etanercept\n\nEtanercept (Enbrel, Pfizer) is a recombinant human TNF receptor fusion protein. It interferes with the inflammatory cascade by binding to TNF, thereby blocking its interaction with cell-surface receptors. Etanercept has a marketing authorisation for the treatment of moderate to severe active rheumatoid arthritis when the response to DMARDs, including methotrexate, has been inadequate. Etanercept is also indicated in the treatment of severe, active and progressive rheumatoid arthritis in adults not previously treated with methotrexate. The SPC states that etanercept should be given in combination with methotrexate, except when methotrexate is not tolerated or is considered inappropriate.\n\nCommon adverse effects of etanercept therapy include injection-site reactions, infections and allergic reactions. Etanercept is contraindicated in people with sepsis or risk of sepsis, and those with other active infections. Before initiating therapy, physicians should evaluate people for both active and inactive (latent) tuberculosis infection. For the full details of adverse effects, contraindications, special warnings and precautions for use, see the SPC.\n\nEtanercept is administered by subcutaneous injection at a dose of 25\xa0mg twice weekly. Alternatively, the SPC allows for a dose of 50\xa0mg once weekly. The net price for a 25-mg vial is £89.38 (excluding VAT; BNF59). The annual cost of etanercept using either 52 once-weekly doses of 50\xa0mg or 104 twice-weekly doses of 25\xa0mg is £9295. Costs may vary in different settings because of negotiated procurement discounts.\n\n# Infliximab\n\nInfliximab (Remicade, Schering-Plough) is a chimeric monoclonal antibody that binds with high affinity to TNF, thereby neutralising its activity. Infliximab has a marketing authorisation in combination with methotrexate for the treatment of active rheumatoid arthritis when the response to DMARDs, including methotrexate, has been inadequate, and for people with severe, active and progressive disease not previously treated with methotrexate or other DMARDs.\n\nCommon adverse effects of infliximab therapy include acute infusion-related reactions, infections and delayed hypersensitivity reactions. Infliximab is contraindicated in people with moderate or severe heart failure, and those with tuberculosis or other severe or opportunistic infections. For full details of adverse effects, contraindications, special warnings and precautions for use, see the SPC.\n\nInfliximab is administered at a dose of 3\xa0mg/kg by intravenous infusion over 2\xa0hours at an initial infusion (week\xa00) and then at weeks\xa02 and 6, and thereafter every 8\xa0weeks. If there is an inadequate response or a loss of response after 12\xa0weeks, physicians may consider increasing the dose of infliximab stepwise by approximately 1.5\xa0mg/kg, up to a maximum of 7.5\xa0mg/kg every 8\xa0weeks. Alternatively, administration of 3\xa0mg/kg as often as every 4\xa0weeks may be considered. The net price for a 100-mg vial is £419.62 (excluding VAT; BNF59). The annual drug costs associated with infliximab vary according to body weight and the number of infusions required. Assuming an average weight of 70\xa0kg and a dose of 3\xa0mg/kg, each dose of infliximab requires three vials at a cost of £1259. The three loading doses cost £3777, with an annual cost following the loading doses of between £7553 and £8812 depending on whether six or seven doses are required. Costs may vary in different settings because of negotiated procurement discounts.\n\n# Rituximab\n\nRituximab (MabThera, Roche Products) is a genetically engineered chimeric monoclonal antibody that depletes the B-cell population by targeting cells bearing the CD20 surface marker. Rituximab has a marketing authorisation for use in combination with methotrexate for the treatment of adults with severe active rheumatoid arthritis who have had an inadequate response or intolerance to other DMARDs including one or more TNF inhibitor therapies.\n\nCommon adverse effects of rituximab therapy include infusion reactions and infections. Rituximab is contraindicated in people with severe heart failure or severe, uncontrolled cardiac disease, and those with active, severe infections. For full details of undesirable effects, contraindications, special warnings and precautions for use see the SPC.\n\nA course of rituximab consists of two 1000-mg intravenous infusions given 2\xa0weeks apart. The SPC specifies that courses of rituximab should be given at intervals of no less than 16\xa0weeks. The cost to the NHS of 10-ml and 50-ml vials of rituximab is £174.63 and £873.15 respectively (excluding VAT; BNF59). The cost of a single course of rituximab is £3492 (two 1000-mg intravenous infusions). Costs may vary in different settings because of negotiated procurement discounts.\n\n# Abatacept\n\nAbatacept (Orencia, Bristol-Myers Squibb) is a selective T-cell co-stimulation modulator that blocks a key co-stimulatory signal required for T-cell activation. Abatacept has a marketing authorisation for use in combination with methotrexate for the treatment of moderate to severe active rheumatoid arthritis in adults who have had an insufficient response or intolerance to other DMARDs, including at least one TNF inhibitor.\n\nCommon adverse effects of abatacept therapy include infections, including sepsis and pneumonia. Abatacept is contraindicated in people with severe, uncontrolled infections, and opportunistic infections. Before initiating therapy, physicians should evaluate people for both active and inactive (latent) tuberculosis infection. For full details of undesirable effects, contraindications, special warnings and precautions for use, see the SPC.\n\nAbatacept is administered as a 30-minute intravenous infusion. After an initial infusion (week\xa00), it is repeated at week\xa02, week\xa04 and every 4\xa0weeks thereafter. People require a total of 14\xa0infusions in the first year and 13\xa0infusions in subsequent years. Abatacept is available in 250-mg vials at a cost of £242.17 per vial (excluding VAT; BNF59). The dose of abatacept depends on body weight: people weighing less than 60\xa0kg, 60–100\xa0kg and over 100\xa0kg require 500\xa0mg, 750\xa0mg and 1000\xa0mg respectively. The annual drug costs associated with abatacept vary according to body weight and the number of infusions required. For a person weighing between 60 and 100\xa0kg, the annual drug cost will be £10,171.14 in the first year and £9444.63 in subsequent years. Costs may vary in different settings because of negotiated procurement discounts.", 'Evidence and interpretation': "The Appraisal Committee (appendix A) considered evidence from a number of sources (appendix B).\n\n# Clinical effectiveness\n\nThe Assessment Group completed a systematic review of the efficacy of the technologies for the treatment of rheumatoid arthritis after the failure of a TNF inhibitor. Thirty-five studies met the criteria for inclusion. Five of these were randomised controlled trials (RCTs), one was a non-randomised controlled study, and 29 were included in the Assessment Report as uncontrolled studies (including two long-term RCT extensions). Three of the RCTs were subsequently excluded from the review by the Assessment Group because the studies included regimens outside of their marketing authorisation or the comparator was not considered relevant. A sixth RCT (the SUNRISE trial) was identified but not included in the systematic review because the trial was unpublished and data from the manufacturer were not provided in time for inclusion in the analyses. The two included RCTs compared rituximab with placebo (the REFLEX trial) and abatacept with placebo (the ATTAIN trial), with all people in these two RCTs also receiving ongoing methotrexate or other conventional DMARDs. This section summarises the outcomes for clinical effectiveness in terms of ACR\xa020, 50 and 70 response rate and improvement in DAS28 and/or HAQ score for the studies identified in the Assessment Group's systematic review.\n\n## Adalimumab\n\nFor adalimumab, the Assessment Group identified five uncontrolled studies with durations of follow-up ranging from 3 to 12\xa0months. Four studies had small sample sizes ranging from 24 to 41. The fifth, a multicentre study, included 899\xa0people. The Assessment Group did not pool the results because of substantial clinical and statistical heterogeneity between studies. Three studies reported ACR 20, 50 and 70 response rates ranging from 46% to 75%, 27% to 50% and 13% to 33% respectively. Four studies reported mean improvements in DAS28 score ranging from 1.30 to 1.90 when compared with pre-treatment values. Three studies reported mean improvements in HAQ ranging from 0.21 to 0.48 when compared with pre-treatment values. None of the studies assessed joint damage or quality of life.\n\n## Etanercept\n\nFor etanercept, the Assessment Group identified seven uncontrolled studies with durations of follow-up ranging from 3\xa0months to over 9\xa0months. Sample sizes ranged from 25 to 201. The results were not pooled because of substantial clinical and statistical heterogeneity between studies. Four studies reported ACR 20, 50 and 70 response rates ranging from 38% to 72%, 18% to 21% and 8% to 20% respectively. Four studies reported mean improvements in DAS28 score ranging from 0.47 to 1.80 when compared with pre-treatment values. Three studies reported mean improvements in HAQ score ranging from zero to 0.45 when compared with pre-treatment values. None of the studies assessed joint damage or quality of life.\n\n## Infliximab\n\nFor infliximab, the Assessment Group identified three uncontrolled studies, each with a small sample size ranging from 20 to 24. The Assessment Group could not determine the duration of follow-up in the studies. None of the studies reported ACR response criteria or quantitative results of changes in DAS28 and HAQ scores, or assessed joint damage or quality of life.\n\n## TNF inhibitors as a group\n\nEight studies were identified. None provided separate outcome data for individual TNF inhibitors. One non-randomised controlled study compared TNF inhibitors with rituximab (see section 4.1.10) and seven studies had no control group. The duration of follow-up in the studies ranged from 3\xa0months to 4\xa0years and sample sizes ranged from 70 to 818. One study reported ACR 20, 50 and 70 response rates of 46%, 26% and 7% respectively. A different study reported a mean improvement in HAQ score of 0.11 when compared with pre-treatment values. Three studies reported mean improvements in DAS28 score ranging from 0.88 to 1.00 when compared with pre-treatment values. No studies assessed joint damage or quality of life.\n\n## Rituximab\n\nThe Assessment Group identified one RCT (REFLEX, n\xa0=\xa0517), as well as the trial's long-term extension. The REFLEX trial compared rituximab with placebo (with ongoing methotrexate in both groups) in people who had had an inadequate response to one or more TNF inhibitors. The primary outcome in the REFLEX trial was ACR 20 response rate at 6\xa0months. The REFLEX trial reported statistically significant differences favouring the rituximab group for ACR 20, 50 and 70 response rates. For the rituximab group the values were 51%, 27% and 12%, and for the placebo group these were 18%, 5% and 1% respectively (for all comparisons p\xa0<\xa00.0001). A statistically significant difference in mean improvement in DAS28 was reported (1.9 in the rituximab group compared with 0.4 in the placebo group, p\xa0<\xa00.0001). A statistically significant difference was also reported for mean improvement in HAQ score (0.40 in the rituximab group compared with 0.10 in the placebo group, p\xa0<\xa00.0001). The long-term observational extension of the REFLEX trial included people who had received up to three courses of rituximab. This reported that people receiving further courses of rituximab responded in terms of ACR comparably to patients who received rituximab in the randomised phase of the RCT.\n\nThe SUNRISE trial (n\xa0=\xa0559) compared the safety and efficacy of one course of rituximab with two courses of rituximab. This trial was not included in the Assessment Group's analysis, but the results were later submitted by consultees. The study reported that of the people who had been randomised to a second course of rituximab at week\xa024, 54% had an ACR 20 at 48\xa0weeks, whereas of those who had been randomised to placebo, 45% had an ACR 20 at 48\xa0weeks (p\xa0=\xa00.02). A statistically significant difference in mean improvement in DAS28 was also reported (1.9 in the rituximab retreatment group compared with 1.5 in the placebo retreatment group, p\xa0<\xa00.01).\n\nIn addition to the REFLEX trial, the Assessment Group identified one non-randomised controlled study comparing TNF inhibitors with rituximab (see section 4.1.10), five uncontrolled studies and a pooled analysis combining data from the REFLEX trial, its long-term extension and other studies. Durations of follow-up in the uncontrolled studies ranged from 6\xa0months to 1\xa0year and sample sizes ranged from 20 to 158. The Assessment Group could not determine how many people the pooled analysis included. One study reported ACR 20, 50 and 70 response rates of 65%, 33% and 12% respectively. Another study reported a mean improvement in DAS of 1.61 when compared with pre-treatment values. None of the uncontrolled studies assessed improvement in HAQ score, joint damage or quality of life. The pooled analysis included people who had had up to five courses of rituximab treatment; this study showed clinical outcomes similar to those seen for rituximab in the REFLEX trial.\n\n## Abatacept\n\nThe Assessment Group identified one RCT (ATTAIN) and its long-term extension. The ATTAIN trial compared abatacept with placebo (with ongoing DMARDs in both groups) in people with an inadequate response to one or more TNF inhibitors. The co-primary outcomes in the ATTAIN trial were ACR 20 response rate and change in HAQ score at 6\xa0months. The ATTAIN trial reported statistically significant differences in response rates for abatacept compared with placebo. The values were 50% compared with 20% (p\xa0<\xa00.001) for ACR 20, 20% compared with 4% (p\xa0<\xa00.001) for ACR 50, and 10% compared with 2% (p\xa0<\xa00.01) for ACR 70. The ATTAIN trial also reported a statistically significant improvement in mean DAS28 score favouring the abatacept group (1.98 compared with 0.71, p\xa0<\xa00.001). In addition, the ATTAIN trial reported a statistically significant difference in mean improvement in the HAQ score favouring the abatacept group (0.45 compared with 0.11, p\xa0<\xa00.001). The long-term extension of the ATTAIN trial followed people for up to 5\xa0years. This analysis showed that among people continuing on abatacept, clinical outcomes in terms of ACR response rates were comparable to those seen for abatacept in the randomised phase of the RCT. Further data were provided from a large prospective uncontrolled study (ARRIVE, n\xa0=\xa01046); this study reported an improvement in DAS28 of 2.00 when compared with pre-treatment values.\n\n## Comparative effectiveness\n\nThe Assessment Group did not identify any randomised controlled trials directly comparing the five technologies, or trials comparing the technologies with other biological DMARDs or conventional DMARDs not previously tried by study participants. One non-randomised controlled study (n\xa0=\xa0318) compared switching from a TNF inhibitor to rituximab with switching to an alternative TNF inhibitor. When a switch occurred because the first TNF inhibitor was not effective, the mean change in DAS28 score was reported to be significantly higher in the rituximab group (mean change -1.34) compared with the group who received an alternative TNF inhibitor (mean change -0.93) (p\xa0=\xa00.03).\n\nThe Assessment Group conducted an adjusted indirect comparison of rituximab and abatacept using data from placebo-controlled trials that included similar populations. The analysis suggested no statistically significant differences in response rates between abatacept and rituximab for ACR\xa020 (relative risk 1.12, 95% confidence interval [CI] 0.68 to 1.84), ACR\xa050 (relative risk 1.00, 95% CI 0.33 to 2.98) and ACR\xa070 (relative risk 1.80, 95% CI 0.24 to 13.35).\n\n## Subgroup analyses\n\nThe Assessment Group identified evidence for adalimumab, etanercept and abatacept that compared response to treatment according to the reason for withdrawal of the first TNF inhibitor. The evidence compared primary non-responses (when the disease had never responded to treatment with a TNF inhibitor) with secondary non-responses (when there was a reduction in disease response to the first TNF inhibitor). The majority of analyses suggested no statistically significant differences in response according to reason for withdrawal of the first TNF inhibitor. However, two analyses of adalimumab showed statistically significant higher response rates for ACR\xa020 (pooled estimate risk difference -0.20, 95% CI -0.37 to -0.02) and ACR\xa050 (pooled estimate risk difference -0.12, 95% CI -0.20 to -0.04) when the first TNF inhibitor had been withdrawn because of a secondary non-response. Data for abatacept from the ATTAIN long-term extension study also suggested that in a non-intention-to-treat analysis of people who had a change in HAQ greater than 0.3 at 6\xa0months, the proportion whose disease responded was higher among people who had experienced a secondary non-response than among those who experienced a primary non-response (risk difference -0.15, 95% CI -0.28 to -0.02). However, registry data for the TNF inhibitors as a group suggested that, when measured as EULAR response rates at 3\xa0months, and assuming missing observations represented non-responders, there were statistically significantly higher response rates among people who stopped their first TNF inhibitor because of primary non-response (risk difference 0.30, 95% CI 0.13 to 0.46). No specific data for infliximab and rituximab were identified.Evidence for the influence of the presence of auto-antibodies (that is, rheumatoid factor and anti-CCP antibody status) on effectiveness was available only for rituximab, from the REFLEX trial. The trial reported no statistically significant differences in relative treatment effect by rheumatoid factor status. However, absolute response rates were lower in both the rituximab and the placebo groups for people who were rheumatoid factor-negative than those who were rheumatoid factor-positive. When participants were stratified according to both rheumatoid factor and anti-CCP antibody status, the data suggested a greater treatment response in people who were either rheumatoid factor-positive or anti-CCP antibody-positive than in those who were negative for both rheumatoid factor and anti-CCP. The Assessment Group noted that this retrospective analysis should be treated with caution.\n\n# Cost effectiveness\n\n## Published literature\n\nThe Assessment Group identified four published economic analyses – two of rituximab and two of abatacept – that met the criteria for inclusion in the systematic review. All four used a decision analytic model. Three of the studies carried out a cost–utility analysis and reported results in terms of costs per quality-adjusted life years (QALYs) gained. The remaining study (of abatacept) reported results in terms of costs per additional case of 'low disease activity state' gained (DAS28 less than 2.6) and costs per additional remission gained (DAS28 up to 3.2). The Assessment Group could not perform a direct comparison of the incremental cost-effectiveness ratios (ICERs) from these studies because of different specifications of the models, including treatment sequence, time horizon, perspective and country of origin.\n\n## Manufacturers' submissions\n\nAll five manufacturers provided economic analyses to support their submissions. One analysis (etanercept, Pfizer) was provided only as a narrative summary and not as a fully executable model. All submissions were based on cost–utility analyses run over a lifetime horizon and from the perspective of the healthcare provider. All but one submission (abatacept, Bristol-Myers Squibb) used conventional DMARDs as the base-case comparator.\n\n## Abbott Laboratories (adalimumab)\n\nAbbott Laboratories developed a discrete-event simulation model and performed a cost–utility analysis of adalimumab, etanercept, infliximab, rituximab and abatacept (all of which were considered in combination with methotrexate), each in comparison with conventional DMARDs. The model also compared adalimumab with conventional DMARDs only, and the sequence of adalimumab followed by rituximab compared with each of the remaining biological DMARDs. The model simulated people with profiles based on the baseline characteristics of people in the British Society for Rheumatology Biologics Register. The model included adverse events. It also included a continuation rule using ACR\xa050 response to determine whether a person continued therapy after an initial trial period.\n\nResponse to treatment was based on ACR response rates mapped to a change in HAQ score. The manufacturer derived the ACR response rates from a mixed treatment comparison of 34\xa0studies and assumed that the responses were equal across all TNF inhibitors (that is, that the response to adalimumab was not different from other TNF inhibitors). To map ACR to HAQ, the change in HAQ score associated with each ACR response category was calculated from adalimumab clinical trial data in which both HAQ and ACR were measured. The model assumed that when people discontinued treatment with a TNF inhibitor, the initial effect of treatment was lost. The model assumed that disease progressed while on treatment and that it progressed at a constant annual rate to a greater degree on conventional than on biological DMARDS. This was modelled in terms of an annual increase in HAQ score of 0.030 for biological DMARDs, 0.045 for conventional DMARDs and 0.060 for rescue therapy. To convert HAQ scores to EuroQol (EQ-5D) scores, the manufacturer used a non-linear mapping mechanism estimated using EQ-5D data collected in trials of tocilizumab (another biological DMARD).\n\nCosts included drug acquisition, administration, monitoring and hospitalisation (including joint replacement surgery). The cost of administering intravenous drugs was estimated to be £462 for each infusion, based on the Healthcare Resource Group 2007/08 tariff. The manufacturer of adalimumab assumed that administering subcutaneous drugs would require 3\xa0hours of nurse training incurring a one-off cost of £129. The manufacturer assumed retreatment with rituximab would occur every 9\xa0months. This assumption was tested in a sensitivity analysis using a retreatment schedule of every 6\xa0months.\n\nThe base-case analysis showed that for rituximab in comparison with conventional DMARDs, the incremental QALY gain was 1.375 at an incremental cost of £15,100, giving an ICER of £10,986 per QALY gained. When it was assumed that treatment with rituximab was repeated every 6\xa0months instead of every 9\xa0months, the ICER increased from £10,986 per QALY gained in the base case to £15,856 per QALY gained. The base-case analysis showed that for adalimumab or etanercept in comparison with conventional DMARDs, the QALY gain was 1.467 at an incremental cost of £23,423, giving an ICER of £15,962 per QALY gained. For infliximab and abatacept (each in comparison with conventional DMARDs), the QALY gains were 1.451 and 1.136 respectively. The incremental costs were £31,241 and £34,188 respectively, giving ICERs of £21,529 and £30,104 per QALY gained. From the data presented, the ICER for adalimumab or etanercept compared with rituximab, given every 9\xa0months, could be calculated to be £83,230 per QALY gained. Infliximab was dominated by adalimumab and etanercept, and abatacept was dominated by rituximab. From the data presented, the ICER for adalimumab or etanercept in comparison with rituximab given every 6\xa0months could be calculated to be £16,280 per QALY gained. Infliximab was dominated by adalimumab and etanercept, and abatacept was dominated by rituximab. Univariate sensitivity analyses (altering one variable at a time) suggested that the model was most sensitive to the HAQ score at the start of treatment, change in HAQ score while on treatment (that is, underlying disease progression), assumptions regarding the loss or maintenance of initial treatment effect upon stopping treatment, the way in which HAQ was mapped to EQ-5D and the dosing schedule of rituximab.\n\n## Pfizer (etanercept)\n\nPfizer presented the results of a Markov model with a 6-month cycle. The model compared three strategies: treatment with two sequential TNF inhibitors, treatment with a TNF inhibitor followed by a conventional DMARD and treatment with a TNF inhibitor followed by rituximab. The manufacturer did not include abatacept in the economic analyses. Baseline patient characteristics reflected those of the patients in the TEMPO trial (an RCT of etanercept in people whose rheumatoid arthritis had had an inadequate response to conventional DMARDs). The model included serious adverse events. The base-case model included a continuation rule using HAQ score mapped from DAS28 to determine whether a person continued therapy after an initial trial period.\n\nThe manufacturer defined response to treatment in terms of mean change in HAQ score in people treated with a second TNF inhibitor after primary non-response, secondary loss of response or intolerance of their first TNF inhibitor. The data were taken from a trial of adalimumab; the values used were -0.44, -0.51 and -0.55 respectively. The manufacturer estimated the mean changes in HAQ score for those treated with rituximab (-0.40) from the REFLEX trial; all were unadjusted estimates of absolute treatment effect observed in the trial. The effect of conventional DMARDs following failure of a TNF inhibitor was assumed to be zero, based on data from the British Society for Rheumatology Biologics Register. The model included underlying disease progression while on treatment, modelled in terms of worsening HAQ score over time. The manufacturer assumed that while on treatment with biological DMARDs the HAQ score remained unchanged (that is, disease did not progress/worsen) but that while on conventional DMARDs the HAQ score changed at a rate of 0.075 per 6-month cycle from the first 6\xa0months up to 3\xa0years, and then 0.10 per 6-month cycle from year\xa03 onwards. The manufacturer used a linear mapping mechanism to convert HAQ scores to EQ-5D scores during each model cycle.\n\nCosts included drug acquisition and administration, and costs associated with hospitalisation, outpatient visits, primary care visits, investigations and monitoring. The cost of administration was unclear. Rituximab was assumed to be provided once every 6\xa0months.\n\nThe manufacturer presented the base-case results for a range of assumptions regarding changes in HAQ score for both TNF inhibitors and conventional DMARDs. Total differences in costs and QALYs were presented only for people who had switched from one TNF inhibitor to another because of an adverse event. The ICER for TNF inhibitors compared with conventional DMARDs was £15,294 per QALY gained when switching as a result of primary non-response and £14,501 per QALY gained when switching as a result of secondary loss of response. The ICER for TNF inhibitors compared with rituximab was £19,077 per QALY gained and £16,225 per QALY gained following switching for primary non-response and secondary loss of response respectively. The manufacturer presented no probabilistic sensitivity analysis results in the submission.\n\n## Schering-Plough (infliximab)\n\nSchering-Plough developed a patient-level simulation model and performed a cost–utility analysis of infliximab compared with adalimumab, etanercept, rituximab, and abatacept, all of which were considered in combination with methotrexate. Comparisons were also made with conventional DMARDs only, and of the TNF inhibitors followed by rituximab. The model simulated people based on the characteristics at baseline of participants in the GO-AFTER trial (a trial of the TNF inhibitor golimumab in people with an inadequate response to a previous TNF inhibitor). The model did not include adverse events. The base-case model included a continuation rule using EULAR response to determine whether a person continued therapy after an initial trial period.\n\nThe manufacturer determined response to treatment by a multi-step process. First, baseline EULAR response rates from the British Society for Rheumatology Biologics Register were converted to baseline ACR response rates using an algorithm derived from the GO-AFTER trial. Treatment-specific ACR response rates were generated from the results of a mixed treatment comparison of RCTs of biological DMARDs. These ACR response rates were then converted back to EULAR response rates using the GO-AFTER algorithm. The EULAR response categories were then mapped to EQ-5D using algorithms derived from British Society for Rheumatology Biologics Register data that indirectly calculated EQ-5D from HAQ. In addition to the initial response to treatment, the model included underlying disease progression while on treatment, modelled using change in HAQ score over time. The manufacturer assumed that people treated with biological DMARDs experienced no progression in their disease whereas the condition deteriorated at a rate of 0.042 per year in people treated with conventional DMARDs.\n\nCosts included drug acquisition and administration, monitoring and hospitalisation. It was assumed that in 63% of cases sharing of vials resulted in no wastage of unused infliximab. The cost of administering infused drugs was assumed to be £162.12, based on the cost given in the assessment report for NICE technology appraisal guidance 130 and adjusted for inflation. The manufacturer presented two analyses for rituximab: one assuming retreatment every 6\xa0months and the other every 9\xa0months.\n\nThe base-case analysis showed that for rituximab in comparison with conventional DMARDs, the incremental QALY gain was 0.65 at an incremental cost of £11,325, giving an ICER of £17,422 per QALY gained (assuming 9-month retreatment intervals). Assuming retreatment with rituximab every 6\xa0months, the ICER for rituximab compared with conventional DMARDs was £27,161 per QALY gained. The QALY gains for adalimumab, etanercept and infliximab were 0.66, 0.62 and 0.65 respectively. The respective incremental costs were £23,129, £22,257 and £18,628, giving ICERs of £35,138, £35,898 and £28,661 per QALY gained compared with conventional DMARDs. The strategy comparing abatacept with conventional DMARDs resulted in an incremental QALY gain of 0.63 for an incremental cost of £28,205, producing an ICER of £44,795 per QALY gained. From the data presented, the ICER for adalimumab in comparison with rituximab given every 9\xa0months could be calculated to be £1,186,230 per QALY gained. Etanercept and abatacept were dominated by rituximab, and infliximab was extendedly dominated by rituximab. When rituximab was assumed to be given every 6\xa0months, the ICER for adalimumab compared with rituximab could be calculated to be £553,700 per QALY gained. Etanercept and abatacept were dominated by rituximab, and infliximab was extendedly dominated by rituximab.\n\n## Roche Products (rituximab)\n\nRoche Products developed a patient-level simulation model and performed a cost–utility analysis of rituximab compared with adalimumab, etanercept, infliximab and abatacept, all of which were followed by a sequence of conventional DMARDs. The manufacturer also compared rituximab with conventional DMARDs alone. The model simulated people whose profiles were based on baseline characteristics of participants in the REFLEX trial. The manufacturer did not include adverse events.\n\nResponse to treatment was defined in terms of ACR response rates mapped to a change in HAQ score. ACR response rates were derived from two sources: a mixed treatment comparison of RCTs of TNF inhibitors in people whose rheumatoid arthritis had had an inadequate response to conventional DMARDs, and an indirect comparison of the abatacept ATTAIN trial and the rituximab REFLEX trial. The manufacturer then adjusted (reduced by 30%) the results of the mixed treatment comparison to reflect a lower response to treatment observed in people who had had an inadequate response to a first TNF inhibitor. The manufacturer converted ACR to HAQ using an algorithm from data in the REFLEX trial. When people discontinued treatment, the manufacturer assumed that the initial effect of treatment was lost. The model included both initial response to treatment and underlying disease progression while on treatment, each modelled as changes in HAQ score. It was assumed that while a person was on a biological DMARD there was no change in HAQ score. People on conventional DMARDs experienced an increase (worsening) in HAQ score of 0.0225 per 6-month cycle and people receiving palliative care experienced an increase in HAQ score of 0.03 per 6-month cycle. The manufacturer mapped HAQ scores to EQ-5D scores using a non-linear mapping mechanism derived from data from the tocilizumab trials.\n\nThe costs included drug acquisition and administration, monitoring and hospitalisation. The cost of administration was assumed to be £162 per infusion and this included all premedication and monitoring costs. Subcutaneous drugs incurred monitoring and premedication costs of £1268 per year and administration costs (£136 for etanercept and £68 for adalimumab) to allow for the 10% of people who will receive injections from a district nurse. Retreatment with rituximab was assumed to occur every 8.7\xa0months. This assumption was tested in sensitivity analysis.\n\nThe base-case analysis showed that for rituximab compared with conventional DMARDs, the incremental QALY gain was 1.071 with an incremental cost of £5,685, giving an ICER of £5,311 per QALY gained. Assuming retreatment with rituximab every 6\xa0months, the ICER for rituximab compared with conventional DMARDs increased from £5,311 to £10,876 per QALY gained. The strategies comparing rituximab with etanercept, infliximab or abatacept showed rituximab to be both more effective and less costly. The strategy comparing rituximab with adalimumab showed rituximab to be less effective and less costly, with a QALY loss of 0.044 and an incremental reduction in cost of £13,551, resulting in an ICER for adalimumab compared with rituximab of £310,771 per QALY gained.\n\n## Bristol-Myers Squibb (abatacept)\n\nBristol-Myers Squibb developed a patient-level simulation model and performed a cost–utility analysis of abatacept compared with rituximab, both followed by infliximab. They also modelled abatacept compared with a basket of TNF inhibitors (reflecting the proportion of each drug's market share), both followed by another basket of TNF inhibitors. The model simulated people whose profiles were based on the baseline characteristics of participants in the ATTAIN trial. The model included adverse events for the first 6\xa0months of treatment.\n\nThe manufacturer defined response to treatment in terms of mean change in HAQ score. Estimates for rituximab (0.38) and abatacept (0.42) were based on a mixed treatment comparison of the ATTAIN and REFLEX trials. Estimates for TNF inhibitors (0.21) were taken from an analysis of data from the British Society for Rheumatology Biologics Register completed by NICE's Decision Support Unit for NICE technology appraisal guidance 130. The manufacturer assumed that people who discontinued treatment lost the initial effect of treatment. Underlying progression of disease while on treatment was modelled using HAQ score. For people treated with abatacept, disease was assumed to improve over time, with an annual improvement (HAQ score decrease) of 0.0729 in analyses compared with rituximab, and of 0.013 in analyses compared with TNF inhibitors. For the other biological treatments, the manufacturer assumed that disease worsened at an annual HAQ score increase of 0.012. A linear mapping mechanism was used to convert HAQ scores to Health Utilities Index Mark 3 scores during each model cycle.\n\nCosts included drug acquisition and administration, monitoring, hospitalisation (including that for joint replacement surgery), outpatient visits and costs associated with adverse events. Different administration costs were used for the different drugs requiring intravenous infusion. For abatacept the cost per infusion was £141.83 based on the assessment report for NICE technology appraisal guidance 130 and adjusted for inflation to 2007/2008; for rituximab and infliximab the cost was £284.73 based on NHS reference costs. For subcutaneous treatments a one-off cost of £25.66 was incurred for training. Retreatment with rituximab occurred once every 6\xa0months.\n\nThe base-case analysis showed that in comparison with the basket of TNF inhibitors, the QALY gain for abatacept was 0.47 at an incremental cost of £10,888, giving an ICER of £23,019 per QALY gained. The strategy comparing abatacept with rituximab resulted in an incremental QALY gain of 0.45 for an incremental cost of £9238, producing an ICER of £20,438 per QALY gained. Sensitivity analyses showed that when it was assumed that there were no differences in the underlying progression of disease between the biological DMARDs (that is, a worsening of HAQ score of 0.012 per year was assumed for each biological treatment), the ICER for abatacept was £40,534 per QALY gained compared with rituximab, and £27,871 per QALY gained compared with TNF inhibitors.\n\n## The Birmingham Rheumatoid Arthritis Model\n\nThe Assessment Group carried out an independent economic analysis using the Birmingham Rheumatoid Arthritis Model. The model simulated people with rheumatoid arthritis based on the baseline characteristics of people in the British Society for Rheumatology Biologics Register. The model sampled people individually and compared each of the technologies (followed by a sequence of conventional DMARDs) with one another or with conventional DMARDs alone. It allowed for two stages of stopping treatment early. The first stage represented the possibility of stopping treatment after 6\xa0weeks (assumed to be because of toxicity) and the second stage represented stopping treatment at between 6 and 24\xa0weeks (assumed to be because of either toxicity or lack of efficacy). The model did not allow for stopping rituximab early because it was necessary to model the full costs of each cycle of treatment.\n\nThe Assessment Group modelled response to treatment using HAQ, with changes in HAQ scores calculated using a multiplier that represents a proportional change from a given baseline HAQ score. The respective HAQ multipliers for rituximab and abatacept were derived from the REFLEX and ATTAIN trials. The HAQ multipliers for adalimumab and etanercept were derived from uncontrolled studies. In the absence of data, the HAQ multiplier for infliximab was assumed to be the same as for etanercept. The Assessment Group assumed that when people discontinue treatment, they lose the initial effect of treatment. In addition to the initial response to treatment, the model assumed that underlying disease progresses during treatment. This was modelled by increases in HAQ score. In the base-case analysis, it was assumed that HAQ score remains constant for a person treated with a biological DMARD, but increases (worsens) for people treated with conventional DMARDs or palliative care. The annual HAQ score increase was 0.045 for conventional DMARDs and 0.06 for palliative care. The Assessment Group used a non-linear equation to convert HAQ scores to EQ-5D scores.\n\nCosts included drug acquisition and administration plus monitoring. The administration cost for drugs requiring infusion was assumed to be £141.83. Costs for hospitalisation and joint replacement were estimated using a cost per unit HAQ score. Retreatment with rituximab was assumed to occur every 8.7\xa0months.\n\nThe base-case analysis showed that for rituximab compared with conventional DMARDs, the incremental QALY gain was 0.96 with an incremental cost of £20,400, giving an ICER of £21,100 per QALY gained. The QALY gains for adalimumab, etanercept and infliximab were 0.75, 0.67 and 0.67 respectively. The respective incremental costs were £25,800, £26,100 and £24,000, giving ICERs (rounded to the nearest £100) of £34,300, £38,900 and £36,100 per QALY gained. The strategy comparing abatacept with conventional DMARDs resulted in an incremental QALY gain of 1.15 for an incremental cost of £44,000, producing an ICER of £38,400 per QALY gained. Compared with the TNF inhibitors, rituximab was shown to be both less costly and more effective. The ICER for abatacept in comparison with rituximab was £130,600 per QALY gained. The strategies comparing abatacept with adalimumab, etanercept and infliximab resulted in ICERs of £46,400 per QALY gained, £37,800 per QALY gained and £41,700 per QALY gained respectively.\n\nScenario analyses were undertaken to explore the impact of varying single assumptions within the model. These included: the time on treatment with the various therapies; the rituximab treatment interval; the efficacy of conventional DMARDs after the failure of a TNF inhibitor; the change in HAQ score while on biological DMARDs; the proportion of people stopping treatment early; the inclusion of costs of adverse events and palliation; and assumptions related to the equation used to map HAQ score to EQ-5D scores. These analyses indicated that the results are subject to considerable uncertainty.\n\nAssuming that there was underlying progression of disease modelled as an increase in HAQ score of 0.03 per year while on biological DMARDs increased the ICERs for the comparison with conventional DMARDs. The ICERs were £61,300 per QALY gained for adalimumab, £76,300 per QALY gained for etanercept, £68,900 per QALY gained for infliximab, £46,000 per QALY gained for rituximab and £63,300 per QALY gained for abatacept.\n\nAssuming conventional DMARDs were no more effective than placebo reduced the base-case ICERs for the comparison with conventional DMARDs to £28,100 per QALY gained for adalimumab, £31,100 per QALY gained for etanercept, £28,800 per QALY gained for infliximab, £16,300 per QALY gained for rituximab and £32,100 per QALY gained for abatacept. An incremental analysis demonstrated that rituximab was shown to be both less costly and more effective than each of the TNF inhibitors. The ICER for abatacept in comparison with rituximab was £158,000 per QALY gained.\n\nUsing the same proportion of people stopping early as was used in the Roche model (based on failure to achieve an ACR\xa020 response) reduced the base-case ICERs for the comparison with conventional DMARDs to £22,200 per QALY gained for adalimumab, £23,400 per QALY gained for etanercept, £26,200 per QALY gained for infliximab, £19,500 per QALY gained for rituximab, and £24,100 per QALY gained for abatacept. A detailed analysis of the costs and QALYs provided as an addendum by the Assessment Group showed that abatacept (with costs of £70,500 and 2.82 QALYs) was dominated by rituximab (with costs of £62,300 and 2.91 QALYs). Adalimumab, etanercept and infliximab were associated with lower costs than rituximab (£61,700, £60,300, and £62,300, respectively). However, they were also associated with fewer QALYs (2.56, 2.47 and 2.49, respectively). In an incremental analysis, rituximab had the lowest ICER, with the other treatments being either dominated or extendedly dominated.\n\nResults suggested that the model was sensitive to changes in the equation converting HAQ to health-related quality of life; and the assumed time between treatments for comparisons involving rituximab. Assuming retreatment with rituximab every 6\xa0months instead of every 8.7\xa0months, the ICER for rituximab in comparison with conventional DMARDs increased from £21,100 to £32,600 per QALY gained.\n\nResults suggested that the model was not sensitive to changes in the cost parameters, including those associated with hospitalisation and joint replacement, palliative care, and adverse events. The base-case analysis assumed a cost of joint replacement and hospitalisation of £1120 per HAQ score unit. The exclusion of these costs increased the ICER in comparison with conventional DMARDs by approximately £2500 per QALY gained. The inclusion of additional drug costs of palliation (that is, a £420 start-up cost and a subsequent annual cost of approximately £1000) reduced the ICERs in comparison with conventional DMARDs by approximately £1000 per QALY gained.\n\n# Consideration of the evidence\n\nThe Appraisal Committee reviewed the data available on the clinical and cost effectiveness of adalimumab, etanercept, infliximab, rituximab and abatacept after the failure of a TNF inhibitor. The Committee considered evidence on the nature of rheumatoid arthritis and the value placed on the benefits of adalimumab, etanercept, infliximab, rituximab and abatacept by people with the condition, those who represent them and clinical specialists. It also took into account the effective use of NHS resources.\n\n## Clinical effectiveness\n\nThe Committee considered the current clinical management of people with rheumatoid arthritis. The Committee heard from clinical specialists that the pathway of care following the failure of treatment with a TNF inhibitor depends on the individual person's responses to therapies, the clinical experience of the physician and the person's preference. The Committee heard from patient experts that rheumatoid arthritis can have a severe impact on quality of life, and that fatigue, pain and depression are common among people with the disease. Patient experts reported that rheumatoid arthritis frequently affects people's ability to work, noting the considerable burden placed on the carers of people with the disease. The Committee heard that rheumatoid arthritis may not respond to a given treatment, or there may be a decline in response over time that requires a change in treatment. Clinical specialists and patient experts emphasised the importance of having the option of multiple treatments for people whose disease has not responded adequately to initial treatment with a TNF inhibitor.\n\nThe Committee heard from clinical specialists that rheumatoid arthritis is heterogeneous and that different people may respond differently to a given treatment. In addition, it is difficult to predict whether an individual's disease will respond to a given treatment. Experts stated that people for whom a TNF inhibitor had never produced a response may be less suitable for a second TNF inhibitor than people whose rheumatoid arthritis had previously responded, and that people with seronegative antibody status may be less suitable for treatment with rituximab, than people with seropositive antibody status, although uncertainty surrounds this. The Committee therefore understood that response to treatments varies, and that it is not currently possible to target specific treatments to individuals because the response to any particular treatment cannot be predicted.\n\nThe Committee heard that the management of rheumatoid arthritis was changing in line with NICE guidelines for rheumatoid arthritis, and that more clinicians start DMARDs early and increase the dose of DMARDs quickly as required. The Committee heard from clinical specialists that, as a consequence of this accelerated approach to the use of DMARDs, physicians initiate treatment with TNF inhibitors sooner after diagnosis than they had done previously and therefore the characteristics of the people being treated with TNF inhibitors have changed over time. The Committee also heard from the clinical specialists that initiating treatment with TNF inhibitors earlier in the treatment pathway may increase people's potential to benefit from such treatment because of the reduced accumulation of irreversible joint damage. The Committee understood that these changes in the management of rheumatoid arthritis limited the generalisability of data from the British Society for Rheumatology Biologics Register, as it represents a cohort of people whose characteristics (including disease duration and number of previously received treatments) may not reflect those of the people currently seen in clinical practice for whom the first biological DMARD has failed.\n\nThe Committee considered the decision problem in the scope, noting comments from consultees that three technologies (certolizumab pegol, golimumab and tocilizumab) defined as comparators in the scope had not been included in the Assessment Report because marketing authorisations had not been obtained at the point at which the protocol was finalised. The Committee noted that golimumab and tocilizumab were subject to separate ongoing appraisals and were not yet in routine clinical use. It recognised that NICE technology appraisal guidance 186 on certolizumab pegol for the treatment of rheumatoid arthritis did not include guidance on its use after the failure of a TNF inhibitor. The Committee heard that in the absence of NICE guidance, the use of certolizumab pegol in this patient group would be subject to local decision making. The Committee concluded that excluding certolizumab pegol, golimumab and tocilizumab from the Assessment Report was appropriate. The Committee noted, however, the availability of RCT data for golimumab (an alternative TNF inhibitor) after the failure of a TNF inhibitor, and agreed that consideration of this data would be relevant to the decision problem in the appraisal (section 4.3.7).\n\nThe Committee considered whether the TNF inhibitors could be considered as a group with respect to clinical effectiveness. The Committee was aware that each of the TNF inhibitors has a different mechanism of action. The Committee heard from clinical specialists that variations in the underlying mechanism of disease across people coupled with different mechanisms of action of the individual drugs can result in a variety of responses to treatment with TNF inhibitors. The Committee heard from patient experts that the technologies should be considered separately. The Committee heard from clinical specialists that data from the British Society for Rheumatology Biologics Register show no statistically significant difference in effect between TNF inhibitors, but that these data reflect the effectiveness of the first use of TNF inhibitors and not the effectiveness after the failure of a previous TNF inhibitor. Based on advice from the clinical specialists and patient experts that disease can respond differently to different TNF inhibitors, the Committee concluded that it may not be appropriate to assume that the TNF inhibitors form a homogeneous group with regard to clinical effectiveness. However, in the absence of evidence either way, it was not currently possible to distinguish with certainty between the TNF inhibitors in terms of their clinical effectiveness.\n\nThe Committee discussed the clinical effectiveness of a second TNF inhibitor after the failure of a first. It noted that the review of the evidence by the Assessment Group had identified no RCTs and that the majority of other studies were uncontrolled observational or registry datasets, some of which had examined the TNF inhibitors as a group. The Committee heard from clinical specialists that for conventional DMARDs, the proportion of people whose condition responded to each successive treatment was reduced as the number of treatments increased, and that the same was considered to hold true for biological DMARDs. The clinical specialists noted that failure of a first TNF inhibitor was associated with an increased risk of failure of a second TNF inhibitor, but that the proportion of people with a good response was comparable. The clinical specialists therefore considered that a second TNF inhibitor was clinically effective. The Committee noted the comment made in consultation that the GO-AFTER trial data for a different TNF inhibitor (golimumab) could be used to inform the relative treatment effect of the TNF inhibitors in comparison with placebo. It discussed data from this trial that showed a statistically significant benefit from treatment with the TNF inhibitor golimumab after the failure of a different TNF inhibitor when compared with placebo. However, while noting the availability of these data, the Committee were mindful of comments from the clinical specialists and patient experts that the TNF inhibitors should be considered separately (see section 4.3.6). Furthermore, the Committee agreed that it would not be appropriate to apply the results from a treatment not included in the appraisal to the drugs in the appraisal, but concluded that the results for golimumab could be seen as confirming a beneficial effect of TNF inhibitor treatment following failure of a first TNF inhibitor.\n\nThe Committee specifically considered the data from the British Society for Rheumatology Biologics Register. It heard from clinical specialists that the register reported an improvement in HAQ score of 0.11 among people receiving a second TNF inhibitor. The Committee also heard that this change did not differ from the average change in HAQ score (0.10) among people whose first TNF inhibitor had failed but who had continued to take it. The Committee heard from the clinical specialists that this change was smaller than the minimum value that is considered a clinically important difference within the context of a clinical trial (0.22) and within the context of an observational study (0.14). The Committee noted the limitations of the British Society for Rheumatology Biologics Register data. Considering these data in conjunction with the evidence discussed in section 4.3.7, the Committee concluded that although the studies suggest that a second TNF inhibitor is effective after the failure of a first, the absence of any rigorously controlled data meant that it could not quantify with certainty the relative effects of adalimumab, etanercept or infliximab in comparison with either conventional DMARDs or alternative biological DMARDs.\n\nThe Committee considered the evidence from the randomised controlled trials of rituximab (REFLEX trial) and of abatacept (ATTAIN trial). The Committee noted the results of the Assessment Group's indirect comparison of rituximab and abatacept based on these trials, which did not show statistically significant differences between the two treatments, and that the conclusions were similar to those from the indirect comparisons carried out by Roche and Bristol Myers Squibb. The Committee concluded that both treatments had been shown to be clinically effective in comparison with placebo, but that one treatment had not been shown to be more effective than the other. The Committee concluded that the data for TNF inhibitors were insufficient to quantify with certainty the relative effect of rituximab and abatacept in comparison with adalimumab, etanercept or infliximab when used after the failure of the first TNF inhibitor.\n\nThe Committee considered specifically the evidence of clinical effectiveness for the subgroup of people defined by reason for withdrawal of the first TNF inhibitor. It heard from clinical specialists that they considered that people whose disease had not responded to the first TNF inhibitor (primary non-response) would be less likely to experience a response to a second TNF inhibitor in comparison with those whose disease had initially responded but who had later experienced diminishing benefit (secondary non-response). However, the Committee considered that the studies identified by the Assessment Group did not show a consistent difference in response (including less response, similar response and better response) between secondary non-response and primary non-response. The Committee concluded that although some evidence and clinical testimony suggested a difference in response by reason for withdrawal, there was currently insufficient evidence for the Committee to use this as a basis for making recommendations for this specific subgroup.\n\nThe Committee also considered subgroups based on the presence of auto-antibodies (rheumatoid factor and anti-CCP antibody status) and the impact of the presence of auto-antibodies on the clinical and cost effectiveness of rituximab. The Committee heard from the clinical specialists that the presence of auto-antibodies is not a consistent measure in that the same person may have a positive test for auto-antibodies in one instance and a negative test in another. The Committee was aware that a post-hoc analysis of the REFLEX study showed no statistically significant differences in relative effectiveness between subgroups defined by auto-antibody status. The Committee recognised that the REFLEX study and several other studies highlighted by consultees showed a lower absolute response rate in people who test seronegative compared with those who test seropositive. The Committee heard from clinical specialists that draft guidelines from the British Society for Rheumatology advise that people who test seropositive for either rheumatoid factor or anti-CCP may be more likely to respond than people who test seronegative for the two antibodies, and that this should be taken into account when considering rituximab. However, the clinical specialists considered that people who test seronegative may still respond to rituximab treatment. The Committee was not aware of data showing with certainty that adalimumab, etanercept, infliximab or abatacept would be more clinically effective than rituximab in this situation and that people who test seronegative are not excluded from the current marketing authorisation for rituximab. On balance, the Committee was not persuaded that there was currently sufficient evidence to conclude that rituximab treatment was inappropriate for people who test seronegative. Therefore, the Committee agreed not to make differential recommendations for a subgroup based on auto-antibody status.\n\nThe Committee noted that no studies had been identified that compared the biological DMARDs with a newly initiated conventional DMARD after the failure of a first TNF inhibitor. The Committee heard from clinical specialists that they considered that any treatment effect for conventional DMARDs in this situation would be very limited. The Committee was aware of evidence from the Behandel Strategieen (BeST) study, which investigated the effectiveness of different treatment sequences of biological and conventional DMARDs in people with early rheumatoid arthritis. The Committee heard from the Assessment Group that evidence from the BeST study was not appropriate in this instance, as it did not address the clinical effectiveness of individual DMARDs and the study population did not represent people with established rheumatoid arthritis. The Committee noted comments received in consultation stating that it would be appropriate to assume no effect of conventional DMARDs after failure of a TNF inhibitor, because data from the British Society for Rheumatology Biologics Register reported that people who stopped treatment with a TNF inhibitor showed no average change in HAQ score 12\xa0months later. However, the Committee was mindful that these data were for people stopping treatment with a TNF inhibitor only and did not specifically measure the effect of treatment for people starting conventional DMARDs at that point. Overall, the Committee concluded that, on the basis of clinical opinion, the effect of conventional DMARDs in people for whom a TNF inhibitor had failed was likely to be small, but it did not accept that there would be no effect at all associated with therapy. In addition, the Committee agreed that the uncertainty about the effectiveness of DMARDs contributed to the difficulty in quantifying with certainty the relative effect of biological treatments compared with DMARDs.\n\nIn summary, the Committee noted that, apart from the randomised controlled trials of rituximab and abatacept, the available evidence on the effectiveness of treatment with the considered technologies after the failure of a TNF inhibitor was mainly derived from observational studies with short follow-up periods that included relatively small numbers of participants. The Committee noted that many of the studies lacked a comparison group, so it was not clear what would have happened had participants not received therapy. The Committee considered that shortcomings in the design of studies of the sequential use of TNF inhibitors could affect the validity of the results. It also considered that characteristics of the study participants, changes in clinical practice, and, in some instances, small participant numbers could affect the generalisability of the results. The Committee considered that there are significant limitations in the evidence base available for this appraisal and that the relative clinical effectiveness of TNF inhibitors after the failure of a first TNF inhibitor remains uncertain. The Committee acknowledged that some of the manufacturers had carried out mixed treatment or indirect comparisons. It noted the concerns of the Assessment Group that these comparisons did not increase the robustness of the results because of the inclusion of populations outside the scope, and because of the possible shortcomings related to dealing with heterogeneity between the included studies. The Committee was aware that the analyses did not consistently demonstrate a similar pattern of effect between the technologies. On balance, the Committee was not persuaded that for this appraisal the nature of the evidence available would allow mixed treatment or indirect comparisons to adequately address the underlying uncertainty in the effectiveness of these technologies. The Committee further noted that more research is needed, specifically using the DAS28 outcome measure (which forms the basis for the rules for continuing treatment in current NICE guidance on treatments for rheumatoid arthritis). The Committee heard from clinical specialists and manufacturers about ongoing research on the treatment of rheumatoid arthritis after the failure of a TNF inhibitor. The Committee heard that a current clinical trial of infliximab (RESTART) is being undertaken in patients with active rheumatoid arthritis in whom treatment with etanercept or adalimumab has failed. It noted that a preliminary analysis from this trial had been provided by the manufacturer of infliximab as commercial in confidence.\n\n## Cost effectiveness\n\nThe Committee examined the cost-effectiveness analysis of sequential use of TNF inhibitors performed by the Assessment Group and the manufacturers of the technologies. The Committee noted that all analyses modelled a sequence of treatments, which it considered appropriate for rheumatoid arthritis. The Committee noted, however, that there were differences in the sequences modelled. The Committee was aware that one of the models (from Pfizer) had not been provided as an executable file, and had not included abatacept. This limited the Committee's ability to use the model to inform decision making. The Committee recognised that one of the models (from Bristol-Myers Squibb) had not included a comparison with conventional DMARDs, which limited the comparability of the model with those of the other manufacturers and of the Assessment Group.\n\nThe Committee was presented with information about the costs used in the economic models. The Committee recognised that the costs of hospitalisation and joint replacement had been included in all of the manufacturers' models, and that these costs were derived from a range of data sources including the British Society for Rheumatology Biologics Register and the Norfolk Arthritis Register. The Committee was aware that the Birmingham Rheumatoid Arthritis Model included an assumed cost for joint replacement and hospitalisation. The Committee noted comments received during consultation that the costs of palliative care had been underestimated in the Birmingham Rheumatoid Arthritis Model. The Committee recognised that the Assessment Group had carried out a series of analyses examining the sensitivity of the ICERs to changes in the cost parameters, including the removal of joint replacement and hospitalisation costs, the addition of extra costs of palliation and inclusion of the costs of adverse events. These analyses showed that the ICERs were not very sensitive to changes in these costs, and that the ICERs were most sensitive to changes in the assumptions about the natural history of the disease, the efficacy of the treatments and the proportion of people stopping treatment early.\n\nThe Committee discussed the different sources of estimates of clinical effectiveness for the biological DMARDs that had been used in the economic modelling. The Committee noted that all models had used the REFLEX and ATTAIN trials to inform the estimates of rituximab and abatacept, but that sources varied for the estimates for TNF inhibitors and conventional DMARDs. It noted that some had included RCT data from populations outside the scope of the appraisal, uncontrolled observational studies or registry data. The Committee was aware that no head-to-head evidence existed that compared all the biological DMARDs, and as a result some models derived relative treatment effect from indirect comparisons. The Committee noted that these had included evidence from studies in which participants had not previously been treated with a TNF inhibitor. The Assessment Group reported that it considered the use of data from populations beyond the scope of the appraisal to complete an indirect comparison inappropriate because of the heterogeneity of the studies from which the data were taken. The Committee heard from the Assessment Group that it had modelled the rates of effectiveness for biological and conventional DMARDs as absolute rather than relative changes, even if from placebo-controlled randomised trials, because it considered that evidence did not allow for the completion of a mixed treatment or indirect comparison. The Committee noted that the use of non-randomised comparisons could affect the robustness of the results, but it accepted that the evidence base available for the sequential use of adalimumab, etanercept and infliximab did not currently allow for a robust analysis of the relative treatment effects.\n\nThe Committee considered the value of HAQ score as a measure of functional assessment. The Committee heard from clinical specialists that HAQ score was affected by both reversible and irreversible components of the disease process, and that longstanding disease lessens the potential for improvements in HAQ score because of irreversible damage. For this reason the Committee considered that HAQ score may not be an appropriate measure of clinical benefit in established disease. The clinical specialists and patient experts considered that treatment might benefit individuals in ways not captured by HAQ score (such as a reduction in inflammation). The Committee recognised that the HAQ may be subject to 'ceiling effects' (in certain circumstances, the score cannot worsen), and that it does not incorporate symptoms such as pain, fatigue and sleep disturbance. The Committee concluded that patients may derive benefits from the treatment that are not reflected in HAQ score because of irreversible joint damage.\n\nThe Committee discussed the range of methods used to model efficacy of the treatments, including responses in ACR categories mapped to changes in HAQ score, ACR response categories mapped to EULAR response and mean HAQ score change without the use of ACR response categories. The Committee was aware of the limitations of the HAQ score, including its insensitivity to small changes within the higher range of scores and its inability to capture meaningful improvements in pain and fatigue (see section 4.3.17). Following explanation from the Assessment Group, the Committee understood that HAQ multipliers represent a proportional change from a given baseline HAQ score. This means that for a baseline HAQ score of 2.00, the use of a HAQ multiplier of 0.25 translates into an HAQ improvement of 0.50, which results in a post-treatment HAQ score of 1.50. The Committee considered that the use of a multiplier to model changes in HAQ meant that absolute changes in the upper range of the HAQ scores were larger than those in the lower range, and that, using a HAQ multiplier, people with more severe disease would have larger absolute HAQ improvements than if the changes in HAQ score observed from the clinical studies were used directly. The Committee discussed comments received in consultation that the HAQ multiplier lacked face validity because the distribution of simulated changes in treatment-related HAQ score did not reflect the ranges observed in clinical trials. Bearing in mind these considerations, the Committee was not persuaded that the use of a HAQ multiplier was an unreasonable way to model changes in HAQ score. However, it agreed that alternative approaches should not be discounted and that it was appropriate to consider the cost-effectiveness analyses of the manufacturers who used alternative methods to calculate clinical effectiveness inputs.\n\nThe Committee discussed how the models had incorporated underlying progression of disease during treatment. The Committee noted that all but two analyses had been carried out assuming that disease did not progress in people receiving TNF inhibitors, rituximab and abatacept, but that disease did progress in people taking conventional DMARDs. The Committee was aware that for the biological DMARDs, the use of no progression assumed both no underlying deterioration of physical function and no reduction in response to treatment. The Committee noted that one of the analyses (from Bristol-Myers Squibb) had assumed that abatacept delayed progression more than the other biological DMARDs. It recognised that the values used came from two different sources: clinical trial data on abatacept and an analysis of natural history data not specific to biological DMARDs. The Committee was not persuaded that the evidence was sufficient to support an assumption that the different biological treatments differentially altered progression of disease. In conclusion, the Committee was persuaded that it was appropriate to assume that biological DMARDs delayed disease more than conventional DMARDs. However, the Committee was aware that people with rheumatoid arthritis normally experience a reduction in the response to treatment before stopping it (secondary loss of response). The Committee agreed to base its discussions on the ICERs that assumed no progression of disease for patients during treatment with the biological DMARDs, but was not persuaded that this assumption fully reflects the disease process. This is because people could experience some worsening of HAQ while on treatment, particularly in the period of time prior to stopping treatment because of secondary loss of response, in which case the ICERs assuming no progression of disease may overestimate the benefits of treatment.\n\nThe Committee noted that none of the economic models included health-related quality of life measured using a generic preference-based measure, but had mapped a disease-specific measure (HAQ or DAS) to a generic measure (EQ-5D). The Committee understood that in the case where DAS was mapped to EQ-5D, the algorithm used had been developed from EQ-5D data itself derived indirectly from HAQ data. The Committee noted that the mapping of HAQ to EQ-5D allowed for the symptoms of rheumatoid arthritis to cover a broad range of values on the quality-of-life scale, from excellent health to states worse than death. The Committee noted that mapping utilities was outside the reference case, but recognised it had been used in previous NICE technology appraisals of treatments for rheumatoid arthritis in the absence of directly-elicited EQ-5D data. The Committee heard from the Assessment Group that the Birmingham Rheumatoid Arthritis Model incorporated HAQ because it did not consider that DAS captured all aspects of disability that one would expect to correlate with health-related quality of life. The Committee heard from clinical specialists that evidence from the British Society for Rheumatology Biologics Register suggested that for more severe HAQ scores, mapping may underestimate the change in EQ-5D. However, the Committee was mindful that none of the models incorporated directly elicited EQ-5D data and all relied on mapping to inform estimates. The Committee noted that some of the manufacturers had mapped HAQ to EQ-5D using a linear function, while others had used a non-linear function. It heard from the Assessment Group that the use of a non-linear function places a greater value on changes at the lower end of the HAQ scale than at the upper end, but that this did not significantly change the estimated ICERs. The Committee concluded that mapping to EQ-5D had shortcomings, but in the absence of an alternative was an acceptable way to derive estimates of utility, and that the use of a non-linear function was not unreasonable.\n\nThe Committee discussed the time intervals between treatments with rituximab. The Committee was aware of the results of the REFLEX trial, in which the average time interval between treatments was 307\xa0days, and the SPC for rituximab, which indicates treatment intervals of no less than 16\xa0weeks. It heard from clinical specialists that they would offer to retreat a patient with rituximab before disease flared, that there was wide variation in time to retreatment with rituximab and that it would be reasonable to assume that treatment with rituximab would occur, on average, less frequently than every 6\xa0months, with some people requiring an infusion less often than once a year. The Committee noted that the Birmingham Rheumatoid Arthritis Model modelled time to repeat treatment as 8.7\xa0months in the base case, basing this estimate on Roche's submission. It noted that similar time to re-treatment had been assumed in a number of the other manufacturers' submissions. The Committee understood that recently published data from the SUNRISE trial indicate that two courses of rituximab given 6-monthly result in a statistically significantly higher ACR\xa020 response rate at 1\xa0year than one course given per year. It noted the comments received in consultation from some of the manufacturers who, because of the newly available data from the SUNRISE trial, considered that their base-case analyses may overestimate the duration of time between rituximab retreatments. The Committee noted that in the Assessment Group's scenario analysis, the ICER for rituximab compared with conventional DMARDs was from £21,100 per QALY gained when time to retreatment was 8.7\xa0months, and that this increased to £32,600 per QALY gained when time to retreatment was 6\xa0months. The Committee concluded that an 8.7-month retreatment interval is likely to overestimate the time between consecutive courses of rituximab. However, on the basis of the clinical specialists' advice, the Committee considered that it was unlikely to be as frequent as every 6\xa0months for every person receiving rituximab.\n\nThe Committee considered the use of stopping and continuation rules in the economic models. The Committee noted that current NICE guidance on the first use of TNF inhibitors (NICE technology appraisal guidance 130) recommends that TNF inhibitors should be not be continued unless there is an adequate response at 6\xa0months following initiation of therapy. An adequate response is defined as an improvement in DAS28 of 1.2\xa0points or more. The Committee heard from the clinical specialists that data from the British Society for Rheumatology Biologics Register indicate that a number of people will continue treatment with a TNF inhibitor in the absence of such a response, indicating that clinicians currently do not adhere strictly to continuation rules. However, it also heard from the clinical specialists that although implementing continuation rules could be difficult, clinicians were increasingly following guidance on continuation rules. The Committee was aware that four of the manufacturers had submitted models that included continuation rules, each based on a different response criterion (that is HAQ score, EULAR response, ACR\xa020 and ACR\xa050). The Committee understood that the Birmingham Rheumatoid Arthritis Model was not designed in a way that could incorporate continuation rules based on response. The Committee noted, however, the scenario analyses that included the proportions of people stopping treatment early that were used in the manufacturers' response-based models. These analyses lowered the ICERs for the TNF inhibitors and abatacept compared with conventional DMARDs by approximately £10,000 per QALY gained, to between £23,800 per QALY gained for adalimumab and £27,400 per QALY gained for infliximab. The Assessment Group explained that ICERs for rituximab did not change because the cost of rituximab treatment occurred at the start of each course of treatment. The Committee understood that consultees considered the modelling of continuation rules appropriate, as it reflects existing NICE guidance for the treatment of rheumatoid arthritis. The Committee concluded that continuation rules should be considered in the estimation of cost effectiveness.\n\nThe Committee discussed the different ways in which the manufacturers and the Assessment Group had modelled the efficacy of conventional DMARDs. The Committee noted that the Birmingham Rheumatoid Arthritis Model assumed that the conventional DMARDs used after the failure of a TNF inhibitor were 50% as effective as when used in early rheumatoid arthritis. The Committee heard from the clinical specialists and from comments received in consultation that the assumption that conventional DMARDs used after the failure of a TNF inhibitor were 50% as effective as when used in early rheumatoid arthritis overestimated their effectiveness at this point in the treatment pathway. The Committee noted that the Assessment Group had completed a scenario analysis that assumed an efficacy of conventional DMARDs equal to that of placebo (reflecting the assumption used in the submission from Roche). This resulted in ICERs of approximately £16,000 per QALY gained for rituximab compared with conventional DMARDs, and between £28,000 and £32,000 per QALY gained for the other technologies compared with conventional DMARDs. The Assessment Group explained that the differences between the ICERs using different assumptions about DMARD efficacy were not larger because the Birmingham Rheumatoid Arthritis Model assumes that TNF inhibitors are added to a sequence rather than used as an alternative treatment. Therefore, the effects of the conventional DMARDs were observed in both the intervention and comparator sequences. The Committee discussed comments received on the effectiveness of conventional DMARDs. The Committee concluded that an analysis that assumed the effect of conventional DMARDs to be no more than that of placebo was not plausible, but accepted that the base-case assumption of a reduction of 50% was an underestimate of the reduction in effect of conventional DMARDs, and therefore overestimated the ICERs in the Assessment Group's base-case analysis.\n\nThe Committee considered the estimates of cost effectiveness for the use of rituximab after the failure of a TNF inhibitor. It recognised that in all but one of the economic models, rituximab had been associated with the lowest ICERs of the biological DMARDs compared with conventional DMARDs. Rituximab was also associated with the lowest ICERs of the biological DMARDs in the Assessment Group's scenario analysis that assumed a poorer response to conventional DMARDs than was assumed in the base case. In addition, the Committee considered it was appropriate to incorporate continuation rules, and noted the ICERs from a sensitivity analysis carried out by the Assessment Group that included the assumptions regarding continuation rule from the model submitted by Roche. This analysis also showed that rituximab had the most favourable ICER among the technologies, with the other drugs being either dominated or extendedly dominated. Taking these results into account, as well as the estimates from the manufacturers' economic models, the Committee considered that the most plausible ICER for rituximab compared with DMARDs would be in the lower end of the range of £20,000 to £30,000 per QALY gained. The Committee concluded that rituximab could be considered a cost-effective use of NHS resources. The Committee recognised that rituximab treatment was not provided at regular intervals, but instead that people were retreated when treatment was required, which could mean some loss of response between infusions. However, the Committee noted the testimony from clinical specialists that they would aim to treat before disease flared. The Committee concluded that treatment could only be considered cost effective if an adequate response could be maintained following retreatment with a dosing interval of at least 6\xa0months.\n\nThe Committee discussed the cost effectiveness of the TNF inhibitors. The Committee understood that that in the absence of robust data on the clinical effectiveness of the TNF inhibitors, the ICERs were uncertain. The Committee noted that the analyses by Pfizer comparing the TNF inhibitors with rituximab produced ICERs of £19,077 per QALY gained (with primary non-response to the first TNF inhibitor) and £16,225 per QALY gained (with secondary loss of response). However, as Pfizer did not include an economic model in their submission, these results could not be validated. The Committee noted that most of the other models, including the Assessment Group's model, showed that in comparison with rituximab, either the ICERs for the TNF inhibitors were very high (above £80,000 per QALY gained) or the TNF inhibitors were dominated by rituximab (that is, rituximab was both more effective and less costly). In the Abbott model the ICER for TNF inhibitors compared with rituximab was £16,000 when rituximab was given every 6\xa0months. However, the Committee did not accept that the re-treatment interval with rituximab would on average be 6 months. The Committee was mindful of the differences in the analyses of clinical effectiveness used in the different economic models, and considered the comments from consultees on the Birmingham Rheumatoid Arthritis Model. The Committee considered the manufacturer's models and agreed that taking into account all data together did not alter the conclusion drawn from the Birmingham Rheumatoid Arthritis Model. The Committee was not persuaded that the current evidence available and the cost-effectiveness analyses presented could support a decision to recommend adalimumab, etanercept or infliximab as an alternative to rituximab after the failure of a previous TNF inhibitor as an appropriate use of NHS resources.\n\nThe Committee discussed the cost effectiveness of abatacept. The Committee considered that most of the economic models showed that in comparison with rituximab, the ICERs for abatacept were either very high (above £100,000 per QALY gained in the Assessment Group base case) or abatacept was dominated by rituximab (that is, rituximab was both more effective and less costly). The analysis by Bristol-Myers Squibb that produced an ICER of £20,438 per QALY gained assumed an improvement in HAQ of 0.013 per year during treatment with abatacept. When the same rate of HAQ score increase was assumed for abatacept as for the other biological DMARDs in the base case (a worsening of 0.012 per year), the ICER increased to £40,534 per QALY gained. The Committee therefore concluded that abatacept when used as an alternative to rituximab after the failure of a previous TNF inhibitor would not be a cost-effective use of NHS resources.\n\nThe Committee was aware that for some people rituximab treatment may not be suitable because of a contraindication to rituximab or methotrexate, or that rituximab or methotrexate may need to be withdrawn because of an adverse event. The Committee was mindful that it had not been presented with any clinical evidence regarding the use of adalimumab, etanercept, infliximab or abatacept for patients for whom rituximab was contraindicated or not tolerated, and that any estimates of their effectiveness in this population were subject to additional uncertainty. However, it acknowledged that for people unable to take rituximab or methotrexate because of adverse events or contraindications, the appropriate comparator was conventional DMARDs. It considered the ICERs in the Birmingham Rheumatoid Arthritis Model that compared the TNF inhibitors with conventional DMARDs, noting that with the addition of continuation rules, the ICERs were between £23,800 and £27,400 per QALY gained, and would be lower if a lower effect of conventional DMARDs was assumed. The Committee considered these ICERs in light of the respective ICERs from the manufacturers' models, which lay between £14,500 and £35,900 per QALY gained. The Committee concluded that, on balance, these ICERs were sufficiently low to compensate for the uncertainty about the effectiveness of these treatments to be accepted. The Committee considered the Assessment Group's ICER for abatacept (including the continuation rule) of £26,200 per QALY gained compared with conventional DMARDs and agreed that this would be lower if the model assumed a lower effect of conventional DMARDs. The Committee considered these ICERs and the respective ICERs for abatacept from the manufacturer's model. It noted that these lay between £21,500 and £44,700 per QALY gained. The Committee was persuaded that these data taken together could support a decision to recommend adalimumab, etanercept, infliximab or abatacept as treatment options to be used after the failure of a first TNF inhibitor for the treatment of people who cannot receive rituximab therapy because have a contraindication to rituximab or who have had an adverse event on treatment with rituximab, as an appropriate use of NHS resources. The Committee recognised that for people who cannot receive rituximab therapy because they have a contraindication to methotrexate or where methotrexate is withdrawn because of an adverse event, this choice would be limited to adalimumab and etanercept, because infliximab and abatacept have marketing authorisations for use in combination with methotrexate.\n\nThe Committee was aware that for some people rituximab treatment may fail to provide an adequate response. The Committee was mindful that it had not been presented with any clinical or cost-effectiveness evidence regarding the use of adalimumab, etanercept, infliximab or abatacept for this group of people. The Committee considered that all estimates of relative clinical effectiveness were subject to uncertainty, and that in this group of patients the estimates were subject to further uncertainty because factors such as disease duration and prior treatment exposure may affect response to treatment (see section 4.3.7). Therefore, while accepting that the evidence submitted could be considered reflective of the group who had not received rituximab because of contraindications, or had not had an adequate trial because rituximab treatment was withdrawn because of an adverse event, the Committee was not persuaded that this evidence could be applied to the group of people for whom rituximab had failed to provide an adequate response. The Committee was therefore unable to make recommendations about the use of adalimumab, etanercept, infliximab or abatacept in people for whom rituximab has failed to provide an adequate response.\n\nThe Committee considered whether its recommendations were associated with any potential issues related to equality. The Committee was made aware that the use of the DAS28 would not be an appropriate tool for people with specific disabilities of the lower limbs and that the DAS44 would be a better tool to use for people with greater lower limb disease burden. The Committee agreed that it was important to allow clinicians to adjust the assessment of disease severity depending on the characteristics of the disease, and that the recommendations should reflect this. The Committee explored whether there were people, other than those who for whom rituximab or methotrexate was contraindicated or who had an adverse event on treatment with rituximab or methotrexate, who were unable to have rituximab because of a specific additional disability or comorbidity. The Committee noted that no such group of people had been identified during scoping or in consultation. The Committee was aware that people with mobility problems or visual impairment may find travel to hospital onerous or inconvenient. However, the Committee concluded that it was not clear that travel to receive infusions one or two times per year was necessarily more onerous or inconvenient than the alternative of much more frequent injections. In any event, the Committee did not consider that the need to travel would make it impossible or unreasonably difficult for these people to obtain treatment with rituximab, and noted that they would need to travel to other hospital or healthcare appointments in relation to their condition. The Committee concluded that rituximab would still be the most appropriate treatment option, taking into account its cost-effectiveness data and the infrequent dosing interval, but that all reasonable steps should be taken to provide practical support and assistance to ensure access to treatment for this group of people.\n\nThe Committee noted a consultee's concerns about equity of access with other countries, but concluded that this concern did not pertain to any group protected by the equalities legislation, and that it would not be appropriate to address this as part of a technology appraisal. The Committee also noted a consultee's comment stating that the guidance may have a disproportional impact on patients who test seronegative, but agreed that its recommendations, not differentiating between groups of people, did not affect any group protected by the equalities legislation and that the issue of auto-antibody status had been addressed in detail.\n\n# Summary of Appraisal Committee's key conclusions\n\nTA195 (MTA)\n\n\n\nAppraisal title: Adalimumab, etanercept, infliximab, rituximab and abatacept for the treatment of rheumatoid arthritis after the failure of a TNF inhibitor (part review of NICE technology appraisal guidance 36, review of NICE technology appraisal guidance 126 and 141)\n\nFAD section\n\nKey conclusions\n\nRituximab in combination with methotrexate is recommended as an option for the treatment of adults with severe active rheumatoid arthritis who have had an inadequate response to, or have an intolerance of, other disease-modifying anti-rheumatic drugs (DMARDs), including at least one tumour necrosis factor (TNF) inhibitor.\n\n\n\nReason for recommendation\n\nRituximab was considered to be a cost-effective option, based on data from most of the models available for this appraisal.\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\nAdalimumab, etanercept, infliximab and abatacept, each in combination with methotrexate) are recommended as treatment options only for adults with severe active rheumatoid arthritis who have had an inadequate response to, or have an intolerance of, other DMARDs, including at least one TNF inhibitor, and who cannot receive rituximab therapy because they have a contraindication to rituximab, or when rituximab is withdrawn because of an adverse event.\n\nAdalimumab monotherapy and etanercept monotherapy are recommended as treatment options for adults with severe active rheumatoid arthritis who have had an inadequate response to, or have an intolerance of, other DMARDs, including at least one TNF inhibitor, and who cannot receive rituximab therapy because have a contraindication to methotrexate, or when methotrexate is withdrawn because of an adverse event.\n\n\n\nReasons for recommendations\n\n\n\nBased on the evidence available, the ICERs for adalimumab, etanercept, infliximab and abatacept compared with rituximab were either very high, or these drugs were dominated by rituximab (that is, rituximab was both more effective and less costly).\n\nFor people who are unable to take rituximab or methotrexate, the appropriate comparator was conventional DMARDs. Based on the evidence available, adalimumab, etanercept, infliximab and abatacept compared with conventional DMARDs were considered cost-effective options based on data from most of the models available for this appraisal.\n\n\n\n& 1.4\n\n\n\nCurrent practice\n\nClinical need of patients\n\n\n\nRheumatoid arthritis has a severe impact on quality of life, with fatigue, pain and depression being common among people with the disease. In addition, rheumatoid arthritis frequently affects patients' abilities to work, and there is considerable burden placed on the carers of patients with the disease.\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\nPatients may not respond to a treatment, or may experience a decline in initial response over time, and therefore need to change treatments.\n\n\n\n\n\nAvailability of alternative treatments\n\n\n\nThe pathway of care following the failure of treatment with a TNF inhibitor depends on the individual person's responses to therapies, the clinical experience of the physician and the person's preference.\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\nIt is not currently possible to target specific treatments to individual patients because the response to any particular treatment cannot be predicted.\n\n\n\n\n\nThe technology\n\nProposed benefits of the technology from the manufacturer, clinician and patient perspective\n\nClinical specialists and patient experts emphasised the importance of having the option of multiple treatments for people whose disease has not responded adequately to initial treatment with a TNF inhibitor.\n\n\n\nHow innovative is the technology?\n\n\n\nThis is a review of established technologies.\n\nN/A\n\nAdverse events\n\n\n\nThis is a review of established technologies with known adverse events. Adverse events were not considered a key factor in distinguishing between the technologies.\n\nN/A\n\nEvidence for clinical effectiveness\n\nQuality of the evidence\n\n\n\nThe evidence review identified no randomised controlled trials (RCTs) on the effectiveness of the TNF inhibitors. The majority of studies were uncontrolled observational or registry datasets.\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\nData from RCTs were available only for rituximab and abatacept.\n\n\n\n\n\n\n\nSubgroup analyses based on rheumatoid factor and anti-CCP antibody status were post hoc.\n\n\n\n\n\nAvailability and nature of evidence\n\n\n\nStudies suggested that a second TNF inhibitor is effective after the failure of a first, but the absence of any rigorously controlled data meant that the relative effects of adalimumab, etanercept, or infliximab in comparison with either conventional DMARDs or alternative biological DMARDs could not be quantified with certainty.\n\n\n\n/9\n\n\n\n\n\n\n\n\n\n\n\nThere was insufficient evidence suggesting a difference in response based on the reason for withdrawal of the first TNF inhibitor.\n\n\n\nThere was insufficient evidence to make differential recommendations for subgroups based on the presence of auto-antibodies (rheumatoid factor and anti-CCP [cyclic citrullinated peptide] antibody).\n\n\n\n\n\n\n\nNo studies were identified that compared biological DMARDs with newly-initiated conventional DMARDs after the failure of a first TNF inhibitor.\n\n\n\n\n\n\n\n\n\nThe Committee concluded that, on the basis of clinical opinion, the effect of conventional DMARDs in people for whom a TNF inhibitor had failed was likely to be small, but it did not accept that there would be no effect at all associated with therapy. In addition, the Committee agreed that the uncertainty about the effectiveness of DMARDs contributed to the difficulty in quantifying with certainty the relative effect of biological treatments compared with DMARDs.\n\n\n\n\n\nRelevance to general clinical practice in the NHS\n\n\n\nChanges in clinical management, including starting DMARDs earlier, increasing DMARD dosage more quickly and starting treatment with TNF inhibitors sooner than in the past limit the generalisability of some of the registry data presented.\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\nPatients may derive benefits from the treatment that would not be reflected in Stanford Health Assessment Questionnaire (HAQ) score because of the inclusion of irreversible joint damage in the score.\n\n\n\nUncertainties generated by the evidence\n\n\n\nBased on advice from the clinical specialists and patient experts, it may not be appropriate to assume that TNF inhibitors form a homogeneous group with regard to clinical effectiveness. However, evidence was not available to enable any distinction to be made.\n\n(See also Availability and nature of evidence above.)\n\n\n\n\n\n\n\n\n\nEvidence for cost effectiveness\n\nAvailability and nature of evidence\n\n\n\nOne of the models was not provided as an executable file, limiting the ability to validate the modelling and ICERs. Another model did not include a comparison with conventional DMARDs, limiting the ability to compare it with other models.\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\nThe model from the Assessment Group was not sensitive to assumptions about costs and was sensitive to assumptions about natural history, clinical effectiveness and number of people stopping treatment early.\n\n\n\n\n\nThe sources of effectiveness evidence varied for the estimates of the TNF inhibitors and conventional DMARDs. Some included RCT data from populations outside the scope of the appraisal and/or uncontrolled observational studies or registry data.\n\n\n\n\n\n\n\nThe Assessment Group modelled rates of effectiveness for biological DMARDs and conventional DMARDs as absolute (rather than relative) changes in disease measures, which could affect the robustness of the results.\n\n\n\n\n\n\n\nA range of methods were used to model efficacy of treatments, including mapping response criteria to HAQ change and use of HAQ change on its own. The Committee was not persuaded that the use of a HAQ multiplier was an unreasonable way to model changes in HAQ score. However, it agreed that alternative approaches should not be discounted and that it was appropriate to consider the cost-effectiveness analyses of the manufacturers who used alternative methods to calculate clinical effectiveness inputs.\n\n\n\n\n\n\n\nA variety of assumptions were made about progression of disease while on treatment with biological DMARDs including no progression, worsening disease and continuing improvement. All models except one assumed no progression for all biological DMARDs. The Committee did not consider that the evidence supported an assumption that the biological DMARDs differentially affected underlying disease progression.\n\n\n\n\n\nUncertainties around and plausibility of assumptions and inputs in the economic model\n\nThe Committee considered estimates of cost effectiveness using an assumption of no progression of disease while on treatment with biological DMARDs, but was not persuaded that this fully reflects the disease process.\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\nBased on evidence from patient experts and clinical specialists, the Committee considered an assumed 50% reduction in the efficacy of conventional DMARDs to be an underestimate of the reduction in effect of conventional DMARDs, although the assumption that they are no more effective than placebo was also considered implausible.\n\n\n\n\n\nThe Committee recognised that incorporating response-based continuation rules into the models lowered the ICERs for the TNF inhibitors and abatacept in comparison with conventional DMARDs. It concluded that the modelling of continuation rules should be considered when examining estimates of cost effectiveness.\n\n\n\n\n\n\n\nOn the basis of the clinical specialists' advice, the Committee considered that treatment with rituximab would occur less frequently than every 6\xa0months, but accepted that 8.7\xa0months may be an overestimate.\n\n\n\n\n\nIncorporation of health-related quality of life benefits and utility values\n\nAll models presented EuroQol (EQ-5D) data derived from a disease-specific measure. Mapping to EQ-5D has shortcomings but, in the absence of an alternative approach, was considered an acceptable way to derive estimates of utility. Use of a non-linear mapping function was not unreasonable.\n\n\n\nMost likely cost-effectiveness estimate (given as an ICER)\n\n\n\nFor rituximab, the most plausible estimated ICER would be in the lower range of £20,000 to £30,000 per QALY gained.\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\nIn the absence of robust data on the clinical effectiveness of the TNF inhibitors, the estimates of cost effectiveness were uncertain. Most models showed that, when compared with rituximab, the ICERs for the TNF inhibitors were either very high (above £80,000 per QALY gained) or that rituximab dominated the TNF inhibitors (that is, rituximab was both more effective and less costly than the TNF inhibitors). In the Abbott model the ICER for TNF inhibitors compared with rituximab was £16,000 when rituximab was given every 6 months. However, the Committee did not accept that the re-treatment interval with rituximab would on average be 6 months.\n\n\n\n\n\n\n\nThe Committee considered that most of the economic models showed that in comparison with rituximab, the ICERs for abatacept were either very high (above £100,000 per QALY gained in the Assessment Group base case) or abatacept was dominated by rituximab. The only exception was the analysis from the manufacturer of abatacept, which assumed an HAQ improvement while on abatacept (an assumption that the Committee did not accept).\n\n\n\n\n\n\n\nFor people who are unable to have rituximab treatment because of a contraindication to rituximab or methotrexate, or for whom rituximab or methotrexate may need to be withdrawn because of an adverse event, the ICERs were based on a comparison with conventional DMARDs. The Assessment Group reported ICERs for adalimumab, etanercept, infliximab and abatacept of between £23,800 and £27,400 per QALY gained, including the addition of continuation rules, which would be lower if the model assumed a lower effect of conventional DMARDs.\n\n\n\nAdditional factors taken into account\n\nEqualities considerations, social value judgements\n\nThe Committee was made aware that the use of the DAS28 would not be an appropriate tool for people with specific disabilities of the lower limbs and that the DAS44 would be a better tool to use for people with greater lower limb disease burden. The Committee agreed that it was important to allow clinicians to adjust the assessment of disease severity depending on the characteristics of the disease, and that the recommendations should reflect this.\n\n\n\nThe Committee was aware that people with mobility problems or visual impairment may find travel to hospital onerous or inconvenient. The Committee concluded that rituximab would still be the most appropriate treatment option, taking into account its cost-effectiveness data and the infrequent dosing interval, but that all reasonable steps should be taken to provide practical support and assistance to ensure access to treatment for this group of people.\n\n\n\n\n\n\n\nThe Committee concluded that concerns about equity of access with other countries did not pertain to any group protected by the equalities legislation, and that it would not be appropriate to address this as part of a technology appraisal. The Committee also noted a consultee's comment stating that the guidance may have a disproportional impact on patients who test seronegative, but agreed that its recommendations, not differentiating between groups of people, did not affect any group protected by the equalities legislation.\n\n\n\n", 'Recommendations for further research ': 'Further clinical trials should be undertaken to compare the clinical effectiveness of adalimumab, etanercept and infliximab used sequentially after the failure of a TNF inhibitor with the clinical effectiveness of management strategies that do not include TNF inhibitors, including strategies that use untried DMARDs or biological DMARDs such as rituximab. This is important because there is currently no evidence on the clinical effectiveness of the TNF inhibitors at this stage in the treatment pathway compared with alternative treatment options (see section 4.3.6).\n\nFurther research should be undertaken to estimate utilities using directly observed health-related quality of life values (such as EQ−5D scores) in people with rheumatoid arthritis. This is important because current methods of establishing utility values do not allow for links to be made between utilities and common clinical measures such as DAS.', 'Related NICE guidance': 'Tocilizumab for the treatment of rheumatoid arthritis. NICE technology appraisal guidance 198 (2010). [Replaced by NICE technology appraisal guidance 247]\n\nCertolizumab pegol for the treatment of rheumatoid arthritis. NICE technology appraisal guidance 186 (2010).\n\nRheumatoid arthritis: the management of rheumatoid arthritis in adults. NICE clinical guideline 79 (2009).\n\nAdalimumab, etanercept and infliximab for the treatment of rheumatoid arthritis.NICE technology appraisal guidance 130 (2007).\n\nGolimumab for the treatment of rheumatoid arthritis after the failure of previous disease-modifying anti-rheumatic drugs. NICE technology appraisal 225 (2011).', 'Review of guidance': 'The guidance on these technologies will be considered for review by the Guidance Executive in June 2013. The Guidance Executive will decide whether the technology should be reviewed based on information gathered by NICE, and in consultation with consultees and commentators.\n\nAndrew DillonChief ExecutiveAugust 2010', 'Changes after publication': 'February 2014: implementation section updated to clarify adalimumab, etanercept, infliximab, rituximab and abatacept are recommended as options for treating rheumatoid arthritis after the failure of a TNF inhibitor. Additional minor maintenance update also carried out.\n\nMarch 2012: minor maintenance', 'About this guidance': 'NICE technology appraisal guidance is about the use of new and existing medicines and treatments in the NHS in England and Wales.\n\nThis guidance was developed using the NICE multiple technology appraisal process.\n\nIt replaces NICE technology appraisal guidance 126 and 141 issued in August 2007 and April 2008 respectively. It also replaces the remaining recommendations in NICE technology appraisal guidance 36 issued in March 2002.\n\nThe appraisal of adalimumab and the review of the appraisals of etanercept, infliximab, rituximab and abatacept for the treatment of rheumatoid arthritis have resulted in changes in the guidance. Rituximab in combination with methotrexate is still recommended as an option for the treatment of adults with severe active rheumatoid arthritis who have had an inadequate response to, or have an intolerance of, other DMARDs, including at least one TNF inhibitor. Additional treatment options are now recommended for these adults if rituximab therapy is contraindicated or withdrawn because of an adverse event, specifically:\n\nIf rituximab is contraindicated or withdrawn, adalimumab, etanercept, infliximab and abatacept, each in combination with methotrexate, are now recommended as treatment options.\n\nIf rituximab therapy cannot be given because methotrexate is contraindicated or withdrawn because of an adverse event, adalimumab and etanercept, each as monotherapy, are now recommended as treatment options.\n\nThe price of abatacept has recently increased to £302.40 (excluding VAT) for a 250-mg vial. The manufacturer of abatacept has agreed a simple discount with the Department of Health as part of PPRS modulation with the result that the acquisition cost to the NHS remains the same as considered in the development of TA195 at\xa0 £242.17 (excluding VAT) per 250-mg vial, until NICE next reviews the guidance on abatacept for this indication.\n\nThis change therefore does not affect the recommendations in TA195.\n\nWe have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available.\n\nYour responsibility\n\nThis guidance represents the views of NICE and was arrived at after careful consideration of the evidence available. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. However, the guidance does not override the individual responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.\n\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.\n\nCopyright\n\n© National Institute for Health and Clinical Excellence 2010. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.'}	https://www.nice.org.uk/guidance/ta195	Evidence-based recommendations on adalimumab (Humira), etanercept (Enbrel), infliximab (Remicade), rituximab (MabThera) and abatacept (Orencia). These drugs are for adults with severe rheumatoid arthritis who have tried other disease-modifying antirheumatic drugs (DMARDs) but cannot tolerate them or they haven’t worked well enough.
77feeb97856defc4ffe71a11da45f26058447d2a	nice	Etanercept, infliximab and adalimumab for the treatment of psoriatic arthritis	Etanercept, infliximab and adalimumab for the treatment of psoriatic arthritis Evidence-based recommendations on etanercept (Enbrel), infliximab (Remicade) and adalimumab (Humira) for treating active and progressive psoriatic arthritis in adults. # Guidance This guidance replaces NICE technology appraisal guidance 104 issued in July 2006 and NICE technology appraisal guidance 125 issued in August 2007. For details, see 'About this guidance'. Etanercept, infliximab and adalimumab are recommended for the treatment of adults with active and progressive psoriatic arthritis when the following criteria are met. The person has peripheral arthritis with three or more tender joints and three or more swollen joints, and The psoriatic arthritis has not responded to adequate trials of at least two standard disease-modifying antirheumatic drugs (DMARDs), administered either individually or in combination. Treatment as described in 1.1 should normally be started with the least expensive drug (taking into account drug administration costs, required dose and product price per dose). This may need to be varied for individual patients because of differences in the method of administration and treatment schedules. Etanercept, adalimumab or infliximab treatment should be discontinued in people whose psoriatic arthritis has not shown an adequate response using the Psoriatic Arthritis Response Criteria (PsARC) at 12 weeks. An adequate response is defined as an improvement in at least two of the four PsARC criteria, (one of which has to be joint tenderness or swelling score) with no worsening in any of the four criteria. People whose disease has a Psoriasis Area and Severity Index (PASI) 75 response at 12 weeks but whose PsARC response does not justify continuation of treatment should be assessed by a dermatologist to determine whether continuing treatment is appropriate on the basis of skin response (see 'Etanercept and efalizumab for the treatment of adults with psoriasis' , 'Infliximab for the treatment of adults with psoriasis' and 'Adalimumab for the treatment of adults with psoriasis' for guidance on the use of tumour necrosis factor inhibitors in psoriasis). When using the PsARC healthcare professionals should take into account any physical, sensory or learning disabilities, or communication difficulties that could affect a person's responses to components of the PsARC and make any adjustments they consider appropriate.# Clinical need and practice Psoriatic arthritis is an inflammatory arthritis affecting the joints and connective tissue and is associated with psoriasis of the skin or nails. The prevalence of psoriasis in the general population is estimated at 2–3%. The prevalence of inflammatory arthritis in people with psoriasis is estimated at up to 30%. At least 20% of people with psoriasis have severe psoriatic arthritis with progressive joint lesions. Psoriatic arthritis is a progressive disorder ranging from mild synovitis to severe progressive erosive arthropathy. People with psoriatic arthritis presenting with oligoarticular disease progress to polyarticular disease and a large percentage develop joint lesions and deformities, which progress over time. Despite clinical improvement with current DMARD treatment, joint damage has been shown radiologically in up to 47% of people with psoriatic arthritis at a median interval of 2 years. Psoriatic arthritis can affect people's ability to work and carry out daily activities, which can have a substantial impact on quality of life. The impact of severe psoriasis on health-related quality of life is considered to be similar to that of other major medical conditions including diabetes, heart disease and cancer. People with psoriatic arthritis have a higher self-rated disease severity than those with psoriasis only. People with psoriatic arthritis have a 60% higher risk of mortality than the general population and their life expectancy is estimated to be approximately 3 years shorter. Most people with psoriatic arthritis develop skin symptoms before joint symptoms, although joint symptoms may appear first or simultaneously. Psoriatic arthritis usually develops within 10 years of a diagnosis of psoriasis. The rheumatic characteristics of psoriatic arthritis include joint stiffness, pain and swelling, and tenderness of the joints and surrounding ligaments and tendons. Symptoms can range from mild to very severe. Assessing the effectiveness of treatments for psoriatic arthritis relies on outcome measures that accurately and sensitively measure disease activity. Outcomes of effectiveness are based on measures of the anti-inflammatory response (such as the PsARC, and the American College of Rheumatology response criteria ), measures of psoriatic skin lesions (PASI), functional measures (Health Assessment Questionnaire ) and radiological assessments (Total Sharp Score, van der Heijde-Sharp Score) of disease progression, quality of life and overall global assessments. Overall response criteria have not yet been clearly defined. The aim of psoriatic arthritis treatment is to relieve symptoms, slow disease progression and maintain quality of life. To effectively manage psoriatic arthritis, any associated skin disease also needs to be effectively treated. Non-steroidal anti-inflammatory drugs (NSAIDs) and local corticosteroid injections are widely used. Disease that is unresponsive to NSAIDs, in particular polyarticular disease, is treated with DMARDs (currently, methotrexate and sulfasalazine are considered the DMARDs of choice) to reduce joint damage and prevent disability. Aggressive treatment of early stage progressive psoriatic arthritis can help to improve prognosis.# The technologies # Etanercept Etanercept (Enbrel, Wyeth Pharmaceuticals) is a human TNF receptor fusion protein that inhibits TNF-α binding to cell surface TNF receptors. Etanercept is licensed for the treatment of active and progressive psoriatic arthritis in adults whose disease has not responded adequately to previous DMARD therapy. The most common adverse events reported in the trials were infections (including upper respiratory tract infections, bronchitis, cystitis and skin infections), injection site reactions (including bleeding, bruising, erythema, itching, pain and swelling), and allergic reactions, such as pruritus. For full details of undesirable effects and contraindications, see the summary of product characteristics. The acquisition cost of etanercept is £89.38 per 25-mg prefilled syringe or 25-mg vial with powder for reconstitution (with solvent), and £178.75 per 50-mg prefilled syringe (excluding VAT; British national formulary edition 58). The annual cost of etanercept using either 50-mg once-weekly doses (52 doses per year) or 25-mg twice-weekly doses (104 doses per year) is £9295. Costs may vary in different settings because of negotiated procurement discounts. # Infliximab Infliximab (Remicade, Schering-Plough) is a chimeric human-murine monoclonal antibody that inhibits the functional activity of TNF-α. Infliximab is licensed for the treatment of active and progressive psoriatic arthritis in adults when the disease has not responded adequately to previous DMARD therapy. Infliximab should be administered: in combination with methotrexate, or alone in people who show intolerance to methotrexate or for whom methotrexate is contraindicated. The most common reported adverse events in the trials were infusion reactions and hypersensitivity, infections (tuberculosis, bacterial infections – including sepsis and pneumonia – invasive fungal infections, and other opportunistic infections), hepatitis B reactivation and heart failure. For full details of undesirable effects and contraindications, see the summary of product characteristics. The acquisition cost of infliximab is £419.62 per 100-mg vial with powder for reconstitution (excluding VAT; BNF edition 58). The drug cost differs between individuals because the dose is adjusted to each person's body weight. For example, for an adult weighing 75 kg, if it is assumed that vials are not shared between patients, each infusion of 5 mg/kg requires four 100-mg vials at a cost of £1678. The three initial infusions are given at weeks 0, 2 and 6, at a cost of £5035. The subsequent annual cost following the loading doses is £10,910 per year based on infusions repeated every 8 weeks (average 6.5 doses per year). Costs may vary in different settings because of negotiated procurement discounts. # Adalimumab Adalimumab (Humira, Abbott Laboratories) is a recombinant human monoclonal antibody that binds specifically to TNF and neutralises its function. Adalimumab is licensed for the treatment of active and progressive psoriatic arthritis in adults when the disease has not responded adequately to previous DMARD therapy. The most common reported adverse events in the trials were infections (including sepsis due to bacterial, mycobacterial, invasive fungal, parasitic, viral, or other opportunistic infections such as listeriosis and pneumocystis), tuberculosis, hepatitis B reactivation, formation of autoimmune antibodies and congestive heart failure. For full details of undesirable effects and contraindications, see the summary of product characteristics. The acquisition cost of adalimumab is £357.50 per 40-mg prefilled pen or prefilled syringe (excluding VAT; BNF edition 58). The annual acquisition cost of adalimumab to the NHS is £9295 per patient (based on 26 injections per year). Costs may vary in different settings because of negotiated procurement discounts.# Evidence and interpretation The Appraisal Committee (appendix A) considered evidence from a number of sources (appendix B). # Clinical effectiveness The Assessment Group identified six double-blind, placebo-controlled, randomised controlled trials (RCTs) in people with psoriatic arthritis for the technologies: two for etanercept, two for infliximab and two for adalimumab. ## Etanercept The two double-blind, placebo-controlled RCTs of etanercept in adults with active psoriatic arthritis were Mease 2000 (n = 60; follow-up 12 weeks) and Mease 2004 (n = 205; follow-up 24 weeks). In both trials 25 mg etanercept was administered by subcutaneous injection twice a week. The inclusion criteria for both trials were active psoriatic arthritis (defined as more than three swollen joints and more than three tender or painful joints, although only the more recent trial specified stable plaque psoriasis), and psoriatic arthritis that had not responded adequately to NSAIDs. The primary outcome variable in the Mease 2000 trial was PsARC and in Mease 2004 it was ACR 20. Data for PASI at week 12 were available from Mease 2000 only. The Assessment Group conducted a meta-analysis of the outcomes for etanercept at 12 weeks and the pooled estimates from both trials showed that etanercept was statistically significantly more effective than placebo for all outcomes (PsARC, ACR 20, ACR 50, ACR 70, and HAQ percentage change from baseline). For PsARC the pooled relative risk (RR) estimate was 2.60 (95% confidence interval 1.96 to 3.45), with some evidence of statistical heterogeneity (I2 = 34%) between the two studies' estimates. For PASI 50, the results from the Mease 2000 trial at 12 weeks showed that etanercept was more effective than placebo (RR = 2.00 ) although this was not statistically significant. For PASI 75 the results showed that etanercept was statistically significantly more effective than placebo (RR = 11.00 ; p = 0.0154). At 24 weeks the treatment effect for all joint disease outcome measures was statistically significantly greater for etanercept than for placebo, though these data were available only for one trial, Mease 2004. At 24 weeks, the annualised rate of progression as measured radiologically using the Total Sharp Score was statistically significantly lower in people treated with etanercept than in people treated with placebo (Total Sharp Score −0.56; 95% CI −0.86 to −0.26). At 24 weeks the treatment effect on psoriasis favoured etanercept with RRs for PASI 75 of 7.05 (95% CI 1.68 to 29.56), PASI 50 of 2.65 (95% CI 1.46 to 4.80) and PASI 90 of 1.88 (95% CI 0.36 to 9.90). At 1 year the mean annualised rate of progression on the Total Sharp Score for all people was −0.03 (standard deviation 0.87), indicating that on average there was no clinically significant progression of joint erosion based on uncontrolled follow-up data. ## Infliximab The two double-blind, placebo-controlled RCTs of infliximab for the treatment of psoriatic arthritis were IMPACT and IMPACT 2. In the IMPACT trial, participants (n = 104) were randomised to receive infusions of infliximab (5 mg/kg) or placebo at weeks 0, 2, 6 and 14 with follow-up at week 16. In IMPACT 2, people (n = 200) were randomised to receive infusions of placebo or infliximab 5 mg/kg at weeks 0, 2, 6, 14 and 22, with assessments at weeks 14 and 24. In both RCTs the inclusion criteria required that participants' psoriatic arthritis should have five or more swollen/tender joints, and that their disease had an inadequate response to at least one DMARD. IMPACT 2 also required people to have active plaque psoriasis with at least one qualifying target lesion (2 cm or more in diameter). The Assessment Group conducted a meta-analysis of the outcomes for infliximab at 14 weeks and the results for both trials reported a statistically significant improvement in PsARC for people receiving infliximab, relative to those receiving placebo (pooled RR 3.44, 95% CI 2.53 to 4.69). There was some evidence of statistical heterogeneity (I2 = 68%) between the two study estimates. Infliximab was statistically significantly more effective than placebo for all pooled estimates for outcomes of joint response (ACR 20, ACR 50 and ACR 70) as well as the pooled percentage change from baseline in HAQ score with infliximab compared with placebo (mean difference −60.37 ). The Assessment Group also presented pooled estimates for the outcomes of the skin component of psoriatic arthritis over 14–16 weeks and the results showed that infliximab was statistically significantly more effective than placebo. The IMPACT 2 trial was randomised for 24 weeks followed by an open-label period. The data for all measures of joint disease, psoriasis and HAQ were similar to those at the 14-week follow-up, suggesting that infliximab's benefits were maintained for up to 24 weeks of treatment and for longer-term follow-up (50 weeks for IMPACT and 54 weeks for IMPACT 2) although the data for the longer-term follow-up were uncontrolled. In terms of radiographic assessment, there was no statistically significant change from baseline in the total modified van der Heijde-Sharp Score for infliximab-treated people followed up at 50 weeks in the IMPACT trial (n = 70: −1.72 ) or 54 weeks in the IMPACT 2 trial (infliximab/infliximab −0.94 ; placebo/infliximab 0.53 ), suggesting infliximab may inhibit progression of joint damage. However, as with other outcomes measured after week 24, there was no placebo group for comparison. ## Adalimumab The two double-blind, placebo-controlled RCTs of adalimumab in adults with active psoriatic arthritis were ADEPT (n = 313, follow-up of 24 weeks) and Genovese 2007 (n = 100, follow-up of 12 weeks). In both trials adults were randomised to adalimumab (40 mg every other week) or placebo. The inclusion criteria for both RCTs required people to have active psoriatic arthritis (defined in both trials as more than three swollen joints and more than three tender or painful joints, with active psoriatic skin lesions or a documented history of psoriasis). Overall, the baseline characteristics demonstrated that the trial populations were indistinguishable and represented people who required DMARDs or therapy with TNF inhibitors. The Assessment Group conducted a meta-analysis of the outcomes for adalimumab at 12 weeks and the results from both trials showed a statistically significant improvement for adalimumab compared with placebo for all outcome measures. The pooled RR for PsARC was 2.24 (95% CI 1.74 to 2.88) and the pooled RR for ACR 20 was 3.65 (95% CI 2.57 to 5.17). The pooled RRs for ACR 50 and ACR 70 also favoured adalimumab, although their related CIs were wide. Regarding the associated skin disease, 12-week PASI response measures were reported by only one trial (ADEPT), and the response was statistically significantly greater for adalimumab than placebo at all three PASI thresholds: PASI 50 RR = 5.00 (95% CI 2.77 to 9.03); PASI 75 RR = 11.33 (95% CI 3.65 to 35.17)]; and PASI 90 RR = 43.00 (95% CI 2.66 to 696.04) The CIs, especially for PASI 75 and PASI 90, were wide. The ADEPT trial was randomised for 24 weeks. The data for all measures of joint disease, psoriasis and HAQ were similar to those at 12-week follow-up. In addition, this trial also reported a statistically significant difference in mean change in Total Sharp Score from baseline (−0.2 versus 0.1, p < 0.001) favouring adalimumab over placebo in terms of delayed progression of joint disease, although this duration of follow-up is short. ## Indirect comparison performed by the Assessment Group In the absence of head-to-head RCTs on the relative efficacy of the three TNF inhibitors, an indirect comparison was undertaken by the Assessment Group using placebo as the common comparator. The results were expressed as the probability of each of the TNF inhibitors achieving a response for the outcome measures PsARC, HAQ, PASI and ACR. Infliximab was associated with the highest probability of achieving a response for all of the outcomes measured. The probability of response in joint disease (PsARC and ACR) was higher with etanercept than with adalimumab, and the probability of response in skin disease (PASI) was higher with adalimumab than with etanercept. ## Adverse events There were no RCTs that directly compared the three drugs. To evaluate the adverse events of the three TNF inhibitors the Assessment Group reviewed a range of study types including RCTs, open-label extensions of trials and observational studies. The Assessment Group provided a range of estimates for serious adverse event and withdrawal rates across non-randomised studies and large RCTs. These comprised serious infections, cancer, activation of latent tuberculosis, mortality and withdrawals from treatment because of adverse events. The Assessment Group acknowledged that the adverse event data were primarily from people with rheumatoid arthritis or other indications, so it is unclear to what extent these can be generalised to psoriatic arthritis. Overall, the limited evidence prevented them from drawing firm conclusions from the systematic review about the comparative adverse event profile of the three TNF inhibitors. # Cost effectiveness ## Published economic evaluations The Assessment Group performed a systematic review of published literature and identified three studies (Bansback et al. 2007; Bravo Vergel 2006; and Olivieri et al. 2008) that met the inclusion criteria for the cost-effectiveness review. The study by Olivieri et al. (2008) was difficult to compare with the other studies because in this study all TNF inhibitors were considered as a group compared with DMARDs. There were no model results. The economic evaluation was made using before-and-after studies and the effectiveness evidence was based on a single trial. This produced an incremental cost-effectiveness ratio (ICER) of around €40,000 (£34,700) per quality-adjusted life year (QALY) gained for TNF inhibitors. The study by Bansback et al. (2007) compared etanercept with ciclosporin and leflunomide. The economic model focused on response according to PsARC and associated HAQ score, with changes in HAQ and further withdrawals modelled over 10 years. Mease 2004 was the source of evidence for response rates and HAQ. The base-case results showed an ICER of around £28,000 per QALY gained for etanercept compared with ciclosporin and £38,000 per QALY gained for etanercept compared with leflunomide. The study by Bravo Vergel (2006) compared etanercept with infliximab and palliative care. The model included response according to PsARC and associated HAQ score. Changes in HAQ and further withdrawals were modelled over 40 and 10 years. Evidence from Mease 2000, Mease 2004 and IMPACT was used to model the PsARC response. The ICER for etanercept was between £26,361 and £30,628 per QALY gained compared with palliative care depending on the assumptions made about the deterioration in HAQ score at treatment withdrawal (rebound). Infliximab was the most effective strategy, and generated the highest number of QALYs. ## Manufacturer's submission on the cost effectiveness of etanercept A published cost-effectiveness model originally used to support a submission to NICE in 2004 was adapted to incorporate additional effectiveness evidence and new comparators. The adjusted model compared the costs and benefits associated with etanercept, infliximab, adalimumab and best supportive care over a lifetime horizon. Best supportive care was assumed to be ciclosporin because the population considered in the model were assumed to have already tried other DMARDs (leflunomide, sulfasalazine and methotrexate). The base-case results showed that the costs for best supportive care were £53,860 with QALYs of 5.96, and for etanercept the costs were £65,650 with QALYs of 6.90. This resulted in an ICER of £12,480 per QALY gained for etanercept when compared with best supportive care. Adalimumab was extendedly dominated by a combination of etanercept and palliative care (that is, additional QALYs could be generated with etanercept relative to adalimumab at a lower cost per QALY gained than is generated by adalimumab relative to palliative care). Infliximab was dominated by adalimumab (that is, infliximab was more costly and less effective than adalimumab). ## Manufacturer's submission on the cost effectiveness of infliximab In the economic analysis submitted by the manufacturer of infliximab four treatment alternatives were compared over a lifetime horizon. These included maintenance treatment with a TNF inhibitor (infliximab, adalimumab or etanercept) followed by a sequence of DMARDs. The comparator was palliative care with DMARDs. For the health-economic model, the incremental treatment effects for the comparative treatments were estimated for infliximab, etanercept and adalimumab. The direct drug costs for the TNF inhibitors were obtained from BNF edition 56. The manufacturer presented base-case results for three different scenarios: people weighing 60 kg, 70 kg with vial optimisation for infliximab treatment (that is, making local arrangements so that vials can be shared between patients who are being treated with infliximab, reducing wastage) and 80 kg. For people weighing 60 kg the base-case results showed that infliximab produced an ICER of £16,942 per QALY gained when compared with palliative care. For people weighing 70 kg, and accounting for vial optimisation, infliximab produced an ICER of £19,982 per QALY gained versus palliative care. For people weighing 80 kg infliximab produced an ICER of £23,022 per QALY gained when compared with palliative care. ## Manufacturer's submission on the cost effectiveness of adalimumab The manufacturer of adalimumab used an individual sampling model to simulate the disease progression of a cohort of people with psoriatic arthritis over a lifetime horizon under different treatment sequences. A 3-month cycle was used. Baseline characteristics from the ADEPT trial for people for whom two previous DMARDs had failed were used in the base-case analysis. The cost of all drugs used in the analysis was calculated based on the recommended dosages and vial prices given in the Monthly Index of Medical Specialties. The model assumed that four 100 mg vials of infliximab were required per infusion, based on an average person weighing 80 kg. The base-case results showed that adalimumab, with a mean cost of £73,072 and QALYs of 8.33, was the most cost-effective treatment strategy when compared with a DMARD (mean costs of £47,537 and QALYs of 7.47), resulting in an ICER of £29,827 per QALY gained. Etanercept was more costly and had the same mean QALYs gained as adalimumab (8.33). Infliximab was more costly and more effective than adalimumab, which resulted in an ICER of £199,596 per QALY gained compared with adalimumab. ## Assessment Group's economic assessment The Assessment Group updated the economic model developed for 'Etanercept and infliximab for the treatment of adults with psoriatic arthritis' (NICE technology appraisal 104). This model allowed the three TNF inhibitors to be compared with each other. A probabilistic decision analytic model was developed to estimate the incremental costs and incremental QALYs of the three TNF inhibitors compared with palliative care over a lifetime horizon (40 years), only. The price year was 2008/2009 and costs and benefits were discounted at a rate of 3.5%. The decision analytical model followed a cohort of people that represented the average characteristics of participants in the RCTs and had a Markov structure. People in the cohort were assumed to be 47 years old, had been diagnosed with psoriatic arthritis 7 years previously, were assumed to weigh 60–80 kg, and had psoriatic arthritis that had inadequately responded to at least two DMARDS. People in the treatment arm received etanercept, infliximab or adalimumab and people in the control arm received palliative care. The disease's response to treatment was assessed between 12 and 16 weeks. It was assumed that people whose disease had responded to treatment stayed in the treatment arm, while treatment was discontinued in people whose psoriatic arthritis failed to adequately respond to treatment – these people were assumed to go on to receive palliative care. The following assumptions were included in the Assessment Group's model: people in the initial 3-month trial period had some improvement in HAQ (even if they did not reach the PsARC threshold); people who had a PASI 75 response would gain at least a 75% improvement in psoriasis compared with baseline PASI; people continuing on TNF inhibitors maintained their initial improvement in HAQ; and the same ongoing risk of withdrawal from treatment was used for all TNF inhibitors (withdrawal because of reduction in efficacy, adverse events or other reasons). The base-case analysis in the Assessment Group's model assumed a lifetime (40-year) time horizon for costs and QALYs, a baseline HAQ of 1.05, a baseline PASI of 7.5, rebound equal to gain, and incorporate the correlation between PsARC and PASI 75 outcomes. Health utility was measured as a function of HAQ and PASI based on linear regressions of EQ5D utility versus HAQ and PASI provided by the manufacturers based on RCT evidence. The total lifetime discounted health associated with palliative care was about 5.2 QALYs because the base case assumed that utility declined fairly rapidly in people with uncontrolled arthritis, and may have been less than 0 (representing a health state worse than death) in later years. The base-case model assumed that people's psoriatic arthritis had failed to respond to treatment with at least two DMARDS but they had not received previous treatment with TNF inhibitors. The Assessment Group also modelled the cost effectiveness of sequencing TNF inhibitor therapies after people's psoriatic arthritis failed to respond to a first-line TNF inhibitor. The base-case analysis reported the lifetime costs and QALYs of the three TNF inhibitors in people with mild-to-moderate psoriatic arthritis, which was presented as an incremental analysis ranking the alternative strategies by mean cost. Following comments made by NICE consultees on the Technology Assessment Report and model of December 2009, the Assessment Group revised the cost-effectiveness analysis results. The Assessment Group took into account the manufacturer of adalimumab's revised estimates from their RCTs of the effect of adalimumab on HAQ change for PsARC responders and non-responders. The Assessment Group corrected a standard error calculation when extracting data for the evidence synthesis and used the correct calculation of the costs of adalimumab and etanercept. The results for the base case showed that infliximab was the most effective treatment taking into account both joint and skin effects (QALYs of 7.3), followed by etanercept (QALYs of 7.0), then adalimumab (QALYs of 6.6). Infliximab was also the most costly treatment (£88,442), followed by etanercept (£74,841), then adalimumab (£68,638). The ICER of etanercept compared with palliative care was £17,853 per QALY gained. The ICER for infliximab compared with etanercept was £44,326 per QALY gained. Adalimumab was extendedly dominated by a combination of etanercept and palliative care (that is, additional QALYs could be generated with etanercept relative to adalimumab at a lower cost per QALY gained than the ICER of adalimumab relative to palliative care, adalimumab was therefore excluded from the incremental analysis). Etanercept had the highest probability of being cost effective with probabilities of being cost effective of 44% if the maximum acceptable amount to pay for an additional QALY was £20,000 and 48% if the maximum acceptable amount to pay for an additional QALY was £30,000. The Assessment Group conducted several univariate sensitivity analyses using different sets of assumptions. The Assessment Group presented the results according to whether the ICER was less than £20,000 per QALY gained, between £20,000 and £30,000 per QALY gained or greater than £30,000 per QALY gained. The results of these analyses suggested that the ICER of etanercept increased to above £20,000 per QALY gained or was dominated by other strategies when the following assumptions were used and all other variables take mean values as in the base case: A patient treated for psoriatic arthritis whose skin disease does not achieve a PASI 75 response is admitted to hospital for treatment of psoriasis (annual treatment). The base case assumed these patients are offered ultraviolet (UV) light therapy. The HAQ rebounds after withdrawal from TNF inhibitors to natural history rather than to initial gain. Treatment with TNF inhibitors becomes ineffective (relative to no treatment) after 10 years. Infliximab requires three vials rather than four vials per administration. All responders to PsARC have the same change in HAQ at 3 months, regardless of the TNF inhibitor used. For most sensitivity analyses performed by the Assessment Group, the ICER for infliximab was greater than £30,000 per QALY gained. The ICER of infliximab fell below £30,000 per QALY gained, when the following assumptions were used and all other variables take mean values as in the base case: A patient treated for psoriatic arthritis whose skin disease does not achieve a PASI 75 response is admitted to hospital for treatment of psoriasis (annual treatment). The base case assumed these patients are offered UV light therapy. Infliximab requires three vials rather than four vials per administration. If the manufacturer of infliximab's estimates of the cost of treating psoriasis with UV light therapy are used in the Assessment Group's model. HAQ improves while on biological therapy. The base case assumes no change after the first 3 months. The ICER of adalimumab fell below £20,000 per QALY gained and was no longer dominated by other strategies, when the following assumptions were used and all other variables take mean values as in the base case: All responders to PsARC have the same change in HAQ at 3 months, regardless of the TNF inhibitor used. A patient treated for psoriatic arthritis whose skin disease does not achieve a PASI 75 response is admitted to hospital for treatment of psoriasis (annual treatment). The base case assumed these patients are offered UV light therapy. If the manufacturer of infliximab's estimates of the cost of treating psoriasis with UV light therapy are used in the Assessment Group's model. The Assessment Group performed a sensitivity analysis assuming all TNF inhibitors had the same change in HAQ benefit at 3 months for a PsARC responder. The Assessment Group calculated that the ICERs per QALY gained were £17,717 for adalimumab compared with palliative care, £22,056 for etanercept compared with adalimumab and £50,806 for infliximab compared with etanercept. The Assessment Group also provided cost-effectiveness results for subgroups with different patient characteristics. For a cohort in which baseline PASI was moderate to severe (PASI of 12.5 instead of 7.5 as in the base-case) the ICER of adalimumab versus palliative care was £16,310 per QALY gained, the ICER of etanercept versus adalimumab was £19,319 per QALY gained and the ICER of infliximab versus etanercept was £27,778 per QALY gained. For a cohort of people with negligible baseline psoriasis etanercept was the most cost-effective strategy with an ICER of £18,512 per QALY gained compared with palliative care, the ICER of infliximab compared with etanercept was £64,744 per QALY gained and adalimumab was extendedly dominated by a combination of etanercept and palliative care. For a cohort of people with moderate-to-severe psoriasis (baseline PASI of 12.5) whose disease did not achieve a PASI 75 response and are assumed to be admitted to hospital for treatment of psoriasis (annual treatment) instead of annual UV light therapy, the ICER for adalimumab compared with palliative care was £7901 per QALY gained, the ICER for infliximab compared with adalimumab was £10,636 per QALY gained and etanercept was dominated by (that is, was more costly and generated less QALYs than) infliximab. The Assessment Group presented an additional analysis in which people were assumed to continue on biological treatment after 3 months if their disease had either an adequate PsARC or a PASI 75 response (base case: PsARC only). For etanercept compared with palliative care the ICER was £17,859 per QALY gained, the ICER for infliximab compared with etanercept was £38,194 per QALY gained and adalimumab was extendedly dominated by a combination of etanercept and palliative care (that is, additional QALYs could be generated with etanercept relative to adalimumab at a lower cost per QALY gained than the ICER of adalimumab relative to palliative care). The Assessment Group presented an analysis that compared the sequencing of the different TNF inhibitors in people with mild-to-moderate skin disease if a first TNF inhibitor has failed. The ICERs depended on which drug was used as first-line therapy, and was therefore ineligible for use as second-line therapy. The Assessment Group noted that the ICERs were broadly similar for people whose psoriatic arthritis failed to respond to first-line therapy because of adverse effects and those whose disease failed first-line therapy because of inefficacy. An additional sensitivity analysis was performed by the Assessment Group at the Committee meeting and subsequently confirmed by running the model probabilistically. This analysis assumed that adalimumab and etanercept were equally effective while the PsARC responses for infliximab remained the same as in the original analysis (that is, infliximab was assumed to be more effective than adalimumab and etanercept). The ICER for both adalimumab and etanercept compared with palliative care was £18,296 per QALY gained and the ICER for infliximab compared with adalimumab and etanercept was £45,557 per QALY gained. # Consideration of the evidence The Appraisal Committee reviewed the data available for the clinical and cost effectiveness of etanercept, infliximab and adalimumab, having considered evidence on the nature of psoriatic arthritis and the value placed on the benefits of etanercept, infliximab and adalimumab by people with the condition, those who represent them, and clinical specialists. It also took into account the effective use of NHS resources. The Committee considered the clinical effectiveness evidence for etanercept, infliximab and adalimumab. The Committee noted that there were no head-to-head RCTs comparing the TNF inhibitors and so indirect methods of comparison had to be used. The Committee also noted that the RCTs were powered primarily to detect statistically significant differences in the effectiveness of TNF inhibitors compared with placebo on joint disease and only secondarily on any associated skin disease. Nevertheless, the Committee concluded that the RCT evidence was sufficient to appraise the clinical effectiveness of TNF inhibitors. The Committee considered the clinical-effectiveness data presented by the manufacturers and noted that etanercept, infliximab and adalimumab all showed a statistically significant response in the joint disease (PsARC, ACR) and skin disease (PASI) criteria at 12-week and 24-week follow-up compared with placebo. Clinical specialists confirmed that in clinical practice improvement in psoriatic arthritis was maintained beyond 24 months, and that some people had been treated with TNF inhibitors for up to 10 years. The Committee heard from a patient expert that TNF inhibitors are effective and valued options for the treatment of psoriatic arthritis and have an appreciable impact on quality of life. The Committee heard from the clinical specialists that there was no theoretical reason to believe that the TNF inhibitors would differ in their efficacy in treating psoriatic arthritis. It heard that etanercept, infliximab and adalimumab were similarly effective in the treatment of psoriatic arthritis in clinical practice, and were used interchangeably. Although the indirect comparison conducted by the Assessment Group suggested that infliximab is the most effective treatment overall, taking into account both skin and joint disease, the Committee concluded that there was not enough evidence to indicate clinically important differences in the effectiveness of individual TNF inhibitors in the treatment of psoriatic arthritis. The Committee considered the evidence on the adverse event rates associated with the TNF inhibitors, including the reactivation of tuberculosis and the rate of serious infections reported in RCTs, and noted that these data were mainly for people with rheumatoid arthritis. The Committee heard from clinical specialists that the adverse event profile of TNF inhibitors was comparable to that of conventional DMARDs. It also heard that adverse events could result in a break from treatment, for example, by stopping treatment while an infection is resolved, then restarting. The Committee concluded that the tolerability profile of the three TNF inhibitors was comparable. The Committee then considered the economic models presented by the manufacturers and the Assessment Group. The Committee noted that the Assessment Group updated the economic model submitted for 'Etanercept and infliximab for the treatment of psoriatic arthritis' (NICE technology appraisal 104) by taking into account the beneficial effect of TNF inhibitors on the skin disease as well as the joint disease. The Committee considered the utility estimates incorporated in the Assessment Group model and noted that the utility formula was derived from the PASI and HAQ. The HAQ response had a greater effect on utility than the PASI, indicating that the calculated utility benefit was mainly driven by the response in joint symptoms rather than skin disease. The Committee accepted that the Assessment Group's approach represented the best means of estimating utility for the purposes of the economic analysis given the available data. The Committee considered the results of the Assessment Group's base-case model, which incrementally ranked the costs and QALYs associated with the different TNF inhibitors compared with palliative care. The Committee was aware that the acquisition costs of adalimumab and etanercept were similar, and the acquisition cost of infliximab was dependent on the patient's weight and the number of vials required, with additional administration costs (related to intravenous infusion) when compared with etanercept and adalimumab. The results of the model indicated that infliximab was the most effective treatment with an ICER of £44,000 per QALY gained compared with etanercept, while etanercept had an ICER of £18,000 per QALY gained compared with palliative care. The Committee noted that adalimumab was extendedly dominated by a combination of etanercept and palliative care (that is, additional QALYs could be generated with etanercept relative to adalimumab at a lower cost per QALY gained than the ICER of adalimumab relative to palliative care), and had therefore been excluded from the incremental analysis. However, the Committee noted that the estimate of relative effectiveness was based on indirect comparison only and noted the comments of the clinical experts that the TNF inhibitors were used interchangeably in clinical practice. The Committee therefore concluded that treatment should be initiated with the least expensive drug. The Committee considered the results of the univariate sensitivity analysis performed by the Assessment Group. The Committee noted that the model was most sensitive to assumptions around the cost of treating uncontrolled skin disease associated with psoriatic arthritis, differences in the relative improvements measured by HAQ score and the cost of infliximab (depending on the average number of vials required to treat people with psoriatic arthritis). The Committee took account of evidence from consultees that vial sharing arrangements for infliximab are available in some clinical settings and may reduce drug wastage by up to 50%. The Committee considered various ways of incorporating vial sharing but concluded that there were insufficient data to incorporate it into the economic model. The Committee accepted the clinical specialists' view that there was no robust evidence that etanercept, infliximab and adalimumab differ in their effectiveness for the treatment of psoriatic arthritis in clinical practice and agreed that the sensitivity analyses performed by the Assessment Group were comprehensive and robust. It noted that the calculated cost-effectiveness ratios of the TNF inhibitors varied depending on the assumptions used. The Committee concluded that, given the lack of conclusive evidence of difference between the TNF inhibitors, treatment choice should be based on cost, taking into account any local discounting agreements and/or vial-sharing arrangements. The Committee considered the evidence for adalimumab, etanercept and infliximab in the context of clinical practice. The Committee considered that the criteria for recommending etanercept and infliximab (in NICE technology appraisal guidance 104) and adalimumab (in NICE technology appraisal guidance 125) remained valid. The Committee therefore concluded that etanercept, infliximab and adalimumab should be recommended for people with active and progressive psoriatic arthritis when the person has peripheral arthritis with three or more tender joints and three or more swollen joints and whose psoriatic arthritis has not responded to adequate trials of at least two standard DMARDs, administered either individually or in combination. The Committee considered the recommendations on discontinuing treatment with etanercept and infliximab (in NICE technology appraisal 104) and with adalimumab (in NICE technology appraisal 125). The Committee considered that the recommendations to discontinue treatment based on an inadequate PsARC response at 12 weeks remained valid. The Committee noted that in the Assessment Group scenario analysis, the TNF inhibitors might be equally cost effective in people whose skin disease has a PASI 75 response but whose psoriatic arthritis does not have a PsARC response. The Committee noted that the trial evidence was less robust for PASI response because the degree of skin disease at randomisation was not consistent across the trials. The Committee was aware that previous NICE guidance had recommended the TNF inhibitors for people with severe or very severe plaque psoriasis (see 'Etanercept and efalizumab for the treatment of adults with psoriasis' , 'Infliximab for the treatment of adults with psoriasis' and 'Adalimumab for the treatment of adults with psoriasis' for guidance on the use of tumour necrosis factor inhibitors in psoriasis). It concluded that people whose skin disease achieves a PASI 75 response but whose psoriatic arthritis does not achieve an adequate PsARC response should be assessed by a dermatologist to determine whether the criteria for continued treatment with etanercept, adalimumab or infliximab are met for the treatment of the psoriatic component of the condition alone. The Committee also noted the comments from clinical specialists about the benefits of having combined input from rheumatologists and dermatologists in managing this multisystem disease. The Committee considered the evidence presented by the Assessment Group on the cost effectiveness for the sequencing of TNF inhibitor treatments. The Committee heard from the clinical experts that very limited data were available for the response rate for second-line treatment with TNF inhibitors. These were derived either from trials for people with rheumatoid arthritis or from registry data, which were uncontrolled and comprised predominantly people with rheumatoid arthritis. The Committee concluded that there were insufficient data to make a recommendation on the sequential use of TNF inhibitors in psoriatic arthritis. The Committee was aware of registries that collect data for the long-term outcomes of treatment with TNF inhibitors for rheumatoid arthritis and psoriasis. The Committee noted the importance of registries in collecting data and supported including outcomes specific to psoriatic arthritis in a suitable registry so that specific information about these treatments in psoriatic arthritis can be captured. In summary, the Committee considered the clinical and cost effectiveness of etanercept, infliximab and adalimumab in the light of clinical specialists' and patient experts' comments. It considered that there was insufficient evidence of superiority of any one agent over the others. On balance, considering the RCT data, modelling assumptions, modelling results and sensitivity analyses, together with expert opinion, the Committee concluded that etanercept, infliximab and adalimumab were similarly effective. The Committee considered the higher treatment cost with infliximab compared with adalimumab and etanercept in the base-case model and the possibility of locally arranged discounts for infliximab. The Committee therefore concluded that etanercept, infliximab and adalimumab should be recommended as treatment options for people with psoriatic arthritis with three or more affected joints whose disease had inadequately responded to at least two conventional DMARDs and that the choice of treatment should be based on cost, taking into account acquisition and administration costs and any local discounting agreements and/or vial-sharing arrangements. # Summary of the Appraisal Committee's key conclusions TA 199 (MTA): Etanercept, infliximab and adalimumab for the treatment of psoriatic arthritis (review of technology appraisal guidance 104 and 125) FAD section Key conclusion Etanercept, infliximab and adalimumab are recommended for the treatment of adults with active and progressive psoriatic arthritis in specific circumstances (see section 1.1) and treatment should normally be started with the least expensive drug (taking into account drug administration costs, required dose and product price per dose). Treatment should be discontinued in people whose psoriatic arthritis has not shown an adequate response using the Psoriatic Arthritis Response Criteria (PsARC) at 12 weeks. People whose disease has a Psoriasis Area and Severity Index (PASI) 75 response at 12 weeks but whose PsARC response does not justify continuation of treatment should be assessed by a dermatologist to determine whether continuing treatment is appropriate on the basis of skin response (see 'Etanercept and efalizumab for the treatment of adults with psoriasis' , 'Infliximab for the treatment of adults with psoriasis' and 'Adalimumab for the treatment of adults with psoriasis' for guidance on the use of tumour necrosis factor inhibitors in psoriasis). Current practice Clinical need of patients including the availability of alternative treatments Psoriatic arthritis can affect people's ability to work and carry out daily activities, which can have a substantial impact on quality of life. People with psoriatic arthritis have a 60% higher risk of mortality than the general population and their life expectancy is estimated to be approximately 3 years shorter. The aim of psoriatic arthritis treatment is to relieve symptoms, slow disease progression and maintain quality of life. Non-steroidal anti-inflammatory drugs (NSAIDs) and local corticosteroid injections are widely used. Disease that is unresponsive to NSAIDs, in particular polyarticular disease, is treated with disease modifying antirheumatic drugs (DMARDs) to reduce joint damage and prevent disability. The technology Proposed benefits of the technology How innovative is the technology in its potential to make a significant and substantial impact on health-related benefits and how it might improve the way that current need is met (is this a 'step-change' in the management of the condition?) The Committee heard from a patient expert that tumour necrosis factor (TNF) inhibitors are effective and valued options for the treatment of psoriatic arthritis and have an appreciable impact on quality of life. What is the position of the treatment in the pathway of care for the condition? The Committee considered that the criteria for recommending etanercept and infliximab (in NICE technology appraisal guidance 104) and adalimumab (in NICE technology appraisal guidance 125) remained valid. Adverse effects The Committee considered the tolerability profile of the three TNF inhibitors to be comparable. Evidence for clinical effectiveness Availability, nature and quality of evidence There were no head-to-head randomised controlled trials (RCTs) comparing the TNF inhibitors and so indirect methods of comparison had to be used. RCTs were powered primarily to detect statistically significant differences in the effectiveness of TNF inhibitors compared with placebo on joint disease and only secondarily on any associated skin disease. The Committee considered the evidence to be sufficient to appraise the clinical effectiveness of TNF inhibitors. Relevance to general clinical practice in the NHS The Committee considered the evidence for adalimumab, etanercept and infliximab in the context of NICE technology appraisal guidance 104 and 125. Uncertainties generated by the evidence The Committee concluded that there was not enough evidence to indicate clinically important differences in the effectiveness of individual TNF inhibitors in the treatment of psoriatic arthritis. Are there any clinically relevant subgroups for which there is evidence of differential effectiveness The Committee considered the subgroup of people whose skin disease has a PASI 75 response at 12 weeks but whose psoriatic arthritis does not have an adequate PsARC response, indicating treatment should be discontinued. The Committee was aware that previous NICE guidance had recommended the TNF inhibitors for people with severe or very severe plaque psoriasis (see 'Etanercept and efalizumab for the treatment of adults with psoriasis' , 'Infliximab for the treatment of adults with psoriasis' and 'Adalimumab for the treatment of adults with psoriasis' for guidance on the use of tumour necrosis factor inhibitors in psoriasis). The Committee considered that these people should be referred to a dermatologist to determine whether the criteria for continued treatment with etanercept, adalimumab or infliximab are met for the treatment of the psoriatic component of the condition alone. Estimate of the size of the clinical effectiveness including strength of supporting evidence The Committee accepted the clinical specialists' view that there was no robust evidence that etanercept, infliximab and adalimumab differ in their effectiveness for the treatment of psoriatic arthritis in clinical practice. Evidence for cost effectiveness Availability and nature of evidence The Committee noted that the Assessment Group updated the economic model submitted for 'Etanercept and infliximab for the treatment of psoriatic arthritis' (NICE technology appraisal 104) by including the effectiveness of the TNF inhibitors treatment on the skin disease as well as the joint disease. Uncertainties around and plausibility of assumptions and inputs in the economic model The Committee noted that the model was most sensitive to assumptions around the cost of treating uncontrolled psoriasis, differences in the relative HAQ score and the cost of infliximab (depending on the average number of vials required to treat people with psoriatic arthritis). Incorporation of health-related quality of life benefits and utility values Have any potential significant and substantial health-related benefits been identified that were not included in the quality-adjusted life year (QALY) calculation? How have these been separately evaluated and what is the impact (if any) on the judgement of the most plausible incremental cost-effectiveness ratio) ICER? The utility was driven by the patients' joint disease response (the Health Assessment Questionnaire response) rather than the skin response (PASI). The Committee considered that the model (updated from NICE technology appraisal 104) took into account the beneficial effects of TNF inhibitors on the skin disease as well as the joint disease. The Committee accepted that the Assessment Group's approach represented the best means of estimating utility for the purposes of the economic analysis given the available data. Are there specific groups of people for whom the technology is particularly cost effective? The Committee considered a subgroup of people whose disease achieved a response to PASI but not PsARC. They considered that they should be referred to a dermatologist to determine whether continued treatment is indicated for the symptoms of psoriasis alone. What are the key drivers of cost effectiveness? The relative effectiveness of the TNF inhibitors on skin disease and vial sharing arrangements for infliximab. Most likely cost-effectiveness estimate (given as an ICER) The Assessment Group base-case analysis found that infliximab was the most effective treatment with an ICER of £44,000 per QALY gained compared with etanercept, while etanercept had an ICER of £18,000 per QALY gained compared with palliative care. The Committee noted that adalimumab was extendedly dominated by a combination of etanercept and palliative care (that is, additional QALYs could be generated with etanercept relative to adalimumab at a lower cost per QALY gained than the ICER of adalimumab relative to palliative care), and had therefore been excluded from the incremental analysis. The Committee took account of evidence from consultees that vial sharing arrangements for infliximab are available in some clinical settings and may reduce drug wastage by up to 50%. The Committee concluded that, given the lack of conclusive evidence of difference between the TNF inhibitors, treatment choice should be based on cost, taking into account any local discounting agreements and/or vial-sharing arrangements. Additional factors taken into account Patient access schemes (Pharmaceutical Price Regulation Programme) No patient access scheme was submitted for any of the technologies under appraisal. End-of-life considerations The end-of-life criteria were not applicable for this population. Equalities considerations, Social Value Judgement No equalities issues were raised. # Recommendations for further research The Committee highlighted the importance of collecting further data within registries of patients receiving biological treatments for psoriatic arthritis to obtain information on long-term outcomes including adverse events.# Review of guidance The guidance on this technology will be considered for review in June 2013. The Guidance Executive will decide whether the technology should be reviewed based on information gathered by NICE, and in consultation with consultees and commentators. Andrew DillonChief ExecutiveAugust 2010# Changes after publication February 2014: minor maintenance March 2012: minor maintenance# About this guidance NICE technology appraisal guidance is about the use of new and existing medicines and treatments in the NHS in England and Wales. This guidance was developed using the NICE multiple technology appraisal process. It replaces NICE technology appraisal guidance 104 issued in July 2006 and NICE technology appraisal guidance 125 issued in August 2007. NICE reviews each piece of guidance it issues. This review and re-appraisal has resulted in an extension to the guidance: Etanercept, infliximab and adalimumab are all recommended for the treatment of active and progressive psoriatic arthritis, based on specific criteria. Treatment choice should be started with the least expensive drug (taking into account drug administration costs, required dose and product price per dose). The guidance recommends that treatment should be discontinued if people's disease does not show an adequate response on the Psoriatic Arthritis Response Criteria (PsARC) at 12 weeks. Healthcare professionals should also consider continuing treatment if people's skin disease has a Psoriasis Area and Severity Index (PASI) 75 response at 12 weeks in the absence of an adequate PsARC response. This assessment should be done by a dermatologist to determine whether continued treatment is appropriate on the basis of the skin response alone. We have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available. Your responsibility This guidance represents the views of NICE and was arrived at after careful consideration of the evidence available. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. However, the guidance does not override the individual responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or guardian or carer. Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties. Copyright © National Institute for Health and Clinical Excellence 2010. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.	{'Guidance': "This guidance replaces NICE technology appraisal guidance 104 issued in July 2006 and NICE technology appraisal guidance 125 issued in August 2007. For details, see 'About this guidance'.\n\nEtanercept, infliximab and adalimumab are recommended for the treatment of adults with active and progressive psoriatic arthritis when the following criteria are met.\n\nThe person has peripheral arthritis with three or more tender joints and three or more swollen joints, and\n\nThe psoriatic arthritis has not responded to adequate trials of at least two standard disease-modifying antirheumatic drugs (DMARDs), administered either individually or in combination.\n\nTreatment as described in 1.1 should normally be started with the least expensive drug (taking into account drug administration costs, required dose and product price per dose). This may need to be varied for individual patients because of differences in the method of administration and treatment schedules.\n\nEtanercept, adalimumab or infliximab treatment should be discontinued in people whose psoriatic arthritis has not shown an adequate response using the Psoriatic Arthritis Response Criteria (PsARC) at 12 weeks. An adequate response is defined as an improvement in at least two of the four PsARC criteria, (one of which has to be joint tenderness or swelling score) with no worsening in any of the four criteria. People whose disease has a Psoriasis Area and Severity Index (PASI) 75 response at 12 weeks but whose PsARC response does not justify continuation of treatment should be assessed by a dermatologist to determine whether continuing treatment is appropriate on the basis of skin response (see 'Etanercept and efalizumab for the treatment of adults with psoriasis' [NICE technology appraisal guidance 103], 'Infliximab for the treatment of adults with psoriasis' [NICE technology appraisal guidance 134] and 'Adalimumab for the treatment of adults with psoriasis' [NICE technology appraisal guidance 146] for guidance on the use of tumour necrosis factor [TNF] inhibitors in psoriasis).\n\nWhen using the PsARC healthcare professionals should take into account any physical, sensory or learning disabilities, or communication difficulties that could affect a person's responses to components of the PsARC and make any adjustments they consider appropriate.", 'Clinical need and practice': "Psoriatic arthritis is an inflammatory arthritis affecting the joints and connective tissue and is associated with psoriasis of the skin or nails. The prevalence of psoriasis in the general population is estimated at 2–3%. The prevalence of inflammatory arthritis in people with psoriasis is estimated at up to 30%. At least 20% of people with psoriasis have severe psoriatic arthritis with progressive joint lesions. Psoriatic arthritis is a progressive disorder ranging from mild synovitis to severe progressive erosive arthropathy. People with psoriatic arthritis presenting with oligoarticular disease progress to polyarticular disease and a large percentage develop joint lesions and deformities, which progress over time. Despite clinical improvement with current DMARD treatment, joint damage has been shown radiologically in up to 47% of people with psoriatic arthritis at a median interval of 2 years.\n\nPsoriatic arthritis can affect people's ability to work and carry out daily activities, which can have a substantial impact on quality of life. The impact of severe psoriasis on health-related quality of life is considered to be similar to that of other major medical conditions including diabetes, heart disease and cancer. People with psoriatic arthritis have a higher self-rated disease severity than those with psoriasis only. People with psoriatic arthritis have a 60% higher risk of mortality than the general population and their life expectancy is estimated to be approximately 3\xa0years shorter.\n\nMost people with psoriatic arthritis develop skin symptoms before joint symptoms, although joint symptoms may appear first or simultaneously. Psoriatic arthritis usually develops within 10 years of a diagnosis of psoriasis. The rheumatic characteristics of psoriatic arthritis include joint stiffness, pain and swelling, and tenderness of the joints and surrounding ligaments and tendons. Symptoms can range from mild to very severe.\n\nAssessing the effectiveness of treatments for psoriatic arthritis relies on outcome measures that accurately and sensitively measure disease activity. Outcomes of effectiveness are based on measures of the anti-inflammatory response (such as the PsARC, and the American College of Rheumatology response criteria [ACR\xa020/50/70]), measures of psoriatic skin lesions (PASI), functional measures (Health Assessment Questionnaire [HAQ]) and radiological assessments (Total Sharp Score, van der Heijde-Sharp Score) of disease progression, quality of life and overall global assessments. Overall response criteria have not yet been clearly defined.\n\nThe aim of psoriatic arthritis treatment is to relieve symptoms, slow disease progression and maintain quality of life. To effectively manage psoriatic arthritis, any associated skin disease also needs to be effectively treated. Non-steroidal anti-inflammatory drugs (NSAIDs) and local corticosteroid injections are widely used. Disease that is unresponsive to NSAIDs, in particular polyarticular disease, is treated with DMARDs (currently, methotrexate and sulfasalazine are considered the DMARDs of choice) to reduce joint damage and prevent disability. Aggressive treatment of early stage progressive psoriatic arthritis can help to improve prognosis.", 'The technologies': "# Etanercept\n\nEtanercept (Enbrel, Wyeth Pharmaceuticals) is a human TNF receptor fusion protein that inhibits TNF-α binding to cell surface TNF receptors. Etanercept is licensed for the treatment of active and progressive psoriatic arthritis in adults whose disease has not responded adequately to previous DMARD therapy.\n\nThe most common adverse events reported in the trials were infections (including upper respiratory tract infections, bronchitis, cystitis and skin infections), injection site reactions (including bleeding, bruising, erythema, itching, pain and swelling), and allergic reactions, such as pruritus. For full details of undesirable effects and contraindications, see the summary of product characteristics.\n\nThe acquisition cost of etanercept is £89.38 per 25-mg prefilled syringe or 25-mg vial with powder for reconstitution (with solvent), and £178.75 per 50-mg prefilled syringe (excluding VAT; British national formulary [BNF] edition 58). The annual cost of etanercept using either 50-mg\xa0once-weekly doses (52 doses per year) or 25-mg\xa0twice-weekly doses (104 doses per year) is £9295. Costs may vary in different settings because of negotiated procurement discounts.\n\n# Infliximab\n\nInfliximab (Remicade, Schering-Plough) is a chimeric human-murine monoclonal antibody that inhibits the functional activity of TNF-α. Infliximab is licensed for the treatment of active and progressive psoriatic arthritis in adults when the disease has not responded adequately to previous DMARD therapy. Infliximab should be administered:\n\nin combination with methotrexate, or\n\nalone in people who show intolerance to methotrexate or for whom methotrexate is contraindicated.\n\nThe most common reported adverse events in the trials were infusion reactions and hypersensitivity, infections (tuberculosis, bacterial infections – including sepsis and pneumonia – invasive fungal infections, and other opportunistic infections), hepatitis B reactivation and heart failure. For full details of undesirable effects and contraindications, see the summary of product characteristics.\n\nThe acquisition cost of infliximab is £419.62 per 100-mg vial with powder for reconstitution (excluding VAT; BNF edition 58). The drug cost differs between individuals because the dose is adjusted to each person's body weight. For example, for an adult weighing 75 kg, if it is assumed that vials are not shared between patients, each infusion of 5\xa0mg/kg requires four 100-mg vials at a cost of £1678. The three initial infusions are given at weeks 0, 2 and 6, at a cost of £5035. The subsequent annual cost following the loading doses is £10,910 per year based on infusions repeated every 8\xa0weeks (average 6.5 doses per year). Costs may vary in different settings because of negotiated procurement discounts.\n\n# Adalimumab\n\nAdalimumab (Humira, Abbott Laboratories) is a recombinant human monoclonal antibody that binds specifically to TNF and neutralises its function. Adalimumab is licensed for the treatment of active and progressive psoriatic arthritis in adults when the disease has not responded adequately to previous DMARD therapy.\n\nThe most common reported adverse events in the trials were infections (including sepsis due to bacterial, mycobacterial, invasive fungal, parasitic, viral, or other opportunistic infections such as listeriosis and pneumocystis), tuberculosis, hepatitis B reactivation, formation of autoimmune antibodies and congestive heart failure. For full details of undesirable effects and contraindications, see the summary of product characteristics.\n\nThe acquisition cost of adalimumab is £357.50 per 40-mg prefilled pen or prefilled syringe (excluding VAT; BNF edition 58). The annual acquisition cost of adalimumab to the NHS is £9295 per patient (based on 26 injections per year). Costs may vary in different settings because of negotiated procurement discounts.", 'Evidence and interpretation': "The Appraisal Committee (appendix A) considered evidence from a number of sources (appendix B).\n\n# Clinical effectiveness\n\nThe Assessment Group identified six double-blind, placebo-controlled, randomised controlled trials (RCTs) in people with psoriatic arthritis for the technologies: two for etanercept, two for infliximab and two for adalimumab.\n\n## Etanercept\n\nThe two double-blind, placebo-controlled RCTs of etanercept in adults with active psoriatic arthritis were Mease 2000 (n\xa0=\xa060; follow-up 12 weeks) and Mease 2004 (n\xa0=\xa0205; follow-up 24\xa0weeks). In both trials 25\xa0mg etanercept was administered by subcutaneous injection twice a week. The inclusion criteria for both trials were active psoriatic arthritis (defined as more than three swollen joints and more than three tender or painful joints, although only the more recent trial specified stable plaque psoriasis), and psoriatic arthritis that had not responded adequately to NSAIDs. The primary outcome variable in the Mease 2000 trial was PsARC and in Mease 2004 it was ACR\xa020. Data for PASI at week 12 were available from Mease 2000 only.\n\nThe Assessment Group conducted a meta-analysis of the outcomes for etanercept at 12 weeks and the pooled estimates from both trials showed that etanercept was statistically significantly more effective than placebo for all outcomes (PsARC, ACR 20, ACR 50, ACR 70, and HAQ percentage change from baseline). For PsARC the pooled relative risk (RR) estimate was 2.60 (95% confidence interval [CI] 1.96 to 3.45), with some evidence of statistical heterogeneity (I2\xa0=\xa034%) between the two studies' estimates. For PASI 50, the results from the Mease 2000 trial at 12\xa0weeks showed that etanercept was more effective than placebo (RR = 2.00 [95% CI 0.72 to 5.53]) although this was not statistically significant. For PASI 75 the results showed that etanercept was statistically significantly more effective than placebo (RR = 11.00 [95% CI 0.65 to 186.02]; p\xa0=\xa00.0154).\n\nAt 24 weeks the treatment effect for all joint disease outcome measures was statistically significantly greater for etanercept than for placebo, though these data were available only for one trial, Mease 2004. At 24 weeks, the annualised rate of progression as measured radiologically using the Total Sharp Score was statistically significantly lower in people treated with etanercept than in people treated with placebo (Total Sharp Score −0.56; 95%\xa0CI\xa0−0.86 to −0.26).\n\nAt 24 weeks the treatment effect on psoriasis favoured etanercept with RRs for PASI 75 of 7.05 (95% CI 1.68 to 29.56), PASI 50 of 2.65 (95% CI 1.46 to 4.80) and PASI 90 of 1.88 (95% CI 0.36 to 9.90). At 1\xa0year the mean annualised rate of progression on the Total Sharp Score for all people was −0.03 (standard deviation [SD] 0.87), indicating that on average there was no clinically significant progression of joint erosion based on uncontrolled follow-up data.\n\n## Infliximab\n\nThe two double-blind, placebo-controlled RCTs of infliximab for the treatment of psoriatic arthritis were IMPACT and IMPACT 2. In the IMPACT trial, participants (n\xa0=\xa0104) were randomised to receive infusions of infliximab (5\xa0mg/kg) or placebo at weeks 0, 2, 6 and 14 with follow-up at week\xa016. In IMPACT 2, people (n\xa0=\xa0200) were randomised to receive infusions of placebo or infliximab 5\xa0mg/kg at weeks 0, 2, 6, 14 and 22, with assessments at weeks 14 and 24. In both RCTs the inclusion criteria required that participants' psoriatic arthritis should have five or more swollen/tender joints, and that their disease had an inadequate response to at least one DMARD. IMPACT 2 also required people to have active plaque psoriasis with at least one qualifying target lesion (2\xa0cm or more in diameter).\n\nThe Assessment Group conducted a meta-analysis of the outcomes for infliximab at 14\xa0weeks and the results for both trials reported a statistically significant improvement in PsARC for people receiving infliximab, relative to those receiving placebo (pooled RR 3.44, 95% CI 2.53 to 4.69). There was some evidence of statistical heterogeneity (I2\xa0=\xa068%) between the two study estimates. Infliximab was statistically significantly more effective than placebo for all pooled estimates for outcomes of joint response (ACR 20, ACR\xa050 and ACR 70) as well as the pooled percentage change from baseline in HAQ score with infliximab compared with placebo (mean difference −60.37 [95% CI −75.28 to –45.46]).\n\nThe Assessment Group also presented pooled estimates for the outcomes of the skin component of psoriatic arthritis over 14–16\xa0weeks and the results showed that infliximab was statistically significantly more effective than placebo.\n\nThe IMPACT 2 trial was randomised for 24 weeks followed by an open-label period. The data for all measures of joint disease, psoriasis and HAQ were similar to those at the 14-week follow-up, suggesting that infliximab's benefits were maintained for up to 24\xa0weeks of treatment and for longer-term follow-up (50\xa0weeks for IMPACT and 54 weeks for IMPACT 2) although the data for the longer-term follow-up were uncontrolled.\n\nIn terms of radiographic assessment, there was no statistically significant change from baseline in the total modified van der Heijde-Sharp Score for infliximab-treated people followed up at 50\xa0weeks in the IMPACT trial (n\xa0=\xa070: −1.72 [5.82]) or 54 weeks in the IMPACT 2 trial (infliximab/infliximab −0.94 [3.4]; placebo/infliximab 0.53 [2.6]), suggesting infliximab may inhibit progression of joint damage. However, as with other outcomes measured after week 24, there was no placebo group for comparison.\n\n## Adalimumab\n\nThe two double-blind, placebo-controlled RCTs of adalimumab in adults with active psoriatic arthritis were ADEPT (n = 313, follow-up of 24 weeks) and Genovese 2007 (n = 100, follow-up of 12\xa0weeks). In both trials adults were randomised to adalimumab (40 mg every other week) or placebo. The inclusion criteria for both RCTs required people to have active psoriatic arthritis (defined in both trials as more than three swollen joints and more than three tender or painful joints, with active psoriatic skin lesions or a documented history of psoriasis). Overall, the baseline characteristics demonstrated that the trial populations were indistinguishable and represented people who required DMARDs or therapy with TNF inhibitors.\n\nThe Assessment Group conducted a meta-analysis of the outcomes for adalimumab at 12 weeks and the results from both trials showed a statistically significant improvement for adalimumab compared with placebo for all outcome measures. The pooled RR for PsARC was 2.24 (95% CI 1.74 to 2.88) and the pooled RR for ACR 20 was 3.65 (95% CI 2.57 to 5.17). The pooled RRs for ACR\xa050 and ACR 70 also favoured adalimumab, although their related CIs were wide. Regarding the associated skin disease, 12-week PASI response measures were reported by only one trial (ADEPT), and the response was statistically significantly greater for adalimumab than placebo at all three PASI thresholds: PASI 50 RR\xa0=\xa05.00 (95% CI 2.77 to 9.03); PASI 75 RR = 11.33 (95% CI 3.65 to 35.17)]; and PASI 90 RR = 43.00 (95% CI 2.66 to 696.04) The CIs, especially for PASI 75 and PASI 90, were wide.\n\nThe ADEPT trial was randomised for 24 weeks. The data for all measures of joint disease, psoriasis and HAQ were similar to those at 12-week follow-up. In addition, this trial also reported a statistically significant difference in mean change in Total Sharp Score from baseline (−0.2 versus 0.1, p\xa0< 0.001) favouring adalimumab over placebo in terms of delayed progression of joint disease, although this duration of follow-up is short.\n\n## Indirect comparison performed by the Assessment Group\n\nIn the absence of head-to-head RCTs on the relative efficacy of the three TNF inhibitors, an indirect comparison was undertaken by the Assessment Group using placebo as the common comparator. The results were expressed as the probability of each of the TNF inhibitors achieving a response for the outcome measures PsARC, HAQ, PASI and ACR. Infliximab was associated with the highest probability of achieving a response for all of the outcomes measured. The probability of response in joint disease (PsARC and ACR) was higher with etanercept than with adalimumab, and the probability of response in skin disease (PASI) was higher with adalimumab than with etanercept.\n\n## Adverse events\n\nThere were no RCTs that directly compared the three drugs. To evaluate the adverse events of the three TNF inhibitors the Assessment Group reviewed a range of study types including RCTs, open-label extensions of trials and observational studies.\n\nThe Assessment Group provided a range of estimates for serious adverse event and withdrawal rates across non-randomised studies and large RCTs. These comprised serious infections, cancer, activation of latent tuberculosis, mortality and withdrawals from treatment because of adverse events.\n\nThe Assessment Group acknowledged that the adverse event data were primarily from people with rheumatoid arthritis or other indications, so it is unclear to what extent these can be generalised to psoriatic arthritis. Overall, the limited evidence prevented them from drawing firm conclusions from the systematic review about the comparative adverse event profile of the three TNF inhibitors.\n\n# Cost effectiveness\n\n## Published economic evaluations\n\nThe Assessment Group performed a systematic review of published literature and identified three studies (Bansback et al. 2007; Bravo Vergel 2006; and Olivieri et al. 2008) that met the inclusion criteria for the cost-effectiveness review.\n\nThe study by Olivieri et al. (2008) was difficult to compare with the other studies because in this study all TNF inhibitors were considered as a group compared with DMARDs. There were no model results. The economic evaluation was made using before-and-after studies and the effectiveness evidence was based on a single trial. This produced an incremental cost-effectiveness ratio (ICER) of around €40,000 (£34,700) per quality-adjusted life year (QALY) gained for TNF inhibitors.\n\nThe study by Bansback et al. (2007) compared etanercept with ciclosporin and leflunomide. The economic model focused on response according to PsARC and associated HAQ score, with changes in HAQ and further withdrawals modelled over 10 years. Mease 2004 was the source of evidence for response rates and HAQ. The base-case results showed an ICER of around £28,000 per QALY gained for etanercept compared with ciclosporin and £38,000 per QALY gained for etanercept compared with leflunomide.\n\nThe study by Bravo Vergel (2006) compared etanercept with infliximab and palliative care. The model included response according to PsARC and associated HAQ score. Changes in HAQ and further withdrawals were modelled over 40 and 10\xa0years. Evidence from Mease 2000, Mease 2004 and IMPACT was used to model the PsARC response. The ICER for etanercept was between £26,361 and £30,628 per QALY gained compared with palliative care depending on the assumptions made about the deterioration in HAQ score at treatment withdrawal (rebound). Infliximab was the most effective strategy, and generated the highest number of QALYs.\n\n## Manufacturer's submission on the cost effectiveness of etanercept\n\nA published cost-effectiveness model originally used to support a submission to NICE in 2004 was adapted to incorporate additional effectiveness evidence and new comparators. The adjusted model compared the costs and benefits associated with etanercept, infliximab, adalimumab and best supportive care over a lifetime horizon. Best supportive care was assumed to be ciclosporin because the population considered in the model were assumed to have already tried other DMARDs (leflunomide, sulfasalazine and methotrexate).\n\nThe base-case results showed that the costs for best supportive care were £53,860 with QALYs of 5.96, and for etanercept the costs were £65,650 with QALYs of 6.90. This resulted in an ICER of £12,480 per QALY gained for etanercept when compared with best supportive care. Adalimumab was extendedly dominated by a combination of etanercept and palliative care (that is, additional QALYs could be generated with etanercept relative to adalimumab at a lower cost per QALY gained than is generated by adalimumab relative to palliative care). Infliximab was dominated by adalimumab (that is, infliximab was more costly and less effective than adalimumab).\n\n## Manufacturer's submission on the cost effectiveness of infliximab\n\nIn the economic analysis submitted by the manufacturer of infliximab four treatment alternatives were compared over a lifetime horizon. These included maintenance treatment with a TNF\xa0inhibitor (infliximab, adalimumab or etanercept) followed by a sequence of DMARDs. The comparator was palliative care with DMARDs. For the health-economic model, the incremental treatment effects for the comparative treatments were estimated for infliximab, etanercept and adalimumab. The direct drug costs for the TNF inhibitors were obtained from BNF edition\xa056.\n\nThe manufacturer presented base-case results for three different scenarios: people weighing 60 kg, 70 kg with vial optimisation for infliximab treatment (that is, making local arrangements so that vials can be shared between patients who are being treated with infliximab, reducing wastage) and 80 kg. For people weighing 60\xa0kg the base-case results showed that infliximab produced an ICER of £16,942 per QALY gained when compared with palliative care. For people weighing 70 kg, and accounting for vial optimisation, infliximab produced an ICER of £19,982 per QALY gained versus palliative care. For people weighing 80 kg infliximab produced an ICER of £23,022 per QALY gained when compared with palliative care.\n\n## Manufacturer's submission on the cost effectiveness of adalimumab\n\nThe manufacturer of adalimumab used an individual sampling model to simulate the disease progression of a cohort of people with psoriatic arthritis over a lifetime horizon under different treatment sequences. A 3-month cycle was used. Baseline characteristics from the ADEPT trial for people for whom two previous DMARDs had failed were used in the base-case analysis. The cost of all drugs used in the analysis was calculated based on the recommended dosages and vial prices given in the Monthly Index of Medical Specialties. The model assumed that four 100\xa0mg vials of infliximab were required per infusion, based on an average person weighing 80\xa0kg.\n\nThe base-case results showed that adalimumab, with a mean cost of £73,072 and QALYs of 8.33, was the most cost-effective treatment strategy when compared with a DMARD (mean costs of £47,537 and QALYs of 7.47), resulting in an ICER of £29,827 per QALY gained. Etanercept was more costly and had the same mean QALYs gained as adalimumab (8.33). Infliximab was more costly and more effective than adalimumab, which resulted in an ICER of £199,596 per QALY gained compared with adalimumab.\n\n## Assessment Group's economic assessment\n\nThe Assessment Group updated the economic model developed for 'Etanercept and infliximab for the treatment of adults with psoriatic arthritis' (NICE technology appraisal 104). This model allowed the three TNF inhibitors to be compared with each other. A\xa0probabilistic decision analytic model was developed to estimate the incremental costs and incremental QALYs of the three TNF\xa0inhibitors compared with palliative care over a lifetime horizon (40\xa0years), only. The price year was 2008/2009 and costs and benefits were discounted at a rate of 3.5%.\n\nThe decision analytical model followed a cohort of people that represented the average characteristics of participants in the RCTs and had a Markov structure. People in the cohort were assumed to be 47 years old, had been diagnosed with psoriatic arthritis 7 years previously, were assumed to weigh 60–80\xa0kg, and had psoriatic arthritis that had inadequately responded to at least two DMARDS. People in the treatment arm received etanercept, infliximab or adalimumab and people in the control arm received palliative care. The disease's response to treatment was assessed between 12\xa0and 16 weeks. It was assumed that people whose disease had responded to treatment stayed in the treatment arm, while treatment was discontinued in people whose psoriatic arthritis failed to adequately respond to treatment – these people were assumed to go on to receive palliative care.\n\nThe following assumptions were included in the Assessment Group's model: people in the initial 3-month trial period had some improvement in HAQ (even if they did not reach the PsARC threshold); people who had a PASI 75 response would gain at least a 75% improvement in psoriasis compared with baseline PASI; people continuing on TNF inhibitors maintained their initial improvement in HAQ; and the same ongoing risk of withdrawal from treatment was used for all TNF inhibitors (withdrawal because of reduction in efficacy, adverse events or other reasons).\n\nThe base-case analysis in the Assessment Group's model assumed a lifetime (40-year) time horizon for costs and QALYs, a baseline HAQ of 1.05, a baseline PASI of 7.5, rebound equal to gain, and incorporate the correlation between PsARC and PASI 75 outcomes. Health utility was measured as a function of HAQ and PASI based on linear regressions of EQ5D utility versus HAQ and PASI provided by the manufacturers based on RCT evidence. The total lifetime discounted health associated with palliative care was about 5.2 QALYs because the base case assumed that utility declined fairly rapidly in people with uncontrolled arthritis, and may have been less than 0 (representing a health state worse than death) in later years.\n\nThe base-case model assumed that people's psoriatic arthritis had failed to respond to treatment with at least two DMARDS but they had not received previous treatment with TNF inhibitors. The Assessment Group also modelled the cost effectiveness of sequencing TNF inhibitor therapies after people's psoriatic arthritis failed to respond to a first-line TNF inhibitor. The base-case analysis reported the lifetime costs and QALYs of the three TNF inhibitors in people with mild-to-moderate psoriatic arthritis, which was presented as an incremental analysis ranking the alternative strategies by mean cost.\n\nFollowing comments made by NICE consultees on the Technology Assessment Report and model of December 2009, the Assessment Group revised the cost-effectiveness analysis results. The Assessment Group took into account the manufacturer of adalimumab's revised estimates from their RCTs of the effect of adalimumab on HAQ change for PsARC responders and non-responders. The Assessment Group corrected a standard error calculation when extracting data for the evidence synthesis and used the correct calculation of the costs of adalimumab and etanercept. The results for the base case showed that infliximab was the most effective treatment taking into account both joint and skin effects (QALYs of 7.3), followed by etanercept (QALYs of 7.0), then adalimumab (QALYs of 6.6). Infliximab was also the most costly treatment (£88,442), followed by etanercept (£74,841), then adalimumab (£68,638). The ICER of etanercept compared with palliative care was £17,853 per QALY gained. The ICER for infliximab compared with etanercept was £44,326 per QALY gained. Adalimumab was extendedly dominated by a combination of etanercept and palliative care (that is, additional QALYs could be generated with etanercept relative to adalimumab at a lower cost per QALY gained than the ICER of adalimumab relative to palliative care, adalimumab was therefore excluded from the incremental analysis). Etanercept had the highest probability of being cost effective with probabilities of being cost effective of 44% if the maximum acceptable amount to pay for an additional QALY was £20,000 and 48% if the maximum acceptable amount to pay for an additional QALY was £30,000.\n\nThe Assessment Group conducted several univariate sensitivity analyses using different sets of assumptions. The Assessment Group presented the results according to whether the ICER was less than £20,000 per QALY gained, between £20,000 and £30,000 per QALY gained or greater than £30,000 per QALY gained.\n\nThe results of these analyses suggested that the ICER of etanercept increased to above £20,000 per QALY gained or was dominated by other strategies when the following assumptions were used and all other variables take mean values as in the base case:\n\nA patient treated for psoriatic arthritis whose skin disease does not achieve a PASI 75 response is admitted to hospital for treatment of psoriasis (annual treatment). The base case assumed these patients are offered ultraviolet (UV) light therapy.\n\nThe HAQ rebounds after withdrawal from TNF inhibitors to natural history rather than to initial gain.\n\nTreatment with TNF inhibitors becomes ineffective (relative to no treatment) after 10\xa0years.\n\nInfliximab requires three vials rather than four vials per administration.\n\nAll responders to PsARC have the same change in HAQ at 3\xa0months, regardless of the TNF inhibitor used.\n\nFor most sensitivity analyses performed by the Assessment Group, the ICER for infliximab was greater than £30,000 per QALY gained. The ICER of infliximab fell below £30,000 per QALY gained, when the following assumptions were used and all other variables take mean values as in the base case:\n\nA patient treated for psoriatic arthritis whose skin disease does not achieve a PASI 75 response is admitted to hospital for treatment of psoriasis (annual treatment). The base case assumed these patients are offered UV light therapy.\n\nInfliximab requires three vials rather than four vials per administration.\n\nIf the manufacturer of infliximab's estimates of the cost of treating psoriasis with UV light therapy are used in the Assessment Group's model.\n\nHAQ improves while on biological therapy. The base case assumes no change after the first 3 months.\n\nThe ICER of adalimumab fell below £20,000 per QALY gained and was no longer dominated by other strategies, when the following assumptions were used and all other variables take mean values as in the base case:\n\nAll responders to PsARC have the same change in HAQ at 3\xa0months, regardless of the TNF inhibitor used.\n\nA patient treated for psoriatic arthritis whose skin disease does not achieve a PASI 75 response is admitted to hospital for treatment of psoriasis (annual treatment). The base case assumed these patients are offered UV light therapy.\n\nIf the manufacturer of infliximab's estimates of the cost of treating psoriasis with UV light therapy are used in the Assessment Group's model.\n\nThe Assessment Group performed a sensitivity analysis assuming all TNF inhibitors had the same change in HAQ benefit at 3 months for a PsARC responder. The Assessment Group calculated that the ICERs per QALY gained were £17,717 for adalimumab compared with palliative care, £22,056 for etanercept compared with adalimumab and £50,806 for infliximab compared with etanercept.\n\nThe Assessment Group also provided cost-effectiveness results for subgroups with different patient characteristics. For a cohort in which baseline PASI was moderate to severe (PASI of 12.5 instead of 7.5 as in the base-case) the ICER of adalimumab versus palliative care was £16,310 per QALY gained, the ICER of etanercept versus adalimumab was £19,319 per QALY gained and the ICER of infliximab versus etanercept was £27,778 per QALY gained. For a cohort of people with negligible baseline psoriasis etanercept was the most cost-effective strategy with an ICER of £18,512 per QALY gained compared with palliative care, the ICER of infliximab compared with etanercept was £64,744 per QALY gained and adalimumab was extendedly dominated by a combination of etanercept and palliative care. For a cohort of people with moderate-to-severe psoriasis (baseline PASI of 12.5) whose disease did not achieve a PASI 75 response and are assumed to be admitted to hospital for treatment of psoriasis (annual treatment) instead of annual UV light therapy, the ICER for adalimumab compared with palliative care was £7901 per QALY gained, the ICER for infliximab compared with adalimumab was £10,636 per QALY gained and etanercept was dominated by (that is, was more costly and generated less QALYs than) infliximab.\n\nThe Assessment Group presented an additional analysis in which people were assumed to continue on biological treatment after 3\xa0months if their disease had either an adequate PsARC or a PASI\xa075 response (base case: PsARC only). For etanercept compared with palliative care the ICER was £17,859 per QALY gained, the ICER for infliximab compared with etanercept was £38,194 per QALY gained and adalimumab was extendedly dominated by a combination of etanercept and palliative care (that is, additional QALYs could be generated with etanercept relative to adalimumab at a lower cost per QALY gained than the ICER of adalimumab relative to palliative care).\n\nThe Assessment Group presented an analysis that compared the sequencing of the different TNF inhibitors in people with mild-to-moderate skin disease if a first TNF inhibitor has failed. The ICERs depended on which drug was used as first-line therapy, and was therefore ineligible for use as second-line therapy. The Assessment Group noted that the ICERs were broadly similar for people whose psoriatic arthritis failed to respond to first-line therapy because of adverse effects and those whose disease failed first-line therapy because of inefficacy.\n\nAn additional sensitivity analysis was performed by the Assessment Group at the Committee meeting and subsequently confirmed by running the model probabilistically. This analysis assumed that adalimumab and etanercept were equally effective while the PsARC responses for infliximab remained the same as in the original analysis (that is, infliximab was assumed to be more effective than adalimumab and etanercept). The ICER for both adalimumab and etanercept compared with palliative care was £18,296 per QALY gained and the ICER for infliximab compared with adalimumab and etanercept was £45,557 per QALY gained.\n\n# Consideration of the evidence\n\nThe Appraisal Committee reviewed the data available for the clinical and cost effectiveness of etanercept, infliximab and adalimumab, having considered evidence on the nature of psoriatic arthritis and the value placed on the benefits of etanercept, infliximab and adalimumab by people with the condition, those who represent them, and clinical specialists. It also took into account the effective use of NHS resources.\n\nThe Committee considered the clinical effectiveness evidence for etanercept, infliximab and adalimumab. The Committee noted that there were no head-to-head RCTs comparing the TNF inhibitors and so indirect methods of comparison had to be used. The Committee also noted that the RCTs were powered primarily to detect statistically significant differences in the effectiveness of TNF inhibitors compared with placebo on joint disease and only secondarily on any associated skin disease. Nevertheless, the Committee concluded that the RCT evidence was sufficient to appraise the clinical effectiveness of TNF inhibitors.\n\nThe Committee considered the clinical-effectiveness data presented by the manufacturers and noted that etanercept, infliximab and adalimumab all showed a statistically significant response in the joint disease (PsARC, ACR) and skin disease (PASI) criteria at 12-week and 24-week follow-up compared with placebo. Clinical specialists confirmed that in clinical practice improvement in psoriatic arthritis was maintained beyond 24\xa0months, and that some people had been treated with TNF inhibitors for up to 10 years. The Committee heard from a patient expert that TNF inhibitors are effective and valued options for the treatment of psoriatic arthritis and have an appreciable impact on quality of life. The Committee heard from the clinical specialists that there was no theoretical reason to believe that the TNF inhibitors would differ in their efficacy in treating psoriatic arthritis. It heard that etanercept, infliximab and adalimumab were similarly effective in the treatment of psoriatic arthritis in clinical practice, and were used interchangeably. Although the indirect comparison conducted by the Assessment Group suggested that infliximab is the most effective treatment overall, taking into account both skin and joint disease, the Committee concluded that there was not enough evidence to indicate clinically important differences in the effectiveness of individual TNF inhibitors in the treatment of psoriatic arthritis.\n\nThe Committee considered the evidence on the adverse event rates associated with the TNF inhibitors, including the reactivation of tuberculosis and the rate of serious infections reported in RCTs, and noted that these data were mainly for people with rheumatoid arthritis. The Committee heard from clinical specialists that the adverse event profile of TNF inhibitors was comparable to that of conventional DMARDs. It also heard that adverse events could result in a break from treatment, for example, by stopping treatment while an infection is resolved, then restarting. The Committee concluded that the tolerability profile of the three TNF inhibitors was comparable.\n\nThe Committee then considered the economic models presented by the manufacturers and the Assessment Group. The Committee noted that the Assessment Group updated the economic model submitted for 'Etanercept and infliximab for the treatment of psoriatic arthritis' (NICE technology appraisal 104) by taking into account the beneficial effect of TNF inhibitors on the skin disease as well as the joint disease. The Committee considered the utility estimates incorporated in the Assessment Group model and noted that the utility formula was derived from the PASI and HAQ. The HAQ response had a greater effect on utility than the PASI, indicating that the calculated utility benefit was mainly driven by the response in joint symptoms rather than skin disease. The Committee accepted that the Assessment Group's approach represented the best means of estimating utility for the purposes of the economic analysis given the available data.\n\nThe Committee considered the results of the Assessment Group's base-case model, which incrementally ranked the costs and QALYs associated with the different TNF inhibitors compared with palliative care. The Committee was aware that the acquisition costs of adalimumab and etanercept were similar, and the acquisition cost of infliximab was dependent on the patient's weight and the number of vials required, with additional administration costs (related to intravenous infusion) when compared with etanercept and adalimumab. The results of the model indicated that infliximab was the most effective treatment with an ICER of £44,000 per QALY gained compared with etanercept, while etanercept had an ICER of £18,000 per QALY gained compared with palliative care. The Committee noted that adalimumab was extendedly dominated by a combination of etanercept and palliative care (that is, additional QALYs could be generated with etanercept relative to adalimumab at a lower cost per QALY gained than the ICER of adalimumab relative to palliative care), and had therefore been excluded from the incremental analysis. However, the Committee noted that the estimate of relative effectiveness was based on indirect comparison only and noted the comments of the clinical experts that the TNF inhibitors were used interchangeably in clinical practice. The Committee therefore concluded that treatment should be initiated with the least expensive drug.\n\nThe Committee considered the results of the univariate sensitivity analysis performed by the Assessment Group. The Committee noted that the model was most sensitive to assumptions around the cost of treating uncontrolled skin disease associated with psoriatic arthritis, differences in the relative improvements measured by HAQ score and the cost of infliximab (depending on the average number of vials required to treat people with psoriatic arthritis). The Committee took account of evidence from consultees that vial sharing arrangements for infliximab are available in some clinical settings and may reduce drug wastage by up to 50%. The Committee considered various ways of incorporating vial sharing but concluded that there were insufficient data to incorporate it into the economic model. The Committee accepted the clinical specialists' view that there was no robust evidence that etanercept, infliximab and adalimumab differ in their effectiveness for the treatment of psoriatic arthritis in clinical practice and agreed that the sensitivity analyses performed by the Assessment Group were comprehensive and robust. It noted that the calculated cost-effectiveness ratios of the TNF inhibitors varied depending on the assumptions used. The Committee concluded that, given the lack of conclusive evidence of difference between the TNF inhibitors, treatment choice should be based on cost, taking into account any local discounting agreements and/or vial-sharing arrangements.\n\nThe Committee considered the evidence for adalimumab, etanercept and infliximab in the context of clinical practice. The Committee considered that the criteria for recommending etanercept and infliximab (in NICE technology appraisal guidance 104) and adalimumab (in NICE technology appraisal guidance 125) remained valid. The Committee therefore concluded that etanercept, infliximab and adalimumab should be recommended for people with active and progressive psoriatic arthritis when the person has peripheral arthritis with three or more tender joints and three or more swollen joints and whose psoriatic arthritis has not responded to adequate trials of at least two standard DMARDs, administered either individually or in combination.\n\nThe Committee considered the recommendations on discontinuing treatment with etanercept and infliximab (in NICE technology appraisal 104) and with adalimumab (in NICE technology appraisal 125). The Committee considered that the recommendations to discontinue treatment based on an inadequate PsARC response at 12 weeks remained valid. The Committee noted that in the Assessment Group scenario analysis, the TNF inhibitors might be equally cost effective in people whose skin disease has a PASI 75 response but whose psoriatic arthritis does not have a PsARC response. The Committee noted that the trial evidence was less robust for PASI response because the degree of skin disease at randomisation was not consistent across the trials. The Committee was aware that previous NICE guidance had recommended the TNF inhibitors for people with severe or very severe plaque psoriasis (see 'Etanercept and efalizumab for the treatment of adults with psoriasis' [NICE technology appraisal guidance 103], 'Infliximab for the treatment of adults with psoriasis' [NICE technology appraisal guidance 134] and 'Adalimumab for the treatment of adults with psoriasis' [NICE technology appraisal guidance 146] for guidance on the use of tumour necrosis factor [TNF] inhibitors in psoriasis). It concluded that people whose skin disease achieves a PASI 75 response but whose psoriatic arthritis does not achieve an adequate PsARC response should be assessed by a dermatologist to determine whether the criteria for continued treatment with etanercept, adalimumab or infliximab are met for the treatment of the psoriatic component of the condition alone. The Committee also noted the comments from clinical specialists about the benefits of having combined input from rheumatologists and dermatologists in managing this multisystem disease.\n\nThe Committee considered the evidence presented by the Assessment Group on the cost effectiveness for the sequencing of TNF inhibitor treatments. The Committee heard from the clinical experts that very limited data were available for the response rate for second-line treatment with TNF inhibitors. These were derived either from trials for people with rheumatoid arthritis or from registry data, which were uncontrolled and comprised predominantly people with rheumatoid arthritis. The Committee concluded that there were insufficient data to make a recommendation on the sequential use of TNF inhibitors in psoriatic arthritis.\n\nThe Committee was aware of registries that collect data for the long-term outcomes of treatment with TNF inhibitors for rheumatoid arthritis and psoriasis. The Committee noted the importance of registries in collecting data and supported including outcomes specific to psoriatic arthritis in a suitable registry so that specific information about these treatments in psoriatic arthritis can be captured.\n\nIn summary, the Committee considered the clinical and cost effectiveness of etanercept, infliximab and adalimumab in the light of clinical specialists' and patient experts' comments. It considered that there was insufficient evidence of superiority of any one agent over the others. On balance, considering the RCT data, modelling assumptions, modelling results and sensitivity analyses, together with expert opinion, the Committee concluded that etanercept, infliximab and adalimumab were similarly effective. The Committee considered the higher treatment cost with infliximab compared with adalimumab and etanercept in the base-case model and the possibility of locally arranged discounts for infliximab. The Committee therefore concluded that etanercept, infliximab and adalimumab should be recommended as treatment options for people with psoriatic arthritis with three or more affected joints whose disease had inadequately responded to at least two conventional DMARDs and that the choice of treatment should be based on cost, taking into account acquisition and administration costs and any local discounting agreements and/or vial-sharing arrangements.\n\n# Summary of the Appraisal Committee's key conclusions\n\nTA 199 (MTA): Etanercept, infliximab and adalimumab for the treatment of psoriatic arthritis (review of technology appraisal guidance 104 and 125)\n\nFAD section\n\nKey conclusion\n\n\n\nEtanercept, infliximab and adalimumab are recommended for the treatment of adults with active and progressive psoriatic arthritis in specific circumstances (see section 1.1) and treatment should normally be started with the least expensive drug (taking into account drug administration costs, required dose and product price per dose).\n\nTreatment should be discontinued in people whose psoriatic arthritis has not shown an adequate response using the Psoriatic Arthritis Response Criteria (PsARC) at 12 weeks. People whose disease has a Psoriasis Area and Severity Index (PASI) 75 response at 12 weeks but whose PsARC response does not justify continuation of treatment should be assessed by a dermatologist to determine whether continuing treatment is appropriate on the basis of skin response (see 'Etanercept and efalizumab for the treatment of adults with psoriasis' [NICE technology appraisal guidance 103], 'Infliximab for the treatment of adults with psoriasis' [NICE technology appraisal guidance 134] and 'Adalimumab for the treatment of adults with psoriasis' [NICE technology appraisal guidance 146] for guidance on the use of tumour necrosis factor [TNF] inhibitors in psoriasis).\n\n\n\nCurrent practice\n\nClinical need of patients including the availability of alternative treatments\n\nPsoriatic arthritis can affect people's ability to work and carry out daily activities, which can have a substantial impact on quality of life. People with psoriatic arthritis have a 60% higher risk of mortality than the general population and their life expectancy is estimated to be approximately 3 years shorter.\n\n\n\n\n\n\n\nThe aim of psoriatic arthritis treatment is to relieve symptoms, slow disease progression and maintain quality of life. Non-steroidal anti-inflammatory drugs (NSAIDs) and local corticosteroid injections are widely used. Disease that is unresponsive to NSAIDs, in particular polyarticular disease, is treated with disease modifying antirheumatic drugs (DMARDs) to reduce joint damage and prevent disability.\n\n\n\nThe technology\n\nProposed benefits of the technology\n\nHow innovative is the technology in its potential to make a significant and substantial impact on health-related benefits and how it might improve the way that current need is met (is this a 'step-change' in the management of the condition?)\n\nThe Committee heard from a patient expert that tumour necrosis factor (TNF) inhibitors are effective and valued options for the treatment of psoriatic arthritis and have an appreciable impact on quality of life.\n\n\n\nWhat is the position of the treatment in the pathway of care for the condition?\n\nThe Committee considered that the criteria for recommending etanercept and infliximab (in NICE technology appraisal guidance 104) and adalimumab (in NICE technology appraisal guidance 125) remained valid.\n\n\n\nAdverse effects\n\nThe Committee considered the tolerability profile of the three TNF inhibitors to be comparable.\n\n\n\nEvidence for clinical effectiveness\n\nAvailability, nature and quality of evidence\n\nThere were no head-to-head randomised controlled trials (RCTs) comparing the TNF inhibitors and so indirect methods of comparison had to be used. RCTs were powered primarily to detect statistically significant differences in the effectiveness of TNF inhibitors compared with placebo on joint disease and only secondarily on any associated skin disease.\n\nThe Committee considered the evidence to be sufficient to appraise the clinical effectiveness of TNF inhibitors.\n\n\n\nRelevance to general clinical practice in the NHS\n\nThe Committee considered the evidence for adalimumab, etanercept and infliximab in the context of NICE technology appraisal guidance 104 and 125.\n\n\n\nUncertainties generated by the evidence\n\nThe Committee concluded that there was not enough evidence to indicate clinically important differences in the effectiveness of individual TNF inhibitors in the treatment of psoriatic arthritis.\n\n\n\nAre there any clinically relevant subgroups for which there is evidence of differential effectiveness\n\nThe Committee considered the subgroup of people whose skin disease has a PASI 75 response at 12 weeks but whose psoriatic arthritis does not have an adequate PsARC response, indicating treatment should be discontinued. The Committee was aware that previous NICE guidance had recommended the TNF inhibitors for people with severe or very severe plaque psoriasis (see 'Etanercept and efalizumab for the treatment of adults with psoriasis' [NICE technology appraisal guidance 103], 'Infliximab for the treatment of adults with psoriasis' [NICE technology appraisal guidance 134] and 'Adalimumab for the treatment of adults with psoriasis' [NICE technology appraisal guidance 146] for guidance on the use of tumour necrosis factor [TNF] inhibitors in psoriasis). The Committee considered that these people should be referred to a dermatologist to determine whether the criteria for continued treatment with etanercept, adalimumab or infliximab are met for the treatment of the psoriatic component of the condition alone.\n\n\n\nEstimate of the size of the clinical effectiveness including strength of supporting evidence\n\nThe Committee accepted the clinical specialists' view that there was no robust evidence that etanercept, infliximab and adalimumab differ in their effectiveness for the treatment of psoriatic arthritis in clinical practice.\n\n\n\nEvidence for cost effectiveness\n\nAvailability and nature of evidence\n\nThe Committee noted that the Assessment Group updated the economic model submitted for 'Etanercept and infliximab for the treatment of psoriatic arthritis' (NICE technology appraisal 104) by including the effectiveness of the TNF inhibitors treatment on the skin disease as well as the joint disease.\n\n\n\nUncertainties around and plausibility of assumptions and inputs in the economic model\n\nThe Committee noted that the model was most sensitive to assumptions around the cost of treating uncontrolled psoriasis, differences in the relative HAQ score and the cost of infliximab (depending on the average number of vials required to treat people with psoriatic arthritis).\n\n\n\nIncorporation of health-related quality of life benefits and utility values\n\nHave any potential significant and substantial health-related benefits been identified that were not included in the quality-adjusted life year (QALY) calculation? How have these been separately evaluated and what is the impact (if any) on the judgement of the most plausible incremental cost-effectiveness ratio) ICER?\n\nThe utility was driven by the patients' joint disease response (the Health Assessment Questionnaire [HAQ] response) rather than the skin response (PASI).\n\nThe Committee considered that the model (updated from NICE technology appraisal 104) took into account the beneficial effects of TNF inhibitors on the skin disease as well as the joint disease.\n\nThe Committee accepted that the Assessment Group's approach represented the best means of estimating utility for the purposes of the economic analysis given the available data.\n\n\n\n\n\nAre there specific groups of people for whom the technology is particularly cost effective?\n\nThe Committee considered a subgroup of people whose disease achieved a response to PASI but not PsARC. They considered that they should be referred to a dermatologist to determine whether continued treatment is indicated for the symptoms of psoriasis alone.\n\n\n\nWhat are the key drivers of cost effectiveness?\n\nThe relative effectiveness of the TNF inhibitors on skin disease and vial sharing arrangements for infliximab.\n\n\n\nMost likely cost-effectiveness estimate (given as an ICER)\n\nThe Assessment Group base-case analysis found that infliximab was the most effective treatment with an ICER of £44,000 per QALY gained compared with etanercept, while etanercept had an ICER of £18,000 per QALY gained compared with palliative care. The Committee noted that adalimumab was extendedly dominated by a combination of etanercept and palliative care (that is, additional QALYs could be generated with etanercept relative to adalimumab at a lower cost per QALY gained than the ICER of adalimumab relative to palliative care), and had therefore been excluded from the incremental analysis.\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\nThe Committee took account of evidence from consultees that vial sharing arrangements for infliximab are available in some clinical settings and may reduce drug wastage by up to 50%. The Committee concluded that, given the lack of conclusive evidence of difference between the TNF inhibitors, treatment choice should be based on cost, taking into account any local discounting agreements and/or vial-sharing arrangements.\n\n\n\nAdditional factors taken into account\n\nPatient access schemes (Pharmaceutical Price Regulation Programme)\n\nNo patient access scheme was submitted for any of the technologies under appraisal.\n\n\n\nEnd-of-life considerations\n\nThe end-of-life criteria were not applicable for this population.\n\n\n\nEqualities considerations, Social Value Judgement\n\nNo equalities issues were raised.\n\n", 'Recommendations for further research ': 'The Committee highlighted the importance of collecting further data within registries of patients receiving biological treatments for psoriatic arthritis to obtain information on long-term outcomes including adverse events.', 'Review of guidance': 'The guidance on this technology will be considered for review in June 2013. The Guidance Executive will decide whether the technology should be reviewed based on information gathered by NICE, and in consultation with consultees and commentators.\n\nAndrew DillonChief ExecutiveAugust 2010', 'Changes after publication': 'February 2014: minor maintenance\n\nMarch 2012:\n minor maintenance', 'About this guidance': "NICE technology appraisal guidance is about the use of new and existing medicines and treatments in the NHS in England and Wales.\n\nThis guidance was developed using the NICE multiple technology appraisal process.\n\nIt replaces NICE technology appraisal guidance 104 issued in July 2006 and NICE technology appraisal guidance 125 issued in August 2007.\n\nNICE reviews each piece of guidance it issues. This review and re-appraisal has resulted in an extension to the guidance:\n\nEtanercept, infliximab and adalimumab are all recommended for the treatment of active and progressive psoriatic arthritis, based on specific criteria. Treatment choice should be started with the least expensive drug (taking into account drug administration costs, required dose and product price per dose).\n\nThe guidance recommends that treatment should be discontinued if people's disease does not show an adequate response on the Psoriatic Arthritis Response Criteria (PsARC) at 12 weeks. Healthcare professionals should also consider continuing treatment if people's skin disease has a Psoriasis Area and Severity Index (PASI) 75 response at 12 weeks in the absence of an adequate PsARC response. This assessment should be done by a dermatologist to determine whether continued treatment is appropriate on the basis of the skin response alone.\n\nWe have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available.\n\nYour responsibility\n\nThis guidance represents the views of NICE and was arrived at after careful consideration of the evidence available. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. However, the guidance does not override the individual responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.\n\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.\n\nCopyright\n\n© National Institute for Health and Clinical Excellence 2010. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE."}	https://www.nice.org.uk/guidance/ta199	Evidence-based recommendations on etanercept (Enbrel), infliximab (Remicade) and adalimumab (Humira) for treating active and progressive psoriatic arthritis in adults.
69259dde0f58963295ea4e73a7e09bac1bfee0ad	nice	Weight management before, during and after pregnancy	Weight management before, during and after pregnancy This guideline covers how to assess and monitor body weight and how to prevent someone from becoming overweight or obese before, during and after pregnancy. The aim is to help all women who have a baby to achieve and maintain a healthy weight by adopting a balanced diet and being physically active. # Introduction The Department of Health (DH) asked the National Institute for Health and Clinical Excellence (NICE) to produce public health guidance on dietary and physical activity interventions for weight management before, during and after pregnancy. The guidance does not cover: women who are underweight (that is, those who have a body mass index less than 18.5 kg/m²) clinical management of women who are obese during pregnancy those who have been diagnosed with, or who are receiving treatment for, an existing condition such as type 1 or type 2 diabetes food safety advice. The guidance is for NHS and other commissioners, managers and professionals who have a direct or indirect role in, and responsibility for, women who are pregnant or who are planning a pregnancy and mothers who have had a baby in the last 2 years. This includes those working in local authorities, education and the wider public, private, voluntary and community sectors. It is particularly aimed at: GPs, obstetricians, midwives, health visitors, dietitians, community pharmacists and all those working in antenatal and postnatal services and children's centres. It may also be of interest to women before, during and after pregnancy and their partners and families, and other members of the public. The guidance complements but does not replace NICE guidance on: obesity, maternal and child nutrition, antenatal care, postnatal care, physical activity, behaviour change, antenatal and postnatal mental health and diabetes in pregnancy. The Public Health Interventions Advisory Committee (PHIAC) developed these recommendations on the basis of a review of the evidence, economic modelling, expert advice, stakeholder comments and fieldwork. Members of PHIAC are listed in appendix A. The methods used to develop the guidance are summarised in appendix B. Supporting documents used to prepare this document are listed in appendix E. Full details of the evidence collated, including fieldwork data and activities and stakeholder comments, along with a list of the stakeholders involved and NICE's supporting process and methods manuals are also available are also available.# Recommendations People have the right to be involved in discussions and make informed decisions about their care, as described in making decisions about your care. Making decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding. # Weight management definition In this guidance the term 'weight management' includes: assessing and monitoring body weight preventing someone from becoming overweight (body mass index 25–29.9 kg/m²) or obese (BMI greater than or equal to 30 kg/m²) helping someone to achieve and maintain a healthy weight before, during and after pregnancy by eating healthily and being physically active and gradually losing weight after pregnancy. The recommendations are based on strategies and weight-loss programmes that are proven to be effective for the whole population. The criteria for effective programmes are listed below. Programmes that do not meet these criteria are unlikely to help women to maintain a healthy weight in the long term. # Achieving and maintaining a healthy weight Women will be more likely to achieve and maintain a healthy weight before, during and after pregnancy if they: base meals on starchy foods such as potatoes, bread, rice and pasta, choosing wholegrain where possible eat fibre-rich foods such as oats, beans, peas, lentils, grains, seeds, fruit and vegetables, as well as wholegrain bread and brown rice and pasta eat at least five portions of a variety of fruit and vegetables each day, in place of foods higher in fat and calories eat a low-fat diet and avoid increasing their fat and/or calorie intake eat as little as possible of fried food; drinks and confectionery high in added sugars (such as cakes, pastries and fizzy drinks); and other food high in fat and sugar (such as some take-away and fast foods) eat breakfast watch the portion size of meals and snacks, and how often they are eating make activities such as walking, cycling, swimming, aerobics and gardening part of everyday life and build activity into daily life – for example, by taking the stairs instead of the lift or taking a walk at lunchtime minimise sedentary activities, such as sitting for long periods watching television, at a computer or playing video games walk, cycle or use another mode of transport involving physical activity. Effective weight-loss programmes: address the reasons why someone might find it difficult to lose weight are tailored to individual needs and choices are sensitive to the person's weight concerns are based on a balanced, healthy diet encourage regular physical activity expect people to lose no more than 0.5–1 kg (1–2 lb) a week identify and address barriers to change. Weight loss programmes are not recommended during pregnancy as they may harm the health of the unborn child, see recommendation 2. Reputable sources of information and advice about diet and physical activity for women before, during and after pregnancy include: The Department of Health's 'The pregnancy book' and 'Birth to five' and the NHS eat well website. # Changing behaviour Evidence-based behaviour change advice includes: understanding the short, medium and longer-term consequences of women's health-related behaviour helping women to feel positive about the benefits of health-enhancing behaviours and changing their behaviours recognising how women's social contexts and relationships may affect their behaviour helping plan women's changes in terms of easy steps over time identifying and planning situations that might undermine the changes women are trying to make and plan explicit 'if–then' coping strategies to prevent relapse. # Recommendation 1 Preparing for pregnancy: women with a BMI of 30 or more ## Whose health will benefit? Women with a BMI of 30 or more who may become pregnant, including those who have previously been pregnant. ## Who should take action? NHS and other commissioners and managers. GPs, health visitors, midwives, practice nurses, pharmacists and other health professionals working in weight management, fertility, pre-conception advice and care services, gynaecology and contraceptive services. Managers and health professionals in children's centres. Directors of public health, planners and organisers of public health campaigns and occupational health advisers. Dietitians and public health nutritionists working in NHS and non-NHS settings. ## What action should they take? NHS and other commissioners and managers, directors of public health and planners and organisers of public health campaigns should ensure health professionals understand the importance of achieving a healthy weight before pregnancy. Local education initiatives should also stress the health risks of being obese, including during pregnancy. Health professionals should use any opportunity, as appropriate, to provide women with a BMI of 30 or more with information about the health benefits of losing weight before becoming pregnant (for themselves and the baby they may conceive). This should include information on the increased health risks their weight poses to themselves and would pose to their unborn child. GPs, dietitians and other appropriately trained health professionals should advise, encourage and help women with a BMI of 30 or more to reduce weight before becoming pregnant. They should explain that losing 5 to 10% of their weight (a realistic target) would have significant health benefits and could increase their chances of becoming pregnant. Further weight loss, to achieve a BMI within the healthy range (between 24.9 and 18.5 kg/m2) should also be encouraged, using evidence-based behaviour change techniques. Losing weight to within this range may be difficult and women will need to be motivated and supported. Health professionals should encourage women to check their weight and waist measurement periodically or, as a simple alternative, check the fit of their clothes. Health professionals should offer a weight-loss support programme involving diet and physical activity. The programme should follow the principles of good practice, as outlined at the beginning of this section. Health professionals should offer specific dietary advice in preparation for pregnancy, including the need to take daily folic acid supplements. This includes professionals working in pre-conception clinics, fertility clinics, sexual and reproductive health services and children's centres. # Recommendation 2 Pregnant women ## Context If a pregnant woman is obese this will have a greater influence on her health and the health of her unborn child than the amount of weight she may gain during pregnancy. That is why it is important, when necessary, to help women lose weight before they become pregnant. Dieting during pregnancy is not recommended as it may harm the health of the unborn child. Many pregnant women ask health professionals for advice on what constitutes appropriate weight gain during pregnancy. However, there are no evidence-based UK guidelines on recommended weight-gain ranges during pregnancy. The amount of weight a woman may gain in pregnancy can vary a great deal. Only some of it is due to increased body fat – the unborn child, placenta, amniotic fluid and increases in maternal blood and fluid volume all contribute. ## Whose health will benefit? All pregnant women but, in particular, those with a BMI of 30 or more. ## Who should take action? Obstetricians, midwives, GPs and practice nurses. Dietitians and public health nutritionists. Managers and health professionals in children's centres. Midwifery assistants, support workers and other healthcare practitioners. ## What action should they take? At the earliest opportunity, for example, during a pregnant woman's first visit to a health professional, discuss her eating habits and how physically active she is. Find out if she has any concerns about diet and the amount of physical activity she does and try to address them. Advise that a healthy diet and being physically active will benefit both the woman and her unborn child during pregnancy and will also help her to achieve a healthy weight after giving birth. Advise her to seek information and advice on diet and activity from a reputable source. Offer practical and tailored information. This includes advice on how to use Healthy Start vouchers to increase the fruit and vegetable intake of those eligible for the Healthy Start scheme (women under 18 years and those who are receiving benefit payments). Dispel any myths about what and how much to eat during pregnancy. For example, advise that there is no need to 'eat for two' or to drink full-fat milk. Explain that energy needs do not change in the first 6 months of pregnancy and increase only slightly in the last 3 months (and then only by around 200 calories per day). Advise that moderate-intensity physical activity will not harm her or her unborn child. Give specific and practical advice about being physically active during pregnancy. Advise women how to exercise safely following national guidelines on physical activity during pregnancy and during postpartum (see the UK Chief Medical Officers' physical activity guidelines for more information). Explain to those women who would find this level of physical activity difficult that it is important not to be sedentary, as far as possible. Encourage them to start walking and to build physical activity into daily life, for example, by taking the stairs instead of the lift, rather than sitting for long periods. Measure weight and height at the first contact with the pregnant woman, being sensitive to any concerns she may have about her weight. If these data are not available at their first booking appointment, then the midwife should do this. Do not rely on self-reported measures of weight and height. Clearly explain why this information is needed and how it will be used to plan her care. Weigh her in light clothing using appropriate, calibrated weighing scales that are regularly checked. Calculate BMI by dividing weight (kg) by the square of height (m2), or use the NHS BMI calculator after measuring and weighing. Use BMI percentile charts for pregnant women under 18 years, as a BMI measure alone does not take growth into account and is inappropriate for this age group. Weight, height and BMI should be recorded in notes, the woman's hand-held record and the patient information system. If a hand-held record is not available, use local protocols to record this information. Do not weigh women repeatedly during pregnancy as a matter of routine. Only weigh again if clinical management can be influenced or if nutrition is a concern. Explain to women with a BMI of 30 or more at the booking appointment how this poses a risk, both to their health and the health of the unborn child. Explain that they should not try to reduce this risk by dieting while pregnant and that the risk will be managed by the health professionals caring for them during their pregnancy. Offer women with a BMI of 30 or more at the booking appointment a referral to a dietitian or appropriately trained health professional for assessment and personalised advice on healthy eating and how to be physically active. Encourage them to lose weight after pregnancy. # Recommendation 3 Supporting women after childbirth ## Whose health will benefit? Women who have had a baby in recent months. ## Who should take action? GPs, health visitors, midwives, practice nurses, pharmacists and other health professionals working in weight management. Managers and health professionals in children's centres. Dietitians and public health nutritionists working in NHS and non-NHS settings. ## What action should they take? Use the 6–8-week postnatal check as an opportunity to discuss the woman's weight. Ask those who are overweight, obese or who have concerns about their weight if they would like any further advice and support now – or later. If they say they would like help later, they should be asked whether they would like to make an appointment within the next 6 months for advice and support. During the 6 to 8-week postnatal check, or during the follow-up appointment within the next 6 months, provide clear, tailored, consistent, up-to-date and timely advice about how to lose weight safely after childbirth. Ensure women have a realistic expectation of the time it will take to lose weight gained during pregnancy. Discuss the benefits of a healthy diet and regular physical activity, acknowledging the woman's role within the family and how she can be supported by her partner and wider family. Advice on healthy eating and physical activity should be tailored to her circumstances. For example, it should take into account the demands of caring for a baby and any other children, how tired she is and any health problems she may have (such as pelvic floor muscle weakness or backache). Health professionals should advise women, their partners and family to seek information and advice from a reputable source. Women who want support to lose weight should be given details of appropriate community-based services. Midwives and other health professionals should encourage women to breastfeed. They should reassure them that a healthy diet and regular, moderate-intensity physical activity and gradual weight loss will not adversely affect the ability to breastfeed or the quantity or quality of breast milk. Health professionals should give advice on recreational exercise from the Royal College of Obstetrics and Gynaecology. In summary, this states that: If pregnancy and delivery are uncomplicated, a mild exercise programme consisting of walking, pelvic floor exercises and stretching may begin immediately. But women should not resume high-impact activity too soon after giving birth. After complicated deliveries, or lower segment caesareans, a medical care-giver should be consulted before resuming pre-pregnancy levels of physical activity, usually after the first check-up at 6 to 8 weeks after giving birth. Health professionals should also emphasise the importance of participating in physical activities, such as walking, which can be built into daily life. # Recommendation 4 Women with a BMI of 30 or more after childbirth ## Whose health will benefit? Women who had a pre-pregnancy BMI of 30 or more. Women with a BMI of 30 or more who have had a baby within recent months. ## Who should take action? GPs, health visitors, practice nurses, pharmacists and other health professionals working in weight management. Managers and health professionals in children's centres. Dietitians and public health nutritionists working in NHS and non-NHS settings. ## What action should they take? Explain the increased risks that being obese poses to them and, if they become pregnant again, their unborn child. Encourage them to lose weight. Offer a structured weight-loss programme. If more appropriate, offer a referral to a dietitian or an appropriately trained health professional. They will provide a personalised assessment, advice about diet and physical activity and advice on behaviour change strategies such as goal setting. Women who are not yet ready to lose weight should be provided with information about where they can get support when they are ready. Use evidence-based behaviour change techniques to motivate and support women to lose weight. Encourage breastfeeding and advise women that losing weight by eating healthily and taking regular exercise will not affect the quantity or quality of their milk. # Recommendation 5 Community-based services ## Whose health will benefit? All women before, during and after pregnancy. ## Who should take action? NHS and other commissioners and managers. Managers of local authority leisure and community services including swimming pools and parks. Managers and health professionals in slimming and weight management clubs. Managers and health professionals in children's centres. NHS health trainers and health and fitness advisers working in local authority leisure services and voluntary, community and commercial organisations. ## What action should they take? Local authority leisure and community services should offer women with babies and children the opportunity to take part in a range of physical or recreational activities. This could include swimming, organised walks, cycling or dancing. Activities need to be affordable and available at times that are suitable for women with older children as well as those with babies. Where possible, affordable childcare (for example, a creche) should be provided and provision made for women who wish to breastfeed. NHS and other commissioners and managers, local authority leisure services and slimming clubs should work together to offer women who wish to lose weight after childbirth the opportunity to join a weight management group or slimming club. Health professionals should continue to monitor, support and care for women with a BMI of 30 or more who join weight management groups and slimming clubs. Weight management groups and slimming clubs should adhere to the principles outlined at the beginning of this section. This includes giving advice about healthy eating and the importance of physical activity and using evidence-based behaviour-change techniques to motivate and support women to lose weight. NHS health trainers and non-NHS health and fitness advisers should advise women that a healthy diet and being physically active will benefit both them and their unborn child during pregnancy. They should also explain that it will help them to achieve a healthy weight after giving birth – and could encourage the whole family to eat healthily and be physically active. NHS health trainers and non-NHS health and fitness advisers should encourage those who have weight concerns before, during or after pregnancy to talk to a health professional such as a GP, practice nurse, dietitian, health visitor or pharmacist. They should also advise women, their partners and family to seek information and advice on healthy eating and physical activity from a reputable source. NHS health trainers and non-NHS health and fitness advisers should offer specific dietary advice in preparation for pregnancy, including the need to take daily folic acid supplements. # Recommendation 6 Professional skills ## Whose health will benefit? All women before, during and after pregnancy, particularly those with a BMI of 30 or more. ## Who should take action? Professional bodies and others responsible for setting competencies and developing continuing professional development programmes for health professionals, healthcare assistants and support staff. Training boards and organisations responsible for training health and fitness advisers and NHS health trainers. ## What action should they take? Ensure health professionals, healthcare assistants and support workers have the skills to advise on the health benefits of weight management and risks of being overweight or obese before, during and after pregnancy, or after successive pregnancies. Ensure they can advise women on their nutritional needs before, during and after pregnancy and can explain why it is important to have a balanced diet and to be moderately physically active. Ensure they have behaviour change knowledge, skills and competencies. This includes being able to help people to identify how their behaviour is affecting their health, draw up an action plan, make the changes and maintain them. Ensure they have the communication techniques needed to broach the subject of weight management in a sensitive manner. They should be able to give women practical advice on how to improve their diet and become more physically active. They should be able to tailor this advice to individual needs and know when to refer them for specialist care and support. Ensure they have the knowledge and skills to help dispel common myths. This includes myths about what to eat and what not to eat during pregnancy and about weight loss in relation to breastfeeding. Ensure they have knowledge, skills and competencies in group facilitation, are aware of the needs of minority ethnic groups and have knowledge of local services. Ensure their training is regularly monitored and updated.# Public health need and practice About half of women of childbearing age are either overweight (BMI 25 to 29.9 kg/m²) or obese (BMI greater than or equal to 30 kg/m²) (The NHS Information Centre 2008). At the start of pregnancy, 15.6% of women in England are obese (Heslehurst et al. 2010). Maternal obesity and weight retention after birth are related to socioeconomic deprivation (Heslehurst et al. 2010). # Health risks for obese women and their babies Women who are obese when they become pregnant face an increased risk of complications during pregnancy and childbirth. These include the risk of impaired glucose tolerance and gestational diabetes, miscarriage, pre-eclampsia, thromboembolism and maternal death (Centre for Maternal and Child Enquiries and the Royal College of Obstetricians and Gynaecologists 2010). Even a relatively small gain of 1 to 2 BMI units (kg/m2) between pregnancies may increase the risk of gestational hypertension and gestational diabetes, even in women who are not overweight or obese. It also increases the likelihood of giving birth to a large baby (Villamor and Cnattingius 2006). An obese woman is more likely to have an induced or longer labour, instrumental delivery, caesarean section or postpartum haemorrhage (Yu et al. 2006). Reduced mobility during labour can result in the need for more pain relief, which can be difficult to administer in obese women, resulting in increased need for general anaesthesia with its associated risks. After birth, wound healing can be slower with an increased risk of infection, and obese women are more likely to require extra support in establishing breastfeeding, due to, for example, difficulties in latching the baby on to the breast (Heslehurst et al. 2007). Obese women may also experience reduced choices about where and how they give birth. There may be restrictions on home births, the use of birthing pools and types of pain relief that can be given. Obese women who are pregnant are likely to spend longer in hospital than those with a healthy weight because of morbidity during pregnancy and labour related to their weight (Chu et al. 2008). In the longer term, weight control after pregnancy may reduce the woman's risk of obesity, coronary heart disease, some cancers and type 2 diabetes. Babies born to obese women also face several health risks. These include a higher risk of fetal death, stillbirth, congenital abnormality, shoulder dystocia, macrosomia and subsequent obesity (Ramachenderan et al. 2008). # Weight gain during pregnancy US Institute of Medicine guidelines (Rasmussen and Yaktine 2009), based on observational data, state that healthy American women who are a normal weight for their height (BMI 18.5 to 24.9) should gain 11.5 to 16 kg (25 to 35 pounds) during pregnancy. Overweight women (BMI 25 to 29.9) should gain 7 to 11.5 kg (15 to 25 pounds) and obese women (BMI greater than 30) should only put on 5 to 9 kg (11 to 20 pounds). Observational studies of American women suggest that those who gain weight within the Institute of Medicine ranges are more likely to have better maternal and infant outcomes than those who gain more or less weight. (The evidence is stronger for some outcomes – such as postpartum weight retention and birthweight – than for others ). There are no formal, evidence-based guidelines from the UK government or professional bodies on what constitutes appropriate weight gain during pregnancy. The Committee on Medical Aspects of Food Policy report on dietary reference values recommends that women should only have around 200 calories more a day in the last trimester of pregnancy (DH 1991). UK health professionals do not, as a matter of course, give women information about the risks of obesity and the importance of weight management before or during pregnancy (Heslehurst et al. 2007a). Pregnant women are advised not to diet, and to talk to their GP or midwife if they are concerned about their weight (Department of Health 2009). # Weight management after pregnancy NICE's guideline on obesity identified the period after pregnancy and childbirth as a time when women are likely to gain weight. In addition, many conceive again during this period. Hence, managing the woman's weight in the first few years after childbirth may reduce her risk of entering the next pregnancy overweight or obese. However, after having a child, many mothers find it difficult to eat a healthy diet and take regular exercise (Hewison and Dowswell 1994). It may be because women receive little or no advice on weight management after childbirth. Women who exclusively breastfeed their infants for the first 6 months may require around an additional 330 calories a day. Some of these additional calories will be derived from fat stores. An additional 400 calories a day may be required for the second 6 months if they continue to breastfeed (DH 1991). Breastfeeding is often recommended as a strategy for promoting weight loss, but findings from studies are mixed (Gore et al. 2003). The additional energy requirements of breastfeeding may help some women return to their pre-pregnancy weight. If women are moderately active on a regular basis, this will not adversely affect a woman's ability to breastfeed and could aid weight management. The Department of Health (2009) does not make specific recommendations on weight management after childbirth. It advises against following a restricted-calorie diet while breastfeeding and suggests that women should talk to their GP if they feel they need to lose weight. However, there is no national guidance for professionals. Women on low incomes may be eligible for Healthy Start vouchers to buy fruit and vegetables (as well as milk and infant formula). These are available to pregnant women and families with a child aged under 4 years. Those eligible include people on income support and income-based jobseekers allowance and those with low incomes. All pregnant women under 18 years also qualify, whether or not they are on state benefits.# Considerations The Public Health Interventions Advisory Committee (PHIAC) took account of a number of factors and issues when developing the recommendations. PHIAC was keen to adopt a 'life course approach' to this guidance, noting that pregnancy and around a year after childbirth are key points in a woman's life when she may gain excess weight. PHIAC also recognised that weight management can be difficult in the current obesogenic environment. Sedentary habits and a high calorie diet are common and physical activity, such as walking, is not part of daily life. However, the period before, during and after pregnancy does provide an opportunity to give women practical advice to help them to improve their diet, become more physically active or to help them manage their weight effectively. To ensure this opportunity is not missed, the recommendations emphasise the need for practical advice that takes into account the woman's particular social and economic circumstances and involves the whole family. PHIAC recognised that health professionals would welcome UK guidance on weight gain in pregnancy. In the absence of such guidance, PHIAC discussed whether it would be appropriate to support the US Institute of Medicine's guidelines. These guidelines, which were revised in 2009, are based on observational data. The data show that women who gained weight within the specified ranges had better outcomes than those who did not. However, the recommendations were not validated by intervention studies. Without evidence from large-scale trials, it is not clear whether or not adhering to the recommended ranges lowers the risk of adverse outcomes for mothers and their babies. In addition, the guidelines were developed for the US population and it is not known whether or not they would apply to other populations with a different ethnic composition. PHIAC was therefore unable to support their use without more evidence and more information about their applicability to the UK population. This is an important area for future research. PHIAC recognised that not only does weight gain in pregnancy vary between individuals, but that the components involved also vary. Weight gain in pregnancy is made up of the fetus, placenta, amniotic fluid, and increases in maternal blood and fluid volume, as well as an increase in body fat. PHIAC noted the lack of intervention studies on weight management during pregnancy. Those that do exist are pilot studies with small sample sizes and insufficient statistical power to detect differences in health outcomes for mothers and their babies. Several large-scale, randomised controlled trials are underway worldwide, but no conclusions could be drawn from them before publication of this guidance. PHIAC agreed to draw on existing NICE guidance which is based on evidence of effectiveness and cost effectiveness. This includes public health guidance on maternal and child nutrition and behaviour change and clinical guidelines on obesity, antenatal care and postnatal care. PHIAC emphasised the importance of women being a healthy weight before pregnancy. Pre-pregnancy BMI is a greater determinant of healthy outcomes for mothers and babies than any weight they may gain during pregnancy. Women with a high BMI might also find it more difficult to conceive. For many women, the first year or two after birth is a time when they start to think about having another baby. Weight management during this time will help them to achieve a healthy weight when they next become pregnant – and help prevent incremental weight gain over successive pregnancies. The guidance is targeted at women who are actively planning a pregnancy and those who are already pregnant or who have had a baby. It is, however, recognised that a population-based approach is important in reaching all women of childbearing age, as many pregnancies are unplanned. Women receive a wealth of sometimes conflicting advice on what constitutes a healthy diet and how much physical activity they should do during pregnancy and after childbirth. This comes not just from health professionals and official sources but from family, friends, the media and new media (such as social networking sites). For example, the press regularly publishes celebrity claims of unrealistic and rapid weight loss after pregnancy. This may create additional pressure on women to lose weight inappropriately at an already stressful time. Concern about obesity or weight gain in pregnancy might lead some women to try to lose weight. Dieting is not advised during pregnancy because it is not known whether it is safe. Restrictive or 'crash' diets may increase blood ketone levels and could adversely affect the neuro-cognitive development of the fetus. PHIAC was aware that the health risks of being overweight or obese during pregnancy, for both the mother and her unborn child, are not routinely discussed. Health professionals recognise the risks but are often unsure what advice to give. In some cases, they lack the training, skills or confidence to discuss weight management. In addition, they may not know how to tailor advice and support for women who are pregnant. The needs of pregnant teenagers may differ from those of pregnant older women. Their social circumstances may differ, as may the health professionals they come into contact with. For example, they may be cared for by specialist teenage pregnancy midwives and teenage pregnancy support nurses. In addition to supporting the growth of the baby, pregnant teenagers may still be growing themselves. Some population groups, such as Asians, face co-morbidity risk at a lower BMI than other groups. However, there is no consensus on how to define overweight and obesity in different ethnic groups for women of childbearing age. The period following childbirth is a time of great change for women and their partners, as they learn to cope with the demands of a new baby. Lack of sleep and a range of physical and psychological problems, such as backache, urinary and faecal incontinence, depression and fatigue, are common. These problems can be compounded when they are caring for another child (or children) as well. Some health problems may impact on a woman's ability to be physically active and therefore, her ability to manage her weight. The additional energy requirements of breastfeeding may help some women return to their pre-pregnancy weight. Those who are breastfeeding and do not increase their energy intake, eat a healthy diet and are moderately active will be more likely to achieve this. Although it cannot be assumed that all women who breastfeed will lose weight, PHIAC considered it important to encourage exclusive breastfeeding for the first 6 months because of the wider health benefits for both the mother and her baby. PHIAC noted that after childbirth, women may resume smoking and drinking alcohol. These habits may also affect their weight. After the birth of their baby, women may not be in regular contact with health services and may need local, community-based sources of support to help them manage their weight. PHIAC discussed the role of children's centres in working with pregnant women and their families in particular, working with teenage parents and families from low income and black and minority ethnic groups. Children's centre services might include: antenatal education, appropriate maternity services (including early antenatal engagement and postnatal support), breastfeeding promotion and support and advice on how to combat obesity and enjoy a healthy diet. On balance, interventions during pregnancy were considered to be cost effective. However, the estimate of cost effectiveness was subject to considerable uncertainty. Weight management interventions during the 6 months after birth also appeared to be cost effective, but the results were sensitive to assumptions made in the modelling. PHIAC was mindful that most of the recommendations did not increase costs in the long term and, as they could be expected to do more good than harm, they are likely to be cost effective. Furthermore, some of the advice has been adapted from previous NICE guidance which has already been shown to be cost effective.# Recommendations for research The Public Health Interventions Advisory Committee (PHIAC) recommends that the following research questions should be addressed. It notes that 'effectiveness' in this context relates not only to the size of the effect, but also to cost effectiveness and duration of effect in terms of outcomes for both the mother and infant. It also takes into account any harmful/negative side effects. . Are the US Institute of Medicine (2009) guidelines on weight gain in pregnancy appropriate for use with the UK population? Does adherence to these recommendations improve outcomes? Are they effective with women under 18 and those from minority ethnic groups? . What are the most effective and cost-effective ways of helping women to manage their weight before pregnancy? This includes women who are obese, those who are under 18 and those from disadvantaged, low income and minority ethnic groups. . What are the most effective and cost-effective ways of helping women to manage their weight during pregnancy? This includes women who are obese, those who are under 18 and those from disadvantaged, low income and minority ethnic groups. . What are the most effective and cost-effective ways of helping women to manage their weight after childbirth? This includes women who are obese, those who are under 18 and those from disadvantaged, low income and minority ethnic groups. When is the most appropriate time to start managing weight after childbirth? What is the optimal rate of weight loss to ensure long-term success? How does resuming behaviours such as smoking and drinking influence postpartum weight management? . How can breastfeeding help with postpartum weight management, both in terms of energy expenditure and energy balance? More detail on the gaps in the evidence identified during development of this guidance is in appendix D.# References Centre for Maternal and Child Enquires and the Royal College of Obstetricians and Gynaecologists (2010) Joint guideline – Management of women with obesity in pregnancy. London: CMACE/ Centre for Maternal and Child Enquires and the Royal College of Obstetricians and Gynaecologists Chu SY, Bachman DJ, Callaghan WM et al. (2008) Association between obesity during pregnancy and increased use of health care. New England Journal of Medicine 358:1444–53 Department of Health (2009) The pregnancy book. London: Department of Health Department of Health (1991) Dietary reference values for food energy and nutrients for the United Kingdom. Report of the panel on dietary reference values of the Committee on Medical Aspects of Food Policy. London: HMSO Gore SA, Brown DM, Smith D (2003) The role of postpartum weight retention in obesity among women: a review of the evidence. Annals of Behavioral Medicine 26: 149–59 Heslehurst N, Lang R, Rankin J et al. (2007) Obesity in pregnancy: a study of the impact of maternal obesity on NHS maternity services. British Journal of Obstetrics and Gynaecology 114: 334–42 Heslehurst N, Rankin J, Wilkinson JR et al. (2010) A nationally representative study of maternal obesity in England, UK: trends in incidence and demographic inequalities in 619 323 births, 1989–2007. International Journal of Obesity 34: 420–8 Hewison J, Dowswell T (1994) Child health care and the working mother. London: Chapman and Hall Ramachenderan J, Bradford J, McLean M (2008) Maternal obesity and pregnancy complications: a review. Australian and New Zealand Journal of Obstetrics and Gynaecology 48: 228–35 Rasmussen KM, Yaktine AL, editors. Committee to Reexamine Institute of Medicine Pregnancy Weight Guidelines (2009) Weight gain during pregnancy: re-examining the guidelines. Siega-Riz AM, Viswanathan M, Moos MK et al. (2009) A systematic review of outcomes of maternal weight gain according to the Institute of Medicine recommendations: birthweight, fetal growth, and postpartum weight retention. American Journal of Obstetrics and Gynecology 201: 339 e1–14 The NHS Information Centre (2008) Health survey for England 2006: CVD and risk factors adults, obesity and risk factors children. London: The NHS Information Centre Villamor E, Cnattingius S (2006) Interpregnancy weight change and risk of adverse pregnancy outcomes: population based study. Lancet 368: 1164–70 World Cancer Research Fund (2007) Food, nutrition, physical activity and the prevention of cancer: a global perspective. London: World Cancer Research Fund Yu CKU, Teoh TG, Robinson S (2006) Obesity in pregnancy. British Journal of Obstetrics and Gynaecology 113: 1117–25# Appendix B: Summary of the methods used to develop this guidance # Introduction The reviews and economic analyses include full details of the methods used to select the evidence (including search strategies), assess its quality and summarise it. The minutes of the PHIAC meetings provide further detail about the Committee's interpretation of the evidence and development of the recommendations. All supporting documents are listed in appendix E. # Key questions The key questions were established as part of the scope. (Weight management before and during pregnancy and weight management after childbirth were scoped separately, but have now been amalgamated into one piece of guidance.) They formed the starting point for the reviews of evidence and were used by PHIAC to help develop the recommendations. The overarching questions were: What is the effectiveness and cost effectiveness of weight management interventions before and during pregnancy? What are the most effective and cost-effective interventions for managing women's weight after childbirth? The subsidiary questions were: What types of dietary interventions and physical activity interventions are most effective and cost effective for weight management in women planning a pregnancy? Do they have any adverse effects? What are the most effective and cost-effective ways of measuring and monitoring weight gain in pregnancy? Are there any adverse effects? What are the views, perceptions and beliefs of health professionals, women actively planning a pregnancy, pregnant women, their partners and families about diet, physical activity and weight management in pregnancy and before pregnancy? What internal and external factors influence the effectiveness of the intervention (such as content, delivery, setting, who is delivering the intervention, intensity, duration and target setting)? What are the most effective and cost-effective dietary interventions for helping mothers, including breastfeeding mothers, achieve and maintain a healthy weight after childbirth? What are the most effective and cost-effective physical activity interventions for helping mothers, including breastfeeding mothers, achieve and maintain a healthy weight after childbirth? What are the most effective and cost effective interventions for helping mothers to avoid gaining more weight with each successive pregnancy? These questions were made more specific for the reviews (see reviews for further details). # Reviewing the evidence of effectiveness Two reviews of effectiveness were conducted. ## Identifying the evidence The following databases were searched for all types of evidence (from 1990–2008): ASSIA (Applied Social Science Index and Abstracts) British Nursing Index CINAHL (Cumulative Index of Nursing and Allied Health Literature) Cochrane Central Register of Controlled Trials Cochrane Database of Systematic Reviews DARE (Database of Abstracts of Reviews of Effectiveness) Econlit EMBASE HTA (Health Technology Assessment) Maternity and Infant Care MEDLINE NHS EED (NHS Economic Evaluation Database) PyscINFO Science Citation Index Social Science Citation Index A search was also conducted of the following websites: American College of Obstetricians and Gynaecologists British Dietetic Association Chartered Society of Physiotherapy Department of Health Food Standards Agency Institute of Medicine Joseph Rowntree Foundation NHS Evidence – Women's Health NHS Scotland NICE Public health observatories Royal College of Midwives Royal College of Obstetricians and Gynaecologists Scientific Advisory Committee on Nutrition Scottish Intercollegiate Guidelines Network (SIGN) Welsh Assembly Government Further details of the databases, search terms and strategies are included in the reviews. ## Selection criteria Studies were included in effectiveness review one if they involved: pregnant women who were expecting a single baby women seeking preconception advice women who were actively planning a pregnancy women in the above groups who had a history of (or who developed) impaired glucose tolerance or gestational diabetes. Studies were excluded if they: were not published in English were conducted in non-OECD (Organisation for Economic Cooperation and Development) countries involved pregnant women expecting more than one baby involved pregnant women who were underweight (BMI <18.5 kg/m2) involved pregnant women who had been diagnosed with pre-existing diabetes (type 1 and 2). Studies were included in effectiveness review two if they involved women with a BMI greater than 18.5 kg/m² up to 2 years following the birth of their baby. Studies were excluded if they involved: women who had been diagnosed with, or who were receiving clinical treatment for, an existing condition such as type 1 or type 2 diabetes women who had been diagnosed with postnatal depression women who were underweight (BMI <18.5 kg/m²) after childbirth women who had given birth more than 2 years before clinical interventions (such as surgery or drug treatment) or complementary therapies (for example, hypnotherapy or acupuncture) to treat obesity. Studies were also excluded if they were: not published in English conducted in non-OECD (Organisation for Economic Cooperation and Development) countries. ## Quality appraisal Included papers were assessed for methodological rigour and quality using the NICE methodology checklist, as set out in the NICE technical manual 'Methods for the development of NICE public health guidance' (see appendix E). Each study was graded (++, +, –) to reflect the risk of potential bias arising from its design and execution. ++ All or most of the methodology checklist criteria have been fulfilled. Where they have not been fulfilled, the conclusions are thought very unlikely to alter. - Some of the methodology checklist criteria have been fulfilled. Those criteria that have not been fulfilled or not adequately described are thought unlikely to alter the conclusions. – Few or no methodology checklist criteria have been fulfilled. The conclusions of the study are thought likely or very likely to alter. The 'Newcastle Ottawa' scale was used in effectiveness review one to assess the quality of cohort and case–control studies. Included studies were scored as follows to indicate the risk of bias: ++ Very low risk. - Low risk. – High risk. u Unclear. ## Summarising the evidence and making evidence statements The review data was summarised in evidence tables (see full reviews). The findings from the reviews were synthesised and used as the basis for a number of evidence statements relating to each key question. The evidence statements were prepared by the public health collaborating centre (see appendix A). The statements reflect its judgement of the strength (quantity, type and quality) of evidence and its applicability to the populations and settings in the scope. # Cost effectiveness For effectiveness review one, the economic analysis consisted of a cost-effectiveness analysis. For effectiveness review two, the economic analysis consisted of a review of economic evaluations and a cost-effectiveness analysis. ## Economic review For the review of economic evaluations, studies were identified by searching EconLit and NHS EED during August 2009. Targeted searches were also undertaken where additional information was required. Studies were included if they were cost-effectiveness, cost-benefit or cost-minimisation analyses of: dietary or physical activity interventions to help manage the weight of postnatal women any dietary or physical activity intervention following pregnancy that may impact on the woman's weight. Studies were excluded if they: were not published in English involved pharmacological interventions, surgery or complementary therapies. ## Economic modelling Two economic models were constructed to incorporate data from the reviews of effectiveness and cost effectiveness. The results are summarised in appendix C and the detailed reports of the economic models are 'Interventions to manage weight gain in pregnancy' and 'The cost-effectiveness of weight management interventions after childbirth'. # Fieldwork Fieldwork was carried out to evaluate how relevant and useful NICE's recommendations are for practitioners and how feasible it would be to put them into practice. It was conducted with practitioners and commissioners who are involved in antenatal and postnatal care services, fertility services, leisure services, community groups, weight management services and children's centres. They included those working in the NHS, local authorities and organisations in the private, voluntary and community sectors. The fieldwork comprised: Three 1-day workshops carried out in London and Manchester with a total of 66 practitioners. They included commissioners, consultants in public health, food and nutrition advisers, midwives, obstetricians and public health specialists. They discussed all the draft recommendations including the role of leisure services, the voluntary sector and other non NHS organisations. Three focus groups held in Doncaster, Harlow and Leicester with 26 practitioners. They included clinical and public health dietitians, consultant midwives, nurses, obesity coordinators and obstetric registrars. They discussed the recommendations in relation to pregnancy. Four focus groups held in children's centres in Leeds, Liverpool, Newham and Sandwell with 21 practitioners. They included breastfeeding coordinators, children's centre managers, commissioning managers, community dietitians, community nutritionists and health visitors. They discussed the recommendations related to the period following childbirth. Twenty-eight telephone interviews carried out with GPs, practice nurses and managers of children's centres and local authority leisure services. They discussed all the recommendations, particularly those most relevant to those professionals and services. These four approaches were commissioned to ensure there was ample geographical coverage. The main issues arising are set out in appendix C under 'fieldwork findings'. The full fieldwork report is 'Weight management during pregnancy and after childbirth'. # How PHIAC formulated the recommendations At its meetings in November 2009 and December 2009, PHIAC considered the evidence of effectiveness and cost effectiveness to determine: whether there was sufficient evidence (in terms of quantity, quality and applicability) to form a judgment whether, on balance, the evidence demonstrates that the intervention is effective, ineffective or equivocal where there is an effect, the typical size of effect. PHIAC developed draft recommendations through informal consensus, based on the following criteria. Strength (type, quality, quantity and consistency) of the evidence. The applicability of the evidence to the populations/settings referred to in the scope. Effect size and potential impact on the target population's health. Impact on inequalities in health between different groups of the population. Equality and diversity legislation. Ethical issues and social value judgements. Cost effectiveness (for the NHS and other public sector organisations). Balance of harms and benefits. Ease of implementation and any anticipated changes in practice. Where possible, recommendations were linked to evidence statements (see appendix C for details). Where a recommendation was inferred from the evidence, this was indicated by the reference 'IDE' (inference derived from the evidence). The draft guidance, including the recommendations, was released for consultation in February 2010. At its meeting in April 2010, PHIAC amended the guidance in light of comments from stakeholders and experts and the fieldwork. The guidance was signed off by the NICE Guidance Executive in June 2010.# Appendix C: The evidence This appendix lists evidence statements from two reviews provided by a public health collaborating centre (see appendix A) and links them to the relevant recommendations. (See appendix B for the key to quality assessments.) The evidence statements are presented here without references – these can be found in the full review (see appendix E for details). It also sets out a brief summary of findings from the economic analysis. The two reviews of effectiveness are: 'Systematic review of dietary and/or physical activity interventions for weight management in pregnancy'. 'Systematic review of weight management interventions after childbirth'. Evidence statement 1.3 indicates that the linked statement is numbered 3 in review 1. Evidence statement 2.3 indicates that the linked statement is numbered 3 in review 2. The reviews, economic analysis and fieldwork report are available. Where a recommendation is not directly taken from the evidence statements but is inferred from the evidence, this is indicated by IDE (inference derived from the evidence). Recommendation 1: evidence statements 1.19, 1.20, 1.21, 1.22; IDE Recommendation 2: evidence statements 1.1, 1.18, 1.20, 1.21, 1.26; IDE Recommendation 3: evidence statements 1.3, 1.4, 1.7, 1.12, 1.14, 1.15, 1.16, 1.17, 1.19, 1.21, 1.22; IDE Recommendation 4: evidence statements 2.1, 2.3, 2.6, 2.12, 2.13; IDE Recommendation 5: evidence statements 1.1, 1.18, 2.1, 2.3, 2.6, 2.12, 2.13; IDE Recommendation 6: IDE Recommendation 7: evidence statements 1.16, 1.17, 1.19, 1.26; IDE # Evidence statements Please note that the wording of some evidence statements has been altered slightly from those in the evidence reviews to make them more consistent with each other and NICE's standard house style. ## Evidence statement 1.1 There is weak evidence from one Australian-based case series that obese women trying to become pregnant but experiencing infertility can achieve a statistically significant reduction in body mass index (BMI) through a programme that includes regular physical activity, advice about healthy eating and group support. ## Evidence statement 1.3 There is evidence from two USA-based and one Canadian randomised controlled trial (RCT) (one and two ) that interventions targeted at healthy weight or overweight pregnant women, encouraging a healthy diet and increased or regular physical activity, supported by weight monitoring, reduces the proportion of women exceeding Institute of Medicine (1990) guidelines for healthy weight gain in pregnancy. ## Evidence statement 1.4 There is weak evidence from two studies (one and one ), conducted in Denmark and Sweden among obese women that interventions promoting healthy eating and/or moderate physical activity leads to a reduction in weight retained postpartum when compared with controls. ## Evidence statement 1.7 There were no adverse effects reported with moderate physical activity and/or dieting during pregnancy. ## Evidence statement 1.12 There is evidence from one US-based observational study (++) that overweight women who consumed three or more servings of fruit and vegetables per day gained significantly less weight than those who consumed fewer servings during pregnancy. ## Evidence statement 1.14 There is evidence from one US-based observational study (+) that not receiving advice regarding appropriate weight gain was associated with weight gain outside the recommended levels among women across the BMI spectrum. ## Evidence statement 1.15 UK-based qualitative evidence (+) suggests that the development and attendance in dietary interventions for young women may be facilitated by taking into account women's age, social, educational and psychological needs as well as provision of incentives such as free food and access to a midwife. ## Evidence statement 1.16 One UK-based qualitative study (+) retrospectively explored mothers' views on monitoring during their pregnancy/ies. Women reported feeling that interactions with health professionals in relation to routine weighing were not enabling, and that they felt a lack of control. Women tended to be given limited explanation or feedback on weighing practices, although they accepted professional advice and intervention. Routine monitoring of weight may not be acceptable to any women anxious about their weight without their consent, meaningful explanation and feedback. ## Evidence statement 1.17 Health professionals reported (one ) that routine weighing of pregnant women was dependent on the location of the initial booking session. NHS premises tended to have resources for weighing whereas this was more ad-hoc in the community where scales may not be available and community midwives were not supplied with portable equipment. It was reported that even in NHS premises, equipment may not be suitable for weighing obese women. ## Evidence statement 1.18 No UK-based qualitative evidence was identified on the views, perceptions and beliefs of health professionals, women actively planning a pregnancy and their partners and families about diet, physical activity and weight management prior to pregnancy. However, there is UK-based qualitative evidence to suggest that women's eating habits during pregnancy are related to pre-pregnancy dietary attitudes and behaviour. Weight and body shape concerns are affected by size prior to pregnancy (+). Women's dietary restraint may be continued or relaxed during pregnancy (+). ## Evidence statement 1.19 Evidence from three UK-based qualitative studies (all ) suggests that weight management information and advice from professionals is not received or assimilated by many women during pregnancy. Available information is often vague, confusing, contradictory, and is not linked to weight management. Overweight women may feel they are not receiving relevant, tailored information about appropriate diet and weight gain during pregnancy (+). ## Evidence statement 1.20 There is evidence from UK-based qualitative research (one and one ) that women may be unaware of the potential effects of obesity during pregnancy. However, they may avoid information about their health if they find it distressing and will only action it when they feel the time is right for the well-being of themselves, their unborn baby and their partners (+). ## Evidence statement 1.21 There is evidence from UK-based qualitative research (++) that health professionals working in maternity units may feel they have insufficient time to discuss weight issues with women during pregnancy and consider that it is too late to give advice on weight management once a woman is pregnant. Health professionals themselves report that women's access to the information and advice on weight management is often ad-hoc. ## Evidence statement 1.22 Evidence from two UK-based qualitative studies (one and one ) suggests that even relatively active women reduce their physical activity during pregnancy (although they are more likely to continue to be active at some level). One study (++) found that pregnant women decreased their activity levels based on advice from health professionals, or more commonly, on information they had read in books and magazines. Family members, friends, and even health trainers tended to discourage physical activity. Women balanced their fears of injury to themselves or harm to the baby with aims toward weight management. Women also reported reduced motivation, physical limitations due to larger size and tiredness during pregnancy and a lack of facilities. Another study reported that pregnant women may feel self-conscious when carrying out physical activity (+). ## Evidence statement 1.26 Qualitative evidence from two UK-based studies (one and one ) suggest there are communication difficulties between overweight women and health professionals. One study of health professionals found that they are often embarrassed to discuss issues of weight with overweight women, and that the women themselves were also embarrassed (++). Such experiences may not be fixed, but may change over the course of a pregnancy. One study (++) explored the views of health professionals, some of which found it difficult to raise this issue sensitively. They reported a lack of guidance on this issue, though were aware of the risks and benefit so raising the issue. They were concerned that some women may stop attending antenatal appointments if they felt victimised. ## Evidence statement 2.1 There is limited evidence from one (+) US-based RCT that dietary intervention alone (aiming for 35% energy deficit) from 12 weeks postpartum, may help women across the BMI spectrum start to lose more weight after childbirth compared to usual care. However, the short length of this intervention (11 days) makes it difficult to draw conclusions on the effectiveness of the study. Four-day weighed food records suggested that calorie intake was not lower in the intervention compared to the control arm of the trial. The setting of this study (US) makes it somewhat relevant to the UK. ## Evidence statement 2.3 Four out of five US-based RCTs addressing diet and physical activity postpartum found a significant reduction in total weight among women across the BMI spectrum in the intervention group compared to control (three and one ). Only one (+) US-based RCT found that total weight was not significantly lower in the intervention group compared to control. Results did not appear to vary based on the start dates of intervention or the length of follow-up. ## Evidence statement 2.6 In line with their results for weight loss, three RCTs from the US (two and one ) found that an intervention focusing on diet and exercise resulted in decreased calorie intake and decreased consumption of foods such as sweet beverages, desserts and snacks. Of these studies, one also found a significant increase in energy expenditure between exercise groups (−) whereas another (+) found no significant difference in total energy expenditure between groups. One (+) did not report results for physical activity. ## Evidence statement 2.12 The evidence suggests weight management interventions addressing diet and physical activity had little or no adverse effects on breastfeeding outcomes, including milk volume, infant intake and weight, time and frequency of feeding (two ). Milk protein was observed to decrease in one short US-based trial (+). Overweight women had higher milk energy outputs and leaner women saw a decrease in milk energy output. ## Evidence statement 2.13 The one high quality (+) RCT which examined correlations between monitoring and weight loss found that there was a significant correlation between number of self-monitoring records returned and weight loss (r = 0.50, p < 0.005). However, homework completion or telephone contact with research staff was not significantly correlated with weight loss. Women enrolled in this trial had an above average BMI bordering on obese classification at start of the intervention. None of the included studies considered the effectiveness of monitoring alone. # Cost-effectiveness evidence For weight management during pregnancy, a short-term model was applied. There was insufficient evidence of effect so the cost effectiveness estimation was subject to great uncertainty. For weight management after childbirth, the model used a study in which women's weight was measured at both 6 months and 15 years postpartum. This was compared with their pre- and post-pregnancy weight. Using a 15-year time horizon, the estimated cost per quality-adjusted life year (QALY) gained was £44,000. Using a lifetime horizon (the usual measure of cost effectiveness) it was £9000. # Fieldwork findings Fieldwork aimed to test the relevance, usefulness and feasibility of putting the recommendations into practice. PHIAC considered the findings when developing the final recommendations. For details, see the fieldwork section in appendix B and the full expert report. Fieldwork participants in antenatal and postnatal care services, fertility services, leisure services, community groups, weight management services and children's centres were generally positive about the recommendations. They believed they could potentially help encourage weight management before, during and after pregnancy by raising awareness of the issue, especially among non-health professionals. However, more focus was needed on the psychological and emotional issues linked to weight management. In addition, the importance of helping not just the women, but her whole family, to change their behaviour was emphasised. Participants also said that the importance of breastfeeding – highlighting the health benefits and its role in weight management – needed to be stressed. Practitioners felt that the recommendations were less relevant to some hard-to-reach groups such as women with a lower socioeconomic status, those from some minority ethnic groups and pregnant teenagers. In addition, there was mixed feedback regarding the feasibility of implementing them. Some reported that they reflected current practice. Others felt it would be difficult to carry them out. The feasibility of carrying out the 6 to 8 week postnatal check on a consistent basis and the limited availability of dietitians in some areas were both cited as obstacles to implementation. Participants emphasised that weight management is a sensitive issue. Many health professionals try to avoid broaching the subject and, when they do, it takes time. Training in communications skills was needed to deal with this type of issue, they said. It was felt that the impact of the recommendations would vary across the country but that they would generally be more effective if actions and services were tailored to meet a woman's individual needs. Participants pointed out that they would have cost and resource implications, due to the large number of women that they would apply to.# Appendix D: Gaps in the evidence PHIAC identified a number of gaps in the evidence relating to the interventions under examination, based on an assessment of the evidence. These gaps are set out below. . There is a lack of evidence on the underlying mechanisms linking gestational weight gain and pregnancy outcomes. This is needed to help determine whether weight management is safe and appropriate for pregnant women. . There is a lack of evidence on how much weight should be gained during pregnancy, when is the most effective time for women to start managing their weight after childbirth and the optimal rate of weight loss. . There are few well-designed UK intervention studies on weight management in pregnancy and after childbirth. In particular, there is a lack of evidence on safe, effective interventions for women who are obese but who do not have diabetes, and those who are breastfeeding. . There is a lack of evidence about the effectiveness and cost effectiveness of weight management interventions for women before pregnancy – including for those who may be planning a pregnancy. . There is limited evidence about the effectiveness and cost effectiveness of weight management interventions in pregnancy and after childbirth for women from disadvantaged, low-income and minority ethnic groups. . Few weight management interventions include adequate and validated measures of diet and physical activity. They often rely on self-reporting. . Few studies of weight management before, during and after pregnancy include interventions that are evaluated using process and qualitative data to determine which components are effective. . There is limited evidence on the role of breastfeeding in helping women to gain or retain a healthy weight after childbirth. The Committee made 5 recommendations for research.# Appendix E: Supporting documents Supporting documents include the following: Evidence reviews: 'Systematic review of dietary and/or physical activity interventions for weight management in pregnancy'; 'Systematic review of weight management interventions after childbirth'. Reviews of economic evaluations: 'Interventions to manage weight gain in pregnancy'; 'The cost-effectiveness of weight management interventions after childbirth'. Fieldwork report: 'Weight management during pregnancy and after childbirth'.# Finding more information You can see everything NICE says on this topic in the NICE Pathways on diet, physical activity and maternal and child nutrition. To find NICE guidance on related topics, including guidance in development, see our topic pages for diet, nutrition and obesity, physical activity and postnatal care. For full details of the evidence and the guideline committee's discussions, see the evidence reviews. You can also find information about how the guideline was developed. NICE has produced tools and resources to help you put this guideline into practice. For general help and advice on putting NICE guidelines into practice, see resources to help you put guidance into practice.	{'Introduction': "The Department of Health (DH) asked the National Institute for Health and Clinical Excellence (NICE) to produce public health guidance on dietary and physical activity interventions for weight management before, during and after pregnancy.\n\nThe guidance does not cover:\n\nwomen who are underweight (that is, those who have a body mass index [BMI] less than 18.5\xa0kg/m²)\n\nclinical management of women who are obese during pregnancy\n\nthose who have been diagnosed with, or who are receiving treatment for, an existing condition such as type\xa01 or type\xa02 diabetes\n\nfood safety advice.\n\nThe guidance is for NHS and other commissioners, managers and professionals who have a direct or indirect role in, and responsibility for, women who are pregnant or who are planning a pregnancy and mothers who have had a baby in the last 2\xa0years. This includes those working in local authorities, education and the wider public, private, voluntary and community sectors.\n\nIt is particularly aimed at: GPs, obstetricians, midwives, health visitors, dietitians, community pharmacists and all those working in antenatal and postnatal services and children's centres. It may also be of interest to women before, during and after pregnancy and their partners and families, and other members of the public.\n\nThe guidance complements but does not replace NICE guidance on: obesity, maternal and child nutrition, antenatal care, postnatal care, physical activity, behaviour change, antenatal and postnatal mental health and diabetes in pregnancy.\n\nThe Public Health Interventions Advisory Committee (PHIAC) developed these recommendations on the basis of a review of the evidence, economic modelling, expert advice, stakeholder comments and fieldwork.\n\nMembers of PHIAC are listed in appendix A. The methods used to develop the guidance are summarised in appendix B.\n\nSupporting documents used to prepare this document are listed in appendix\xa0E. Full details of the evidence collated, including fieldwork data and activities and stakeholder comments, along with a list of the stakeholders involved and NICE's supporting process and methods manuals are also available are also available.", 'Recommendations': "People have the right to be involved in discussions and make informed decisions about their care, as described in making decisions about your care.\n\nMaking decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.\n\n# Weight management definition\n\nIn this guidance the term 'weight management' includes:\n\nassessing and monitoring body weight\n\npreventing someone from becoming overweight (body mass index [BMI] 25–29.9 kg/m²) or obese (BMI greater than or equal to 30 kg/m²)\n\nhelping someone to achieve and maintain a healthy weight before, during and after pregnancy by eating healthily and being physically active and gradually losing weight after pregnancy.\n\nThe recommendations are based on strategies and weight-loss programmes that are proven to be effective for the whole population. The criteria for effective programmes are listed below. Programmes that do not meet these criteria are unlikely to help women to maintain a healthy weight in the long term.\n\n# Achieving and maintaining a healthy weight\n\nWomen will be more likely to achieve and maintain a healthy weight before, during and after pregnancy if they:\n\nbase meals on starchy foods such as potatoes, bread, rice and pasta, choosing wholegrain where possible\n\neat fibre-rich foods such as oats, beans, peas, lentils, grains, seeds, fruit and vegetables, as well as wholegrain bread and brown rice and pasta\n\neat at least five portions of a variety of fruit and vegetables each day, in place of foods higher in fat and calories\n\neat a low-fat diet and avoid increasing their fat and/or calorie intake\n\neat as little as possible of fried food; drinks and confectionery high in added sugars (such as cakes, pastries and fizzy drinks); and other food high in fat and sugar (such as some take-away and fast foods)\n\neat breakfast\n\nwatch the portion size of meals and snacks, and how often they are eating\n\nmake activities such as walking, cycling, swimming, aerobics and gardening part of everyday life and build activity into daily life – for example, by taking the stairs instead of the lift or taking a walk at lunchtime\n\nminimise sedentary activities, such as sitting for long periods watching television, at a computer or playing video games\n\nwalk, cycle or use another mode of transport involving physical activity.\n\nEffective weight-loss programmes:\n\naddress the reasons why someone might find it difficult to lose weight\n\nare tailored to individual needs and choices\n\nare sensitive to the person's weight concerns\n\nare based on a balanced, healthy diet\n\nencourage regular physical activity\n\nexpect people to lose no more than 0.5–1\xa0kg (1–2\xa0lb) a week\n\nidentify and address barriers to change.\n\nWeight loss programmes are not recommended during pregnancy as they may harm the health of the unborn child, see recommendation 2.\n\nReputable sources of information and advice about diet and physical activity for women before, during and after pregnancy include: The Department of Health's 'The pregnancy book' and 'Birth to five' and the NHS eat well website.\n\n# Changing behaviour\n\nEvidence-based behaviour change advice includes:\n\nunderstanding the short, medium and longer-term consequences of women's health-related behaviour\n\nhelping women to feel positive about the benefits of health-enhancing behaviours and changing their behaviours\n\nrecognising how women's social contexts and relationships may affect their behaviour\n\nhelping plan women's changes in terms of easy steps over time\n\nidentifying and planning situations that might undermine the changes women are trying to make and plan explicit 'if–then' coping strategies to prevent relapse.\n\n# Recommendation 1 Preparing for pregnancy: women with a BMI of 30 or more\n\n## Whose health will benefit?\n\nWomen with a BMI of 30 or more who may become pregnant, including those who have previously been pregnant.\n\n## Who should take action?\n\nNHS and other commissioners and managers.\n\nGPs, health visitors, midwives, practice nurses, pharmacists and other health professionals working in weight management, fertility, pre-conception advice and care services, gynaecology and contraceptive services.\n\nManagers and health professionals in children's centres.\n\nDirectors of public health, planners and organisers of public health campaigns and occupational health advisers.\n\nDietitians and public health nutritionists working in NHS and non-NHS settings.\n\n## What action should they take?\n\nNHS and other commissioners and managers, directors of public health and planners and organisers of public health campaigns should ensure health professionals understand the importance of achieving a healthy weight before pregnancy. Local education initiatives should also stress the health risks of being obese, including during pregnancy.\n\nHealth professionals should use any opportunity, as appropriate, to provide women with a BMI of 30 or more with information about the health benefits of losing weight before becoming pregnant (for themselves and the baby they may conceive). This should include information on the increased health risks their weight poses to themselves and would pose to their unborn child.\n\nGPs, dietitians and other appropriately trained health professionals should advise, encourage and help women with a BMI of 30 or more to reduce weight before becoming pregnant. They should explain that losing 5 to 10% of their weight (a realistic target) would have significant health benefits and could increase their chances of becoming pregnant. Further weight loss, to achieve a BMI within the healthy range (between 24.9 and 18.5\xa0kg/m2) should also be encouraged, using evidence-based behaviour change techniques. Losing weight to within this range may be difficult and women will need to be motivated and supported.\n\nHealth professionals should encourage women to check their weight and waist measurement periodically or, as a simple alternative, check the fit of their clothes.\n\nHealth professionals should offer a weight-loss support programme involving diet and physical activity. The programme should follow the principles of good practice, as outlined at the beginning of this section.\n\nHealth professionals should offer specific dietary advice in preparation for pregnancy, including the need to take daily folic acid supplements. This includes professionals working in pre-conception clinics, fertility clinics, sexual and reproductive health services and children's centres.\n\n# Recommendation 2 Pregnant women\n\n## Context\n\nIf a pregnant woman is obese this will have a greater influence on her health and the health of her unborn child than the amount of weight she may gain during pregnancy. That is why it is important, when necessary, to help women lose weight before they become pregnant.\n\nDieting during pregnancy is not recommended as it may harm the health of the unborn child.\n\nMany pregnant women ask health professionals for advice on what constitutes appropriate weight gain during pregnancy. However, there are no evidence-based UK guidelines on recommended weight-gain ranges during pregnancy.\n\nThe amount of weight a woman may gain in pregnancy can vary a great deal. Only some of it is due to increased body fat – the unborn child, placenta, amniotic fluid and increases in maternal blood and fluid volume all contribute.\n\n## Whose health will benefit?\n\nAll pregnant women but, in particular, those with a BMI of 30 or more.\n\n## Who should take action?\n\nObstetricians, midwives, GPs and practice nurses.\n\nDietitians and public health nutritionists.\n\nManagers and health professionals in children's centres.\n\nMidwifery assistants, support workers and other healthcare practitioners.\n\n## What action should they take?\n\nAt the earliest opportunity, for example, during a pregnant woman's first visit to a health professional, discuss her eating habits and how physically active she is. Find out if she has any concerns about diet and the amount of physical activity she does and try to address them.\n\nAdvise that a healthy diet and being physically active will benefit both the woman and her unborn child during pregnancy and will also help her to achieve a healthy weight after giving birth. Advise her to seek information and advice on diet and activity from a reputable source.\n\nOffer practical and tailored information. This includes advice on how to use Healthy Start vouchers to increase the fruit and vegetable intake of those eligible for the Healthy Start scheme (women under 18 years and those who are receiving benefit payments).\n\nDispel any myths about what and how much to eat during pregnancy. For example, advise that there is no need to 'eat for two' or to drink full-fat milk. Explain that energy needs do not change in the first 6\xa0months of pregnancy and increase only slightly in the last 3\xa0months (and then only by around 200\xa0calories per day).\n\nAdvise that moderate-intensity physical activity will not harm her or her unborn child.\n\nGive specific and practical advice about being physically active during pregnancy. Advise women how to exercise safely following national guidelines on physical activity during pregnancy and during postpartum (see the UK Chief Medical Officers' physical activity guidelines for more information).\n\nExplain to those women who would find this level of physical activity difficult that it is important not to be sedentary, as far as possible. Encourage them to start walking and to build physical activity into daily life, for example, by taking the stairs instead of the lift, rather than sitting for long periods.\n\nMeasure weight and height at the first contact with the pregnant woman, being sensitive to any concerns she may have about her weight. If these data are not available at their first booking appointment, then the midwife should do this. Do not rely on self-reported measures of weight and height. Clearly explain why this information is needed and how it will be used to plan her care. Weigh her in light clothing using appropriate, calibrated weighing scales that are regularly checked. Calculate BMI by dividing weight (kg) by the square of height (m2), or use the NHS BMI calculator after measuring and weighing. Use BMI percentile charts for pregnant women under 18 years, as a BMI measure alone does not take growth into account and is inappropriate for this age group.\n\nWeight, height and BMI should be recorded in notes, the woman's hand-held record and the patient information system. If a hand-held record is not available, use local protocols to record this information.\n\nDo not weigh women repeatedly during pregnancy as a matter of routine. Only weigh again if clinical management can be influenced or if nutrition is a concern.\n\nExplain to women with a BMI of 30 or more at the booking appointment how this poses a risk, both to their health and the health of the unborn child. Explain that they should not try to reduce this risk by dieting while pregnant and that the risk will be managed by the health professionals caring for them during their pregnancy.\n\nOffer women with a BMI of 30 or more at the booking appointment a referral to a dietitian or appropriately trained health professional for assessment and personalised advice on healthy eating and how to be physically active. Encourage them to lose weight after pregnancy.\n\n# Recommendation 3 Supporting women after childbirth\n\n## Whose health will benefit?\n\nWomen who have had a baby in recent months.\n\n## Who should take action?\n\nGPs, health visitors, midwives, practice nurses, pharmacists and other health professionals working in weight management.\n\nManagers and health professionals in children's centres.\n\nDietitians and public health nutritionists working in NHS and non-NHS settings.\n\n## What action should they take?\n\nUse the 6–8-week postnatal check as an opportunity to discuss the woman's weight. Ask those who are overweight, obese or who have concerns about their weight if they would like any further advice and support now – or later. If they say they would like help later, they should be asked whether they would like to make an appointment within the next 6 months for advice and support.\n\nDuring the 6 to 8-week postnatal check, or during the follow-up appointment within the next 6\xa0months, provide clear, tailored, consistent, up-to-date and timely advice about how to lose weight safely after childbirth. Ensure women have a realistic expectation of the time it will take to lose weight gained during pregnancy. Discuss the benefits of a healthy diet and regular physical activity, acknowledging the woman's role within the family and how she can be supported by her partner and wider family. Advice on healthy eating and physical activity should be tailored to her circumstances. For example, it should take into account the demands of caring for a baby and any other children, how tired she is and any health problems she may have (such as pelvic floor muscle weakness or backache).\n\nHealth professionals should advise women, their partners and family to seek information and advice from a reputable source. Women who want support to lose weight should be given details of appropriate community-based services.\n\nMidwives and other health professionals should encourage women to breastfeed. They should reassure them that a healthy diet and regular, moderate-intensity physical activity and gradual weight loss will not adversely affect the ability to breastfeed or the quantity or quality of breast milk.\n\nHealth professionals should give advice on recreational exercise from the Royal College of Obstetrics and Gynaecology. In summary, this states that:\n\n\n\nIf pregnancy and delivery are uncomplicated, a mild exercise programme consisting of walking, pelvic floor exercises and stretching may begin immediately. But women should not resume high-impact activity too soon after giving birth.\n\nAfter complicated deliveries, or lower segment caesareans, a medical care-giver should be consulted before resuming pre-pregnancy levels of physical activity, usually after the first check-up at 6 to 8 weeks after giving birth.\n\n\n\nHealth professionals should also emphasise the importance of participating in physical activities, such as walking, which can be built into daily life.\n\n# Recommendation 4 Women with a BMI of 30 or more after childbirth\n\n## Whose health will benefit?\n\nWomen who had a pre-pregnancy BMI of 30 or more.\n\nWomen with a BMI of 30 or more who have had a baby within recent months.\n\n## Who should take action?\n\nGPs, health visitors, practice nurses, pharmacists and other health professionals working in weight management.\n\nManagers and health professionals in children's centres.\n\nDietitians and public health nutritionists working in NHS and non-NHS settings.\n\n## What action should they take?\n\nExplain the increased risks that being obese poses to them and, if they become pregnant again, their unborn child. Encourage them to lose weight.\n\nOffer a structured weight-loss programme. If more appropriate, offer a referral to a dietitian or an appropriately trained health professional. They will provide a personalised assessment, advice about diet and physical activity and advice on behaviour change strategies such as goal setting. Women who are not yet ready to lose weight should be provided with information about where they can get support when they are ready.\n\nUse evidence-based behaviour change techniques to motivate and support women to lose weight.\n\nEncourage breastfeeding and advise women that losing weight by eating healthily and taking regular exercise will not affect the quantity or quality of their milk.\n\n# Recommendation 5 Community-based services\n\n## Whose health will benefit?\n\nAll women before, during and after pregnancy.\n\n## Who should take action?\n\nNHS and other commissioners and managers.\n\nManagers of local authority leisure and community services including swimming pools and parks.\n\nManagers and health professionals in slimming and weight management clubs.\n\nManagers and health professionals in children's centres.\n\nNHS health trainers and health and fitness advisers working in local authority leisure services and voluntary, community and commercial organisations.\n\n## What action should they take?\n\nLocal authority leisure and community services should offer women with babies and children the opportunity to take part in a range of physical or recreational activities. This could include swimming, organised walks, cycling or dancing. Activities need to be affordable and available at times that are suitable for women with older children as well as those with babies. Where possible, affordable childcare (for example, a creche) should be provided and provision made for women who wish to breastfeed.\n\nNHS and other commissioners and managers, local authority leisure services and slimming clubs should work together to offer women who wish to lose weight after childbirth the opportunity to join a weight management group or slimming club. Health professionals should continue to monitor, support and care for women with a BMI of 30 or more who join weight management groups and slimming clubs.\n\nWeight management groups and slimming clubs should adhere to the principles outlined at the beginning of this section. This includes giving advice about healthy eating and the importance of physical activity and using evidence-based behaviour-change techniques to motivate and support women to lose weight.\n\nNHS health trainers and non-NHS health and fitness advisers should advise women that a healthy diet and being physically active will benefit both them and their unborn child during pregnancy. They should also explain that it will help them to achieve a healthy weight after giving birth – and could encourage the whole family to eat healthily and be physically active.\n\nNHS health trainers and non-NHS health and fitness advisers should encourage those who have weight concerns before, during or after pregnancy to talk to a health professional such as a GP, practice nurse, dietitian, health visitor or pharmacist. They should also advise women, their partners and family to seek information and advice on healthy eating and physical activity from a reputable source.\n\nNHS health trainers and non-NHS health and fitness advisers should offer specific dietary advice in preparation for pregnancy, including the need to take daily folic acid supplements.\n\n# Recommendation 6 Professional skills\n\n## Whose health will benefit?\n\nAll women before, during and after pregnancy, particularly those with a BMI of 30 or more.\n\n## Who should take action?\n\nProfessional bodies and others responsible for setting competencies and developing continuing professional development programmes for health professionals, healthcare assistants and support staff.\n\nTraining boards and organisations responsible for training health and fitness advisers and NHS health trainers.\n\n## What action should they take?\n\nEnsure health professionals, healthcare assistants and support workers have the skills to advise on the health benefits of weight management and risks of being overweight or obese before, during and after pregnancy, or after successive pregnancies.\n\nEnsure they can advise women on their nutritional needs before, during and after pregnancy and can explain why it is important to have a balanced diet and to be moderately physically active.\n\nEnsure they have behaviour change knowledge, skills and competencies. This includes being able to help people to identify how their behaviour is affecting their health, draw up an action plan, make the changes and maintain them.\n\nEnsure they have the communication techniques needed to broach the subject of weight management in a sensitive manner. They should be able to give women practical advice on how to improve their diet and become more physically active. They should be able to tailor this advice to individual needs and know when to refer them for specialist care and support.\n\nEnsure they have the knowledge and skills to help dispel common myths. This includes myths about what to eat and what not to eat during pregnancy and about weight loss in relation to breastfeeding.\n\nEnsure they have knowledge, skills and competencies in group facilitation, are aware of the needs of minority ethnic groups and have knowledge of local services.\n\nEnsure their training is regularly monitored and updated.", 'Public health need and practice': "About half of women of childbearing age are either overweight (BMI 25 to 29.9\xa0kg/m²) or obese (BMI greater than or equal to 30\xa0kg/m²) (The NHS Information Centre 2008).\n\nAt the start of pregnancy, 15.6% of women in England are obese (Heslehurst et al. 2010).\n\nMaternal obesity and weight retention after birth are related to socioeconomic deprivation (Heslehurst et al. 2010).\n\n# Health risks for obese women and their babies\n\nWomen who are obese when they become pregnant face an increased risk of complications during pregnancy and childbirth. These include the risk of impaired glucose tolerance and gestational diabetes, miscarriage, pre-eclampsia, thromboembolism and maternal death (Centre for Maternal and Child Enquiries and the Royal College of Obstetricians and Gynaecologists 2010).\n\nEven a relatively small gain of 1 to 2 BMI units (kg/m2) between pregnancies may increase the risk of gestational hypertension and gestational diabetes, even in women who are not overweight or obese. It also increases the likelihood of giving birth to a large baby (Villamor and Cnattingius 2006).\n\nAn obese woman is more likely to have an induced or longer labour, instrumental delivery, caesarean section or postpartum haemorrhage (Yu et al. 2006). Reduced mobility during labour can result in the need for more pain relief, which can be difficult to administer in obese women, resulting in increased need for general anaesthesia with its associated risks. After birth, wound healing can be slower with an increased risk of infection, and obese women are more likely to require extra support in establishing breastfeeding, due to, for example, difficulties in latching the baby on to the breast (Heslehurst et al. 2007).\n\nObese women may also experience reduced choices about where and how they give birth. There may be restrictions on home births, the use of birthing pools and types of pain relief that can be given.\n\nObese women who are pregnant are likely to spend longer in hospital than those with a healthy weight because of morbidity during pregnancy and labour related to their weight (Chu et al. 2008). In the longer term, weight control after pregnancy may reduce the woman's risk of obesity, coronary heart disease, some cancers and type 2 diabetes.\n\nBabies born to obese women also face several health risks. These include a higher risk of fetal death, stillbirth, congenital abnormality, shoulder dystocia, macrosomia and subsequent obesity (Ramachenderan et al. 2008).\n\n# Weight gain during pregnancy\n\nUS Institute of Medicine guidelines (Rasmussen and Yaktine 2009), based on observational data, state that healthy American women who are a normal weight for their height (BMI 18.5 to 24.9) should gain 11.5 to 16\xa0kg (25 to 35\xa0pounds) during pregnancy. Overweight women (BMI 25 to 29.9) should gain 7 to 11.5\xa0kg (15 to 25\xa0pounds) and obese women (BMI greater than 30) should only put on 5 to 9\xa0kg (11 to 20\xa0pounds).\n\nObservational studies of American women suggest that those who gain weight within the Institute of Medicine ranges are more likely to have better maternal and infant outcomes than those who gain more or less weight. (The evidence is stronger for some outcomes – such as postpartum weight retention and birthweight – than for others [Siega-Riz et al. 2009]).\n\nThere are no formal, evidence-based guidelines from the UK government or professional bodies on what constitutes appropriate weight gain during pregnancy.\n\nThe Committee on Medical Aspects of Food Policy report on dietary reference values recommends that women should only have around 200 calories more a day in the last trimester of pregnancy (DH 1991). UK health professionals do not, as a matter of course, give women information about the risks of obesity and the importance of weight management before or during pregnancy (Heslehurst et al. 2007a). Pregnant women are advised not to diet, and to talk to their GP or midwife if they are concerned about their weight (Department of Health 2009).\n\n# Weight management after pregnancy\n\nNICE's guideline on obesity identified the period after pregnancy and childbirth as a time when women are likely to gain weight. In addition, many conceive again during this period. Hence, managing the woman's weight in the first few years after childbirth may reduce her risk of entering the next pregnancy overweight or obese.\n\nHowever, after having a child, many mothers find it difficult to eat a healthy diet and take regular exercise (Hewison and Dowswell 1994). It may be because women receive little or no advice on weight management after childbirth.\n\nWomen who exclusively breastfeed their infants for the first 6\xa0months may require around an additional 330\xa0calories a day. Some of these additional calories will be derived from fat stores. An additional 400\xa0calories a day may be required for the second 6\xa0months if they continue to breastfeed (DH 1991).\n\nBreastfeeding is often recommended as a strategy for promoting weight loss, but findings from studies are mixed (Gore et al. 2003). The additional energy requirements of breastfeeding may help some women return to their pre-pregnancy weight. If women are moderately active on a regular basis, this will not adversely affect a woman's ability to breastfeed and could aid weight management.\n\nThe Department of Health (2009) does not make specific recommendations on weight management after childbirth. It advises against following a restricted-calorie diet while breastfeeding and suggests that women should talk to their GP if they feel they need to lose weight. However, there is no national guidance for professionals.\n\nWomen on low incomes may be eligible for Healthy Start vouchers to buy fruit and vegetables (as well as milk and infant formula). These are available to pregnant women and families with a child aged under 4 years. Those eligible include people on income support and income-based jobseekers allowance and those with low incomes. All pregnant women under 18\xa0years also qualify, whether or not they are on state benefits.", 'Considerations': "The Public Health Interventions Advisory Committee (PHIAC) took account of a number of factors and issues when developing the recommendations.\n\nPHIAC was keen to adopt a 'life course approach' to this guidance, noting that pregnancy and around a year after childbirth are key points in a woman's life when she may gain excess weight. PHIAC also recognised that weight management can be difficult in the current obesogenic environment. Sedentary habits and a high calorie diet are common and physical activity, such as walking, is not part of daily life. However, the period before, during and after pregnancy does provide an opportunity to give women practical advice to help them to improve their diet, become more physically active or to help them manage their weight effectively. To ensure this opportunity is not missed, the recommendations emphasise the need for practical advice that takes into account the woman's particular social and economic circumstances and involves the whole family.\n\nPHIAC recognised that health professionals would welcome UK guidance on weight gain in pregnancy. In the absence of such guidance, PHIAC discussed whether it would be appropriate to support the US Institute of Medicine's guidelines. These guidelines, which were revised in 2009, are based on observational data. The data show that women who gained weight within the specified ranges had better outcomes than those who did not. However, the recommendations were not validated by intervention studies. Without evidence from large-scale trials, it is not clear whether or not adhering to the recommended ranges lowers the risk of adverse outcomes for mothers and their babies. In addition, the guidelines were developed for the US population and it is not known whether or not they would apply to other populations with a different ethnic composition. PHIAC was therefore unable to support their use without more evidence and more information about their applicability to the UK population. This is an important area for future research.\n\nPHIAC recognised that not only does weight gain in pregnancy vary between individuals, but that the components involved also vary. Weight gain in pregnancy is made up of the fetus, placenta, amniotic fluid, and increases in maternal blood and fluid volume, as well as an increase in body fat.\n\nPHIAC noted the lack of intervention studies on weight management during pregnancy. Those that do exist are pilot studies with small sample sizes and insufficient statistical power to detect differences in health outcomes for mothers and their babies. Several large-scale, randomised controlled trials are underway worldwide, but no conclusions could be drawn from them before publication of this guidance. PHIAC agreed to draw on existing NICE guidance which is based on evidence of effectiveness and cost effectiveness. This includes public health guidance on maternal and child nutrition and behaviour change and clinical guidelines on obesity, antenatal care and postnatal care.\n\nPHIAC emphasised the importance of women being a healthy weight before pregnancy. Pre-pregnancy BMI is a greater determinant of healthy outcomes for mothers and babies than any weight they may gain during pregnancy. Women with a high BMI might also find it more difficult to conceive.\n\nFor many women, the first year or two after birth is a time when they start to think about having another baby. Weight management during this time will help them to achieve a healthy weight when they next become pregnant – and help prevent incremental weight gain over successive pregnancies.\n\nThe guidance is targeted at women who are actively planning a pregnancy and those who are already pregnant or who have had a baby. It is, however, recognised that a population-based approach is important in reaching all women of childbearing age, as many pregnancies are unplanned.\n\nWomen receive a wealth of sometimes conflicting advice on what constitutes a healthy diet and how much physical activity they should do during pregnancy and after childbirth. This comes not just from health professionals and official sources but from family, friends, the media and new media (such as social networking sites). For example, the press regularly publishes celebrity claims of unrealistic and rapid weight loss after pregnancy. This may create additional pressure on women to lose weight inappropriately at an already stressful time.\n\nConcern about obesity or weight gain in pregnancy might lead some women to try to lose weight. Dieting is not advised during pregnancy because it is not known whether it is safe. Restrictive or 'crash' diets may increase blood ketone levels and could adversely affect the neuro-cognitive development of the fetus.\n\nPHIAC was aware that the health risks of being overweight or obese during pregnancy, for both the mother and her unborn child, are not routinely discussed. Health professionals recognise the risks but are often unsure what advice to give. In some cases, they lack the training, skills or confidence to discuss weight management. In addition, they may not know how to tailor advice and support for women who are pregnant.\n\nThe needs of pregnant teenagers may differ from those of pregnant older women. Their social circumstances may differ, as may the health professionals they come into contact with. For example, they may be cared for by specialist teenage pregnancy midwives and teenage pregnancy support nurses. In addition to supporting the growth of the baby, pregnant teenagers may still be growing themselves.\n\nSome population groups, such as Asians, face co-morbidity risk at a lower BMI than other groups. However, there is no consensus on how to define overweight and obesity in different ethnic groups for women of childbearing age.\n\nThe period following childbirth is a time of great change for women and their partners, as they learn to cope with the demands of a new baby. Lack of sleep and a range of physical and psychological problems, such as backache, urinary and faecal incontinence, depression and fatigue, are common. These problems can be compounded when they are caring for another child (or children) as well. Some health problems may impact on a woman's ability to be physically active and therefore, her ability to manage her weight.\n\nThe additional energy requirements of breastfeeding may help some women return to their pre-pregnancy weight. Those who are breastfeeding and do not increase their energy intake, eat a healthy diet and are moderately active will be more likely to achieve this. Although it cannot be assumed that all women who breastfeed will lose weight, PHIAC considered it important to encourage exclusive breastfeeding for the first 6 months because of the wider health benefits for both the mother and her baby.\n\nPHIAC noted that after childbirth, women may resume smoking and drinking alcohol. These habits may also affect their weight.\n\nAfter the birth of their baby, women may not be in regular contact with health services and may need local, community-based sources of support to help them manage their weight.\n\nPHIAC discussed the role of children's centres in working with pregnant women and their families in particular, working with teenage parents and families from low income and black and minority ethnic groups. Children's centre services might include: antenatal education, appropriate maternity services (including early antenatal engagement and postnatal support), breastfeeding promotion and support and advice on how to combat obesity and enjoy a healthy diet.\n\nOn balance, interventions during pregnancy were considered to be cost effective. However, the estimate of cost effectiveness was subject to considerable uncertainty. Weight management interventions during the 6 months after birth also appeared to be cost effective, but the results were sensitive to assumptions made in the modelling. PHIAC was mindful that most of the recommendations did not increase costs in the long term and, as they could be expected to do more good than harm, they are likely to be cost effective. Furthermore, some of the advice has been adapted from previous NICE guidance which has already been shown to be cost effective.", 'Recommendations for research': "The Public Health Interventions Advisory Committee (PHIAC) recommends that the following research questions should be addressed. It notes that 'effectiveness' in this context relates not only to the size of the effect, but also to cost effectiveness and duration of effect in terms of outcomes for both the mother and infant. It also takes into account any harmful/negative side effects.\n\n. Are the US Institute of Medicine (2009) guidelines on weight gain in pregnancy appropriate for use with the UK population? Does adherence to these recommendations improve outcomes? Are they effective with women under 18 and those from minority ethnic groups?\n\n. What are the most effective and cost-effective ways of helping women to manage their weight before pregnancy? This includes women who are obese, those who are under 18 and those from disadvantaged, low income and minority ethnic groups.\n\n. What are the most effective and cost-effective ways of helping women to manage their weight during pregnancy? This includes women who are obese, those who are under 18 and those from disadvantaged, low income and minority ethnic groups.\n\n. What are the most effective and cost-effective ways of helping women to manage their weight after childbirth? This includes women who are obese, those who are under 18 and those from disadvantaged, low income and minority ethnic groups.\n\nWhen is the most appropriate time to start managing weight after childbirth?\n\nWhat is the optimal rate of weight loss to ensure long-term success?\n\nHow does resuming behaviours such as smoking and drinking influence postpartum weight management?\n\n. How can breastfeeding help with postpartum weight management, both in terms of energy expenditure and energy balance?\n\nMore detail on the gaps in the evidence identified during development of this guidance is in appendix\xa0D.", 'References': 'Centre for Maternal and Child Enquires and the Royal College of Obstetricians and Gynaecologists (2010) Joint guideline – Management of women with obesity in pregnancy. London: CMACE/ Centre for Maternal and Child Enquires and the Royal College of Obstetricians and Gynaecologists\n\nChu SY, Bachman DJ, Callaghan WM et al. (2008) Association between obesity during pregnancy and increased use of health care. New England Journal of Medicine 358:1444–53\n\nDepartment of Health (2009) The pregnancy book. London: Department of Health\n\nDepartment of Health (1991) Dietary reference values for food energy and nutrients for the United Kingdom. Report of the panel on dietary reference values of the Committee on Medical Aspects of Food Policy. London: HMSO\n\nGore SA, Brown DM, Smith D (2003) The role of postpartum weight retention in obesity among women: a review of the evidence. Annals of Behavioral Medicine 26: 149–59\n\nHeslehurst N, Lang R, Rankin J et al. (2007) Obesity in pregnancy: a study of the impact of maternal obesity on NHS maternity services. British Journal of Obstetrics and Gynaecology 114: 334–42\n\nHeslehurst N, Rankin J, Wilkinson JR et al. (2010) A nationally representative study of maternal obesity in England, UK: trends in incidence and demographic inequalities in 619 323 births, 1989–2007. International Journal of Obesity 34: 420–8\n\nHewison J, Dowswell T (1994) Child health care and the working mother. London: Chapman and Hall\n\nRamachenderan J, Bradford J, McLean M (2008) Maternal obesity and pregnancy complications: a review. Australian and New Zealand Journal of Obstetrics and Gynaecology 48: 228–35\n\nRasmussen KM, Yaktine AL, editors. Committee to Reexamine Institute of Medicine Pregnancy Weight Guidelines (2009) Weight gain during pregnancy: re-examining the guidelines.\n\nSiega-Riz AM, Viswanathan M, Moos MK et al. (2009) A systematic review of outcomes of maternal weight gain according to the Institute of Medicine recommendations: birthweight, fetal growth, and postpartum weight retention. American Journal of Obstetrics and Gynecology 201: 339 e1–14\n\nThe NHS Information Centre (2008) Health survey for England 2006: CVD and risk factors adults, obesity and risk factors children. London: The NHS Information Centre\n\nVillamor E, Cnattingius S (2006) Interpregnancy weight change and risk of adverse pregnancy outcomes: population based study. Lancet 368: 1164–70\n\nWorld Cancer Research Fund (2007) Food, nutrition, physical activity and the prevention of cancer: a global perspective. London: World Cancer Research Fund\n\nYu CKU, Teoh TG, Robinson S (2006) Obesity in pregnancy. British Journal of Obstetrics and Gynaecology 113: 1117–25', 'Appendix B: Summary of the methods used to develop this guidance': "# Introduction\n\nThe reviews and economic analyses include full details of the methods used to select the evidence (including search strategies), assess its quality and summarise it.\n\nThe minutes of the PHIAC meetings provide further detail about the Committee's interpretation of the evidence and development of the recommendations.\n\nAll supporting documents are listed in appendix\xa0E.\n\n# Key questions\n\nThe key questions were established as part of the scope. (Weight management before and during pregnancy and weight management after childbirth were scoped separately, but have now been amalgamated into one piece of guidance.) They formed the starting point for the reviews of evidence and were used by PHIAC to help develop the recommendations.\n\nThe overarching questions were:\n\nWhat is the effectiveness and cost effectiveness of weight management interventions before and during pregnancy?\n\nWhat are the most effective and cost-effective interventions for managing women's weight after childbirth?\n\nThe subsidiary questions were:\n\nWhat types of dietary interventions and physical activity interventions are most effective and cost effective for weight management in women planning a pregnancy? Do they have any adverse effects?\n\nWhat are the most effective and cost-effective ways of measuring and monitoring weight gain in pregnancy? Are there any adverse effects?\n\nWhat are the views, perceptions and beliefs of health professionals, women actively planning a pregnancy, pregnant women, their partners and families about diet, physical activity and weight management in pregnancy and before pregnancy?\n\nWhat internal and external factors influence the effectiveness of the intervention (such as content, delivery, setting, who is delivering the intervention, intensity, duration and target setting)?\n\nWhat are the most effective and cost-effective dietary interventions for helping mothers, including breastfeeding mothers, achieve and maintain a healthy weight after childbirth?\n\nWhat are the most effective and cost-effective physical activity interventions for helping mothers, including breastfeeding mothers, achieve and maintain a healthy weight after childbirth?\n\nWhat are the most effective and cost effective interventions for helping mothers to avoid gaining more weight with each successive pregnancy?\n\nThese questions were made more specific for the reviews (see reviews for further details).\n\n# Reviewing the evidence of effectiveness\n\nTwo reviews of effectiveness were conducted.\n\n## Identifying the evidence\n\nThe following databases were searched for all types of evidence (from 1990–2008):\n\nASSIA (Applied Social Science Index and Abstracts)\n\nBritish Nursing Index\n\nCINAHL (Cumulative Index of Nursing and Allied Health Literature)\n\nCochrane Central Register of Controlled Trials\n\nCochrane Database of Systematic Reviews\n\nDARE (Database of Abstracts of Reviews of Effectiveness)\n\nEconlit\n\nEMBASE\n\nHTA (Health Technology Assessment)\n\nMaternity and Infant Care\n\nMEDLINE\n\nNHS EED (NHS Economic Evaluation Database)\n\nPyscINFO\n\nScience Citation Index\n\nSocial Science Citation Index\n\nA search was also conducted of the following websites:\n\nAmerican College of Obstetricians and Gynaecologists\n\nBritish Dietetic Association\n\nChartered Society of Physiotherapy\n\nDepartment of Health\n\nFood Standards Agency\n\nInstitute of Medicine\n\nJoseph Rowntree Foundation\n\nNHS Evidence – Women's Health\n\nNHS Scotland\n\nNICE\n\nPublic health observatories\n\nRoyal College of Midwives\n\nRoyal College of Obstetricians and Gynaecologists\n\nScientific Advisory Committee on Nutrition\n\nScottish Intercollegiate Guidelines Network (SIGN)\n\nWelsh Assembly Government\n\nFurther details of the databases, search terms and strategies are included in the reviews.\n\n## Selection criteria\n\nStudies were included in effectiveness review one if they involved:\n\npregnant women who were expecting a single baby\n\nwomen seeking preconception advice\n\nwomen who were actively planning a pregnancy\n\nwomen in the above groups who had a history of (or who developed) impaired glucose tolerance or gestational diabetes.\n\nStudies were excluded if they:\n\nwere not published in English\n\nwere conducted in non-OECD (Organisation for Economic Cooperation and Development) countries\n\ninvolved pregnant women expecting more than one baby\n\ninvolved pregnant women who were underweight (BMI <18.5\xa0kg/m2)\n\ninvolved pregnant women who had been diagnosed with pre-existing diabetes (type\xa01 and 2).\n\nStudies were included in effectiveness review two if they involved women with a BMI greater than 18.5\xa0kg/m² up to 2\xa0years following the birth of their baby.\n\nStudies were excluded if they involved:\n\nwomen who had been diagnosed with, or who were receiving clinical treatment for, an existing condition such as type\xa01 or type\xa02 diabetes\n\nwomen who had been diagnosed with postnatal depression\n\nwomen who were underweight (BMI <18.5\xa0kg/m²) after childbirth\n\nwomen who had given birth more than 2\xa0years before\n\nclinical interventions (such as surgery or drug treatment) or complementary therapies (for example, hypnotherapy or acupuncture) to treat obesity.\n\nStudies were also excluded if they were:\n\nnot published in English\n\nconducted in non-OECD (Organisation for Economic Cooperation and Development) countries.\n\n## Quality appraisal\n\nIncluded papers were assessed for methodological rigour and quality using the NICE methodology checklist, as set out in the NICE technical manual 'Methods for the development of NICE public health guidance' (see appendix E). Each study was graded (++, +, –) to reflect the risk of potential bias arising from its design and execution.\n\n++ All or most of the methodology checklist criteria have been fulfilled. Where they have not been fulfilled, the conclusions are thought very unlikely to alter.\n\n+ Some of the methodology checklist criteria have been fulfilled. Those criteria that have not been fulfilled or not adequately described are thought unlikely to alter the conclusions.\n\n– Few or no methodology checklist criteria have been fulfilled. The conclusions of the study are thought likely or very likely to alter.\n\nThe 'Newcastle Ottawa' scale was used in effectiveness review one to assess the quality of cohort and case–control studies. Included studies were scored as follows to indicate the risk of bias:\n\n++ Very low risk.\n\n+ Low risk.\n\n– High risk.\n\nu Unclear.\n\n## Summarising the evidence and making evidence statements\n\nThe review data was summarised in evidence tables (see full reviews).\n\nThe findings from the reviews were synthesised and used as the basis for a number of evidence statements relating to each key question. The evidence statements were prepared by the public health collaborating centre (see appendix A). The statements reflect its judgement of the strength (quantity, type and quality) of evidence and its applicability to the populations and settings in the scope.\n\n# Cost effectiveness\n\nFor effectiveness review one, the economic analysis consisted of a cost-effectiveness analysis.\n\nFor effectiveness review two, the economic analysis consisted of a review of economic evaluations and a cost-effectiveness analysis.\n\n## Economic review\n\nFor the review of economic evaluations, studies were identified by searching EconLit and NHS EED during August 2009. Targeted searches were also undertaken where additional information was required.\n\nStudies were included if they were cost-effectiveness, cost-benefit or cost-minimisation analyses of:\n\ndietary or physical activity interventions to help manage the weight of postnatal women\n\nany dietary or physical activity intervention following pregnancy that may impact on the woman's weight.\n\nStudies were excluded if they:\n\nwere not published in English\n\ninvolved pharmacological interventions, surgery or complementary therapies.\n\n## Economic modelling\n\nTwo economic models were constructed to incorporate data from the reviews of effectiveness and cost effectiveness. The results are summarised in appendix C and the detailed reports of the economic models are 'Interventions to manage weight gain in pregnancy' and 'The cost-effectiveness of weight management interventions after childbirth'.\n\n# Fieldwork\n\nFieldwork was carried out to evaluate how relevant and useful NICE's recommendations are for practitioners and how feasible it would be to put them into practice. It was conducted with practitioners and commissioners who are involved in antenatal and postnatal care services, fertility services, leisure services, community groups, weight management services and children's centres. They included those working in the NHS, local authorities and organisations in the private, voluntary and community sectors.\n\nThe fieldwork comprised:\n\nThree 1-day workshops carried out in London and Manchester with a total of 66 practitioners. They included commissioners, consultants in public health, food and nutrition advisers, midwives, obstetricians and public health specialists. They discussed all the draft recommendations including the role of leisure services, the voluntary sector and other non NHS organisations.\n\nThree focus groups held in Doncaster, Harlow and Leicester with 26 practitioners. They included clinical and public health dietitians, consultant midwives, nurses, obesity coordinators and obstetric registrars. They discussed the recommendations in relation to pregnancy.\n\nFour focus groups held in children's centres in Leeds, Liverpool, Newham and Sandwell with 21 practitioners. They included breastfeeding coordinators, children's centre managers, commissioning managers, community dietitians, community nutritionists and health visitors. They discussed the recommendations related to the period following childbirth.\n\nTwenty-eight telephone interviews carried out with GPs, practice nurses and managers of children's centres and local authority leisure services. They discussed all the recommendations, particularly those most relevant to those professionals and services.\n\nThese four approaches were commissioned to ensure there was ample geographical coverage. The main issues arising are set out in appendix C under 'fieldwork findings'. The full fieldwork report is 'Weight management during pregnancy and after childbirth'.\n\n# How PHIAC formulated the recommendations\n\nAt its meetings in November 2009 and December 2009, PHIAC considered the evidence of effectiveness and cost effectiveness to determine:\n\nwhether there was sufficient evidence (in terms of quantity, quality and applicability) to form a judgment\n\nwhether, on balance, the evidence demonstrates that the intervention is effective, ineffective or equivocal\n\nwhere there is an effect, the typical size of effect.\n\nPHIAC developed draft recommendations through informal consensus, based on the following criteria.\n\nStrength (type, quality, quantity and consistency) of the evidence.\n\nThe applicability of the evidence to the populations/settings referred to in the scope.\n\nEffect size and potential impact on the target population's health.\n\nImpact on inequalities in health between different groups of the population.\n\nEquality and diversity legislation.\n\nEthical issues and social value judgements.\n\nCost effectiveness (for the NHS and other public sector organisations).\n\nBalance of harms and benefits.\n\nEase of implementation and any anticipated changes in practice.\n\nWhere possible, recommendations were linked to evidence statements (see appendix C for details). Where a recommendation was inferred from the evidence, this was indicated by the reference 'IDE' (inference derived from the evidence).\n\nThe draft guidance, including the recommendations, was released for consultation in February 2010. At its meeting in April 2010, PHIAC amended the guidance in light of comments from stakeholders and experts and the fieldwork. The guidance was signed off by the NICE Guidance Executive in June 2010.", 'Appendix C: The evidence': "This appendix lists evidence statements from two reviews provided by a public health collaborating centre (see appendix A) and links them to the relevant recommendations. (See appendix B for the key to quality assessments.) The evidence statements are presented here without references – these can be found in the full review (see appendix E for details). It also sets out a brief summary of findings from the economic analysis.\n\nThe two reviews of effectiveness are:\n\n'Systematic review of dietary and/or physical activity interventions for weight management in pregnancy'.\n\n'Systematic review of weight management interventions after childbirth'.\n\nEvidence statement 1.3 indicates that the linked statement is numbered 3 in review 1. Evidence statement 2.3 indicates that the linked statement is numbered 3 in review 2.\n\nThe reviews, economic analysis and fieldwork report are available. Where a recommendation is not directly taken from the evidence statements but is inferred from the evidence, this is indicated by IDE (inference derived from the evidence).\n\nRecommendation 1: evidence statements 1.19, 1.20, 1.21, 1.22; IDE\n\nRecommendation 2: evidence statements 1.1, 1.18, 1.20, 1.21, 1.26; IDE\n\nRecommendation 3: evidence statements 1.3, 1.4, 1.7, 1.12, 1.14, 1.15, 1.16, 1.17, 1.19, 1.21, 1.22; IDE\n\nRecommendation 4: evidence statements 2.1, 2.3, 2.6, 2.12, 2.13; IDE\n\nRecommendation 5: evidence statements 1.1, 1.18, 2.1, 2.3, 2.6, 2.12, 2.13; IDE\n\nRecommendation 6: IDE\n\nRecommendation 7: evidence statements 1.16, 1.17, 1.19, 1.26; IDE\n\n# Evidence statements\n\nPlease note that the wording of some evidence statements has been altered slightly from those in the evidence reviews to make them more consistent with each other and NICE's standard house style.\n\n## Evidence statement 1.1\n\nThere is weak evidence from one Australian-based case series that obese women trying to become pregnant but experiencing infertility can achieve a statistically significant reduction in body mass index (BMI) through a programme that includes regular physical activity, advice about healthy eating and group support.\n\n## Evidence statement 1.3\n\nThere is evidence from two USA-based and one Canadian randomised controlled trial (RCT) (one [+] and two [−]) that interventions targeted at healthy weight or overweight pregnant women, encouraging a healthy diet and increased or regular physical activity, supported by weight monitoring, reduces the proportion of women exceeding Institute of Medicine (1990) guidelines for healthy weight gain in pregnancy.\n\n## Evidence statement 1.4\n\nThere is weak evidence from two studies (one [−] and one [+]), conducted in Denmark and Sweden among obese women that interventions promoting healthy eating and/or moderate physical activity leads to a reduction in weight retained postpartum when compared with controls.\n\n## Evidence statement 1.7\n\nThere were no adverse effects reported with moderate physical activity and/or dieting during pregnancy.\n\n## Evidence statement 1.12\n\nThere is evidence from one US-based observational study (++) that overweight women who consumed three or more servings of fruit and vegetables per day gained significantly less weight than those who consumed fewer servings during pregnancy.\n\n## Evidence statement 1.14\n\nThere is evidence from one US-based observational study (+) that not receiving advice regarding appropriate weight gain was associated with weight gain outside the recommended levels among women across the BMI spectrum.\n\n## Evidence statement 1.15\n\nUK-based qualitative evidence (+) suggests that the development and attendance in dietary interventions for young women may be facilitated by taking into account women's age, social, educational and psychological needs as well as provision of incentives such as free food and access to a midwife.\n\n## Evidence statement 1.16\n\nOne UK-based qualitative study (+) retrospectively explored mothers' views on monitoring during their pregnancy/ies.\n\nWomen reported feeling that interactions with health professionals in relation to routine weighing were not enabling, and that they felt a lack of control. Women tended to be given limited explanation or feedback on weighing practices, although they accepted professional advice and intervention.\n\nRoutine monitoring of weight may not be acceptable to any women anxious about their weight without their consent, meaningful explanation and feedback.\n\n## Evidence statement 1.17\n\nHealth professionals reported (one [++]) that routine weighing of pregnant women was dependent on the location of the initial booking session. NHS premises tended to have resources for weighing whereas this was more ad-hoc in the community where scales may not be available and community midwives were not supplied with portable equipment. It was reported that even in NHS premises, equipment may not be suitable for weighing obese women.\n\n## Evidence statement 1.18\n\nNo UK-based qualitative evidence was identified on the views, perceptions and beliefs of health professionals, women actively planning a pregnancy and their partners and families about diet, physical activity and weight management prior to pregnancy. However, there is UK-based qualitative evidence to suggest that women's eating habits during pregnancy are related to pre-pregnancy dietary attitudes and behaviour. Weight and body shape concerns are affected by size prior to pregnancy (+). Women's dietary restraint may be continued or relaxed during pregnancy (+).\n\n## Evidence statement 1.19\n\nEvidence from three UK-based qualitative studies (all [++]) suggests that weight management information and advice from professionals is not received or assimilated by many women during pregnancy. Available information is often vague, confusing, contradictory, and is not linked to weight management.\n\nOverweight women may feel they are not receiving relevant, tailored information about appropriate diet and weight gain during pregnancy (+).\n\n## Evidence statement 1.20\n\nThere is evidence from UK-based qualitative research (one [+] and one [++]) that women may be unaware of the potential effects of obesity during pregnancy. However, they may avoid information about their health if they find it distressing and will only action it when they feel the time is right for the well-being of themselves, their unborn baby and their partners (+).\n\n## Evidence statement 1.21\n\nThere is evidence from UK-based qualitative research (++) that health professionals working in maternity units may feel they have insufficient time to discuss weight issues with women during pregnancy and consider that it is too late to give advice on weight management once a woman is pregnant. Health professionals themselves report that women's access to the information and advice on weight management is often ad-hoc.\n\n## Evidence statement 1.22\n\nEvidence from two UK-based qualitative studies (one [++] and one [+]) suggests that even relatively active women reduce their physical activity during pregnancy (although they are more likely to continue to be active at some level). One study (++) found that pregnant women decreased their activity levels based on advice from health professionals, or more commonly, on information they had read in books and magazines. Family members, friends, and even health trainers tended to discourage physical activity. Women balanced their fears of injury to themselves or harm to the baby with aims toward weight management. Women also reported reduced motivation, physical limitations due to larger size and tiredness during pregnancy and a lack of facilities. Another study reported that pregnant women may feel self-conscious when carrying out physical activity (+).\n\n## Evidence statement 1.26\n\nQualitative evidence from two UK-based studies (one [++] and one [+]) suggest there are communication difficulties between overweight women and health professionals. One study of health professionals found that they are often embarrassed to discuss issues of weight with overweight women, and that the women themselves were also embarrassed (++). Such experiences may not be fixed, but may change over the course of a pregnancy.\n\nOne study (++) explored the views of health professionals, some of which found it difficult to raise this issue sensitively. They reported a lack of guidance on this issue, though were aware of the risks and benefit so raising the issue. They were concerned that some women may stop attending antenatal appointments if they felt victimised.\n\n## Evidence statement 2.1\n\nThere is limited evidence from one (+) US-based RCT that dietary intervention alone (aiming for 35% energy deficit) from 12 weeks postpartum, may help women across the BMI spectrum start to lose more weight after childbirth compared to usual care. However, the short length of this intervention (11\xa0days) makes it difficult to draw conclusions on the effectiveness of the study. Four-day weighed food records suggested that calorie intake was not lower in the intervention compared to the control arm of the trial. The setting of this study (US) makes it somewhat relevant to the UK.\n\n## Evidence statement 2.3\n\nFour out of five US-based RCTs addressing diet and physical activity postpartum found a significant reduction in total weight among women across the BMI spectrum in the intervention group compared to control (three [+] and one [−]). Only one (+) US-based RCT found that total weight was not significantly lower in the intervention group compared to control. Results did not appear to vary based on the start dates of intervention or the length of follow-up.\n\n## Evidence statement 2.6\n\nIn line with their results for weight loss, three RCTs from the US (two [+] and one [−]) found that an intervention focusing on diet and exercise resulted in decreased calorie intake and decreased consumption of foods such as sweet beverages, desserts and snacks. Of these studies, one also found a significant increase in energy expenditure between exercise groups (−) whereas another (+) found no significant difference in total energy expenditure between groups. One (+) did not report results for physical activity.\n\n## Evidence statement 2.12\n\nThe evidence suggests weight management interventions addressing diet and physical activity had little or no adverse effects on breastfeeding outcomes, including milk volume, infant intake and weight, time and frequency of feeding (two [+]). Milk protein was observed to decrease in one short US-based trial (+). Overweight women had higher milk energy outputs and leaner women saw a decrease in milk energy output.\n\n## Evidence statement 2.13\n\nThe one high quality (+) RCT which examined correlations between monitoring and weight loss found that there was a significant correlation between number of self-monitoring records returned and weight loss (r\xa0=\xa00.50, p\xa0<\xa00.005). However, homework completion or telephone contact with research staff was not significantly correlated with weight loss. Women enrolled in this trial had an above average BMI bordering on obese classification at start of the intervention. None of the included studies considered the effectiveness of monitoring alone.\n\n# Cost-effectiveness evidence\n\nFor weight management during pregnancy, a short-term model was applied. There was insufficient evidence of effect so the cost effectiveness estimation was subject to great uncertainty. For weight management after childbirth, the model used a study in which women's weight was measured at both 6\xa0months and 15\xa0years postpartum. This was compared with their pre- and post-pregnancy weight. Using a 15-year time horizon, the estimated cost per quality-adjusted life year (QALY) gained was £44,000. Using a lifetime horizon (the usual measure of cost effectiveness) it was £9000.\n\n# Fieldwork findings\n\nFieldwork aimed to test the relevance, usefulness and feasibility of putting the recommendations into practice. PHIAC considered the findings when developing the final recommendations. For details, see the fieldwork section in appendix B and the full expert report.\n\nFieldwork participants in antenatal and postnatal care services, fertility services, leisure services, community groups, weight management services and children's centres were generally positive about the recommendations. They believed they could potentially help encourage weight management before, during and after pregnancy by raising awareness of the issue, especially among non-health professionals.\n\nHowever, more focus was needed on the psychological and emotional issues linked to weight management. In addition, the importance of helping not just the women, but her whole family, to change their behaviour was emphasised.\n\nParticipants also said that the importance of breastfeeding – highlighting the health benefits and its role in weight management – needed to be stressed.\n\nPractitioners felt that the recommendations were less relevant to some hard-to-reach groups such as women with a lower socioeconomic status, those from some minority ethnic groups and pregnant teenagers. In addition, there was mixed feedback regarding the feasibility of implementing them. Some reported that they reflected current practice. Others felt it would be difficult to carry them out.\n\nThe feasibility of carrying out the 6 to 8 week postnatal check on a consistent basis and the limited availability of dietitians in some areas were both cited as obstacles to implementation.\n\nParticipants emphasised that weight management is a sensitive issue. Many health professionals try to avoid broaching the subject and, when they do, it takes time. Training in communications skills was needed to deal with this type of issue, they said.\n\nIt was felt that the impact of the recommendations would vary across the country but that they would generally be more effective if actions and services were tailored to meet a woman's individual needs.\n\nParticipants pointed out that they would have cost and resource implications, due to the large number of women that they would apply to.", 'Appendix D: Gaps in the evidence': 'PHIAC identified a number of gaps in the evidence relating to the interventions under examination, based on an assessment of the evidence. These gaps are set out below.\n\n. There is a lack of evidence on the underlying mechanisms linking gestational weight gain and pregnancy outcomes. This is needed to help determine whether weight management is safe and appropriate for pregnant women.\n\n. There is a lack of evidence on how much weight should be gained during pregnancy, when is the most effective time for women to start managing their weight after childbirth and the optimal rate of weight loss.\n\n. There are few well-designed UK intervention studies on weight management in pregnancy and after childbirth. In particular, there is a lack of evidence on safe, effective interventions for women who are obese but who do not have diabetes, and those who are breastfeeding.\n\n. There is a lack of evidence about the effectiveness and cost effectiveness of weight management interventions for women before pregnancy – including for those who may be planning a pregnancy.\n\n. There is limited evidence about the effectiveness and cost effectiveness of weight management interventions in pregnancy and after childbirth for women from disadvantaged, low-income and minority ethnic groups.\n\n. Few weight management interventions include adequate and validated measures of diet and physical activity. They often rely on self-reporting.\n\n. Few studies of weight management before, during and after pregnancy include interventions that are evaluated using process and qualitative data to determine which components are effective.\n\n. There is limited evidence on the role of breastfeeding in helping women to gain or retain a healthy weight after childbirth.\n\nThe Committee made 5 recommendations for research.', 'Appendix E: Supporting documents': "Supporting documents include the following:\n\nEvidence reviews: 'Systematic review of dietary and/or physical activity interventions for weight management in pregnancy'; 'Systematic review of weight management interventions after childbirth'.\n\nReviews of economic evaluations: 'Interventions to manage weight gain in pregnancy'; 'The cost-effectiveness of weight management interventions after childbirth'.\n\nFieldwork report: 'Weight management during pregnancy and after childbirth'.", 'Finding more information ': "You can see everything NICE says on this topic in the NICE Pathways on diet, physical activity and maternal and child nutrition.\n\nTo find NICE guidance on related topics, including guidance in development, see our topic pages for diet, nutrition and obesity, physical activity and postnatal care.\n\nFor full details of the evidence and the guideline committee's discussions, see the evidence reviews. You can also find information about how the guideline was developed.\n\nNICE has produced tools and resources to help you put this guideline into practice. For general help and advice on putting NICE guidelines into practice, see resources to help you put guidance into practice."}	https://www.nice.org.uk/guidance/ph27	This guideline covers how to assess and monitor body weight and how to prevent someone from becoming overweight or obese before, during and after pregnancy. The aim is to help all women who have a baby to achieve and maintain a healthy weight by adopting a balanced diet and being physically active.
57fc492f5ed2084b18de63b4d9b7075a2da5f403	nice	Capecitabine for the treatment of advanced gastric cancer	Capecitabine for the treatment of advanced gastric cancer Evidence-based recommendations on capecitabine for treating advanced gastric cancer in adults. # Guidance Capecitabine in combination with a platinum-based regimen is recommended for the first-line treatment of inoperable advanced gastric cancer.# The technology Capecitabine (Xeloda, Roche Products) is an orally administered pro-drug of fluorouracil. It is converted to fluorouracil by enzymes that are principally located in the liver and tumour tissue. This leads to a higher concentration of fluorouracil in tumour tissue than in normal tissues. Capecitabine has a UK marketing authorisation for the first-line treatment of advanced gastric cancer in combination with a platinum-based regimen. According to the summary of product characteristics (SPC), contraindications include known dihydropyrimidine dehydrogenase deficiency, severe leucopenia, neutropenia or thrombocytopenia, severe hepatic impairment and severe renal impairment. The SPC states that capecitabine has been associated with hand–foot syndrome, diarrhoea, neutropenia, peripheral neuropathy, headache and alopecia. For full details of side effects and contraindications, see the SPC. Capecitabine is administered orally. The recommended dose of capecitabine is 625 mg/m2 twice daily for 21 days if it is used as part of the epirubicin, cisplatin and capecitabine (ECX) regimen, or the epirubicin, oxaliplatin and capecitabine (EOX) regimen. If it is used as part of a capecitabine and cisplatin (CX) regimen, the recommended dose of capecitabine is 1000 mg/m2 twice daily for 14 days in every 21 days. Treatment should be stopped if the disease gets worse or if there is intolerable toxicity. The cost of 60 150-mg tablets of capecitabine is £40.02 and the cost of 120 500-mg tablets is £265.55 (excluding VAT; Monthly Index of Medical Specialities , March 2010). Costs may vary in different settings because of negotiated procurement discounts.# The manufacturer's submission The Appraisal Committee (appendix A) considered evidence submitted by the manufacturer of capecitabine and a review of this submission by the Evidence Review Group (ERG; appendix B). The manufacturer's submission considered the use of capecitabine with epirubicin plus cisplatin or oxaliplatin compared with fluorouracil with epirubicin plus cisplatin or oxaliplatin, and capecitabine plus cisplatin compared with fluorouracil plus cisplatin. The population was people with locally advanced (that is, the disease had spread to regional lymph nodes) or metastatic (that is, the disease had spread beyond the regional lymph nodes to other parts of the body) inoperable gastric cancer. This was in line with the scope, which restricted the population to people with inoperable advanced gastric cancer. The manufacturer reported details of two phase III multicentre randomised controlled trials (REAL-2 and ML17032). These trials assessed the non-inferiority of capecitabine compared with fluorouracil for the treatment of advanced gastric cancer. REAL-2 compared ECX and EOX combinations with epirubicin/cisplatin/fluorouracil (ECF) and epirubicin/oxaliplatin/fluorouracil (EOF) combinations. ML17032 compared CX with cisplatin/fluorouracil (CF). The REAL-2 trial was an open-label UK multicentre study that enrolled adults with advanced carcinoma of the oesophagus, oesophageal-gastric junction or stomach. People were included in the trial if they had locally advanced or metastatic adenocarcinoma, squamous cell carcinoma or undifferentiated carcinoma. In addition the primary tumour had to be classified as inoperable. People were randomised to receive capecitabine plus platinum-based chemotherapy regimens: ECX regimen (n = 241), ECF regimen (n = 249), EOX regimen (n = 239) or EOF regimen (n = 235). The doses were as specified in the individual SPCs of each drug. In all cases treatment was repeated every 3 weeks for 8 cycles in the absence of progressive disease or unacceptable toxicity. The primary endpoint was to determine non-inferiority of overall survival in people receiving capecitabine compared with those receiving fluorouracil, and non-inferiority of overall survival in people receiving oxaliplatin compared with those receiving cisplatin. The null hypothesis of non-inferiority of the capecitabine regimen was rejected if the upper limit of the 95% confidence interval (CI) around the hazard ratio (HR) for overall survival was more than 1.23. The manufacturer reported that REAL-2 met the two primary non-inferiority endpoints, and that there was a trend towards improved survival in favour of both capecitabine over fluorouracil and oxaliplatin over cisplatin. The manufacturer also reported that the trial showed non-inferiority in terms of overall survival for capecitabine; the HR adjusted for performance status, extent of disease and age was 0.89 (95% CI 0.77 to 1.02) in the per-protocol population. This was based on the comparison of ECF and EOF versus ECX and EOX. The manufacturer also reported that for the secondary endpoints, there was no significant difference in progression-free survival between the capecitabine and the fluorouracil arms or between the cisplatin and the oxaliplatin arms. There was minimal quality-of-life data reported in REAL-2 and there were no differences between the mean scores at baseline and 12 weeks between any of the groups on the General Health Status subscale of the European Organization for Research and Treatment of Cancer (EORTC)-30 questionnaire. ML17032 was an open-label study that enrolled people with advanced gastric adenocarcinoma. Adults were included in the trial if they had histologically confirmed gastric adenocarcinoma with advanced and/or metastatic disease and at least one measurable lesion according to Response Evaluation Criteria in Solid Tumors (RECIST) that had not been irradiated and a Karnofsky performance status score of 70% or higher. People were randomised to receive cisplatin (80 mg/m2 intravenously, day 1) plus fluorouracil (800 mg/m2 intravenously, days 1–5 as a continuous infusion) (n = 156) or cisplatin (80 mg/m2 intravenously, day 1) plus capecitabine (1000 mg/m2 orally, twice daily, days 1–14) (n = 160). The primary endpoint was non-inferiority of progression-free survival. The null hypothesis of non-inferiority of the capecitabine regimen was rejected if the upper limit of the 95% CI around the HR for progression-free survival was more than 1.25. In the per-protocol population, there was non-inferiority of progression-free survival in people receiving CX compared with those receiving CF (adjusted HR 0.85, 95% CI 0.65 to 1.11). The manufacturer reported that the results showed a trend towards improved progression-free survival with CX compared with CF in the unadjusted analysis. The median overall survival was 10.5 months for CX compared with 9.3 months for CF (HR 0.85, 95% CI 0.64 to1.13). It was also reported by the manufacturer that the trial demonstrated non-inferiority of capecitabine compared with fluorouracil for the secondary end-points of overall survival, response rate, mean time of response and duration of response. No quality of life data were collected in ML17032. The manufacturer also reported a published meta-analysis that combined the individual data from 1318 people taking part in the REAL-2 and ML17032 trials. The aim of the meta-analysis was to test whether capecitabine was superior to fluorouracil within the double and triple combination chemotherapy regimens for people with advanced oesophago-gastric cancer. The primary endpoint was overall survival and the secondary endpoints were progression-free survival and response rate. The median overall survival for the intention-to-treat population was 285 days (95% CI 265 to 305 days) for people treated with fluorouracil (n = 664) and 322 days (95% CI 300 to 343 days) for people treated with capecitabine (n = 654). This resulted in an unadjusted HR of 0.87 (95% CI 0.77 to 0.98, p = 0.027) in favour of capecitabine. There was no evidence of any statistically significant heterogeneity of treatment effect according to baseline patient characteristics (such as age, disease site and histology). The meta-analysis reported that superiority of capecitabine over fluorouracil was maintained with multivariate analyses (adjusted HR 0.87, 95% CI 0.77 to 0.98, p = 0.02).The meta-analysis also reported a non statistically significant trend towards improved progression-free survival in people receiving capecitabine (unadjusted HR 0.91, 95% CI 0.81 to 1.02, p = 0.093). In REAL-2, grade 3 and 4 neutropenia was more common in the ECX arm compared with the ECF arm and there was an increased level of fatigue in the EOF arm compared with the EOX arm. Stomatitis occurred more frequently and with greater severity in the CF arm than in the CX arm in ML17032, while hand–foot syndrome was more common in the CX arm. The ML17032 trial also reported that adverse events leading to dose modification were more common in the CX arm (62%) compared with the CF arm (48%). On the basis of equivalent clinical effectiveness, similar safety and improved patient convenience, a cost-minimisation model was developed to evaluate the costs for each regimen. The manufacturer reported that this captured all significant incremental direct costs relating to switching from fluorouracil-based therapies to capecitabine-based therapies. The model considered both the drug acquisition and drug administration costs for all the regimens evaluated. People entered the model at the start of treatment when they received either capecitabine or fluorouracil and left the model after 5.5 cycles (21 days per cycle), which was the time horizon of the model. The costs of treatment-related adverse events were not included. The overall tolerability profile of capecitabine was considered by the manufacturer to be similar and at least as good as fluorouracil. The manufacturer also stated that the adverse events associated with the method by which fluorouracil is administered, such as central-line complications, can be expensive to manage. This meant that the costs associated with the management of adverse events with capecitabine were unlikely to be higher than those associated with fluorouracil. Therefore, the non-inclusion of adverse events costs in the model would be expected to favour fluorouracil. The manufacturer stated that the economic evaluation of capecitabine was undertaken within its licensed indication for the first-line treatment of advanced gastric cancer in combination with a platinum-based regimen. There were three sets of analyses: a comparison of ECX with ECF, EOX with EOF, and CX with CF. A total of six regimens were therefore analysed in the cost-minimisation model. The dosages in each regimen were analysed according to the SPC for each treatment and no drug wastage was taken into account. The manufacturer also conducted some additional sensitivity analyses that included one-way sensitivity analyses, scenario analyses, a worst case scenario analysis and threshold analyses. The base-case results included all the drug acquisition and administration costs for all the regimens considered in the submission. All capecitabine-based regimens were shown to be cost saving compared with equivalent fluorouracil-based regimens. The overall NHS cost saving for switching from ECF to ECX regimens was £1620. The overall NHS cost saving for switching from EOF to EOX regimens was £1572. For the double combination chemotherapy regimens the overall NHS saving of switching from CF to CX was £4210. All the results of the sensitivity and scenario analyses conducted by the manufacturer supported the base case and suggested that capecitabine-based regimens were cost saving compared with fluorouracil-based regimens. The ERG considered that the clinical-effectiveness evidence presented by the manufacturer reflected the available relevant evidence. It noted that the ML17032 trial was underpowered since the trial had only 50% power to detect statistically significant non-inferiority. The REAL-2 and the ML17032 trials used appropriate outcomes, but there were limited data on health-related quality of life. The ERG also noted that in clinical practice, fluorouracil and capecitabine would be administered in lower doses in the double combination chemotherapy regimen compared with the doses used in ML17032. Overall, the ERG considered the manufacturer's approach to the economic evaluation reasonable and that the cost-minimisation analysis used in the submission was acceptable. The ERG stated that there was minimal change to the savings when many of the assumptions used were explored. The ERG pointed out that treatments cannot be considered to be exactly equivalent due to uncertainty in estimating their effectiveness. By conducting a cost-minimisation analysis, the manufacturer did not address the uncertainty around the estimates of efficacy. However, they performed a threshold analysis but the ERG noted that modelling a scenario in which fluorouracil was more effective was unlikely to be relevant to the determination of capecitabine's cost effectiveness. The ERG noted that adverse events had not been included in the cost-minimisation model because the manufacturer assumed that the costs associated with adverse event management were unlikely to be higher for capecitabine than fluorouracil. The ERG highlighted that rare adverse events may not have been identified because of the large sample sizes needed to detect these. Therefore, the ERG felt that some uncertainty remained about treatment-related adverse events associated with capecitabine and fluorouracil regimens. The ERG also noted that number of cycles used in the model did not represent the number used in UK clinical practice: the maximum number of cycles in clinical practice is usually six, but in REAL-2 the median (rather than the maximum) number of cycles received was six. The ERG noted some additional areas of uncertainty. In the model, the manufacturer calculated capecitabine costs based on milligrams used. The ERG considered that in clinical practice, this would be rounded to match the available tablets. It also considered that in calculating fluorouracil costs, wastage had not been taken into account. The ERG noted that when calculating epirubicin, cisplatin and oxaliplatin costs, the manufacturer used an average of the NHS list prices. In practice, the NHS is likely to prefer the cheapest product. The ERG also considered that, in practice, the dose of capecitabine may be reduced by 25–50% because of toxicity. The ERG undertook exploratory analyses that took into account many of the above areas of uncertainty. In all analyses capecitabine was cost saving compared with fluorouracil. Full details of all the evidence are in the manufacturer's submission and the ERG report.# Consideration of the evidence The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of capecitabine, having considered evidence on the nature of gastric cancer and the value placed on the benefits of capecitabine by people with the condition, those who represent them, and clinical specialists. It also took into account the effective use of NHS resources. # Clinical effectiveness The Committee considered the clinical effectiveness of capecitabine for the treatment of advanced gastric cancer from the two open-label trials that assessed the non-inferiority of capecitabine compared with fluorouracil. The Committee noted that the results of the trials indicated that capecitabine was not inferior to fluorouracil for overall survival (REAL-2 trial) and progression-free survival (ML17032 trial). There was also a trend to improved survival with capecitabine in the published meta-analysis of both trials. The Committee noted the ERG concerns that the ML17032 study was underpowered. The Committee also noted that with non-inferiority trials, it was possible for a treatment to achieve non-inferiority with a worse point estimate than the comparator treatment. Therefore, the Committee carefully considered the estimates from the trials and the published meta-analysis and their confidence intervals. The Committee agreed that the results of the studies showed a trend towards improved survival and concluded that capecitabine was probably at least as effective as intravenously administered fluorouracil. The Committee noted that the REAL-2 trial was conducted in UK centres, although it included people with cancer involving the gastro-oesophageal junction and distal oesophagus as well as the stomach, and a small minority with squamous cell carcinoma rather than adenocarcinoma. However, the Committee accepted that the two trials were generalisable to people with advanced, inoperable gastric cancer in the UK. In addition, the Committee noted that the people in both trials were relatively young, with good performance status. The clinical specialists highlighted that even though the people in the trials were younger than the median age of death of people with gastric cancer, the trial population was representative of those in UK clinical practice who would be prescribed a chemotherapy regimen. Therefore the Committee concluded that the trials were sufficiently representative of UK practice. The Committee considered current clinical practice for the first-line treatment of inoperable advanced gastric cancer. It heard about the experience of people receiving treatment and whether people preferred oral treatment with capecitabine or intravenous treatment (via an infusion pump) with fluorouracil. The patient expert and clinical specialists explained that oral treatment allows for easier dose adjustment and less frequent visits to hospital, compared with an infusion pump that has to be replaced weekly. Oral treatment also offers an advantage for people in terms of carrying on with daily physical activities without the continuous presence of a pump. In addition, complications related to the presence of an indwelling venous line such as infection and line misplacement are avoided. The clinical specialists explained that the majority of people prefer oral treatment as long as there is no increase in adverse events. The Committee considered whether there were issues related to equality to be taken into account in its considerations. It acknowledged that some people with inoperable advanced gastric cancer may not be able to swallow oral capecitabine tablets, because of difficulty with swallowing as a result of the cancer, or because of nausea. However the Committee noted that although capecitabine is preferred in most circumstances, fluorouracil remains an alternative where capecitabine is contraindicated or otherwise unsuitable. Therefore, it concluded that there were no specific issues relating to equality that needed to be taken into account. The Committee then discussed hand–foot syndrome, which is a specific adverse event that occurs more frequently with capecitabine therapy than with intravenously administered fluorouracil. The clinical specialists noted that if reported early it can be successfully treated with emollient cream, vitamin B6 and temporary dose reduction. The Committee concluded that oral capecitabine therapy was the preferred first-line treatment option in most people able to tolerate it. # Cost effectiveness The Committee heard evidence on the cost effectiveness of capecitabine for the first-line treatment of inoperable advanced gastric cancer. It agreed that in this case the cost-minimisation analysis was an appropriate approach to the economic evaluation based on the clinical evidence that suggested that capecitabine was at least as effective as fluorouracil. The Committee recognised there were limited quality-of-life data but accepted that there was no reason to anticipate any major differences in quality of life between capecitabine-based and fluorouracil-based regimens. The Committee noted that the model assumed that there were no significant differences in the incidence or severity of adverse events between capecitabine and fluorouracil regimens, and so the costs of treatment-related adverse events were not included in the analysis. The Committee agreed that based on the trial data this was acceptable. The Committee then discussed the length of the model. It agreed that the time horizon of 5.5 cycles was a reasonable assumption as this was the mean number of treatment cycles given in the REAL-2 trial and is reflective of UK clinical practice. The Committee concluded that the parameters used in the model were acceptable. The Committee noted that the model showed that capecitabine-based regimens were cost saving compared with fluorouracil-based regimens. The Committee heard that the ERG had noted some areas of uncertainty and had undertaken exploratory analyses to assess these. However, in all these analyses, capecitabine was still likely to be cost saving compared with fluorouracil. The Committee therefore agreed that capecitabine would be a cost-effective use of NHS resources. The Committee concluded that capecitabine, in combination with a platinum-based regimen, should be recommended for the first-line treatment of inoperable advanced gastric cancer. # Summary of the Appraisal Committee's key conclusions Key conclusion The Committee concluded that capecitabine, in combination with a platinum-based regimen, should be recommended for the first-line treatment of inoperable advanced gastric cancer. Current practice Clinical need The patient expert and clinical specialists explained that oral treatment allows for easier dose adjustment and less frequent visits to the hospital, compared with an infusion pump that has to be replaced weekly. In addition, complications related to the presence of an indwelling venous line such as infection and line misplacement are avoided. Availability of alternative treatments The Committee considered current clinical practice for the first-line treatment of inoperable advanced gastric cancer. It heard about the experience of people receiving treatment and whether people preferred oral treatment with capecitabine or intravenous treatment (via an infusion pump) with fluorouracil. The clinical specialists explained that the majority of people prefer oral treatment as long as there is no increase in adverse events. The position of the treatment in the pathway of care for the condition Capecitabine has a UK marketing authorisation for the first-line treatment of advanced gastric cancer in combination with a platinum-based regimen. The technology Proposed benefits of the technology from the manufacturer, clinician and patient perspective The patient expert and clinical specialists explained that oral treatment allows for easier dose adjustment and less frequent visits to the hospital, compared with an infusion pump that has to be replaced weekly. Oral treatment also offers an advantage for people in terms of carrying on with daily physical activities without the continuous presence of a pump. Distinguishing features of the technology Capecitabine is an orally administered pro-drug of fluorouracil. Adverse effects The Committee discussed hand–foot syndrome, which is a specific adverse event that occurs more frequently with capecitabine therapy than with intravenously administered fluorouracil. The clinical specialists noted that if reported early it can be successfully treated with emollient cream, vitamin B6 and temporary dose reduction. Evidence for clinical effectiveness Availability and nature of evidence The Committee considered the clinical effectiveness of capecitabine for the treatment of advanced gastric cancer from two open-label trials that assessed the non-inferiority of capecitabine compared with fluorouracil. Quality of the evidence The Committee carefully considered the estimates from the trials and the published meta-analysis and their confidence intervals, noting the ERG concerns that one of the studies was underpowered. The Committee agreed that the results of the studies showed a trend towards improved survival and concluded that capecitabine was probably at least as effective as intravenously administered fluorouracil. Relevance to general clinical practice in the NHS The Committee accepted that the two trials were generalisable to people with advanced, inoperable gastric cancer in the UK. In addition, the Committee noted that the people in both trials were relatively young, with good performance status. The clinical specialists highlighted that even though the people in the trials were younger than the median age of death of people with gastric cancer, the trial population was representative of those in UK clinical practice who would be prescribed a chemotherapy regimen. Therefore the Committee concluded that trials were sufficiently representative of UK clinical practice. Uncertainties generated by the evidence The Committee noted the ERG concerns that the ML17032 study was underpowered. The Committee also noted that with non-inferiority trials, it was possible for a treatment to achieve non-inferiority with a worse point estimate than the comparator treatment. Therefore, the Committee carefully considered the estimates from the trials and the published meta-analysis and their confidence intervals. Are there any clinically relevant subgroups for which there is evidence of differential effectiveness? None Evidence for cost effectiveness Availability and nature of evidence The Committee heard evidence on the cost effectiveness of capecitabine for the first-line treatment of inoperable advanced gastric cancer. It agreed that in this case the cost-minimisation analysis was an appropriate approach to the economic evaluation based on the clinical evidence that suggested that capecitabine was at least as effective as fluorouracil. Uncertainties around and plausibility of assumptions and inputs in the economic model The Committee noted that the model assumed that there were no significant differences in the incidence or severity of adverse events between capecitabine and fluorouracil regimens, and so the costs of treatment-related adverse events were not included in the analysis. The Committee agreed that based on the trial data this was acceptable. The Committee then discussed the length of the model. It agreed that the time horizon of 5.5 cycles was a reasonable assumption as this was the mean number of treatment cycles given in the REAL-2 trial and is reflective of UK clinical practice. The Committee concluded that the parameters used in the model were acceptable. Incorporation of health-related quality-of-life benefits and utility values The Committee recognised there were limited quality-of-life data but accepted that there was no reason to anticipate any major differences in the quality of life between capecitabine-based and fluorouracil-based regimens. Are there specific groups of people for whom the technology is particularly cost effective? None Most likely cost-effectiveness estimate (given as an ICER) The Committee noted that the model showed that there were likely to be cost savings with capecitabine-based regimens compared with fluorouracil-based regimens. Additional factors taken into account Patient access scheme (Pharmaceutical Price Regulation Programme) No patient access scheme was submitted for the technology being appraised. End of life considerations (supplementary advice on end of life) Because the most plausible ICER was not more than £30,000 per QALY gained, the supplementary advice was not relevant. Equalities considerations, social value judgement The Committee considered whether there were issues related to equality to be taken into account in its considerations. It acknowledged that some people with inoperable advanced gastric cancer may not be able to swallow oral capecitabine tablets because of difficulty with swallowing as a result of the cancer, or because of nausea. However the Committee agreed noted that although capecitabine is preferred in most circumstances, fluorouracil remains an alternative where capecitabine is contraindicated or otherwise unsuitable. Therefore, it concluded that there were no specific issues relating to equality that needed to be taken into account. # Related NICE guidance Trastuzumab for the treatment of HER2-positive metastatic gastric cancer. NICE technology appraisal guidance 208 (2010)# Review of guidance The guidance on this technology will be considered for review in May 2013. The Guidance Executive will decide whether the technology should be reviewed based on information gathered by NICE, and in consultation with consultees and commentators. Andrew DillonChief ExecutiveJuly 2010# Changes after publication February 2014: minor maintenance March 2012: minor maintenance# About this guidance NICE technology appraisal guidance is about the use of new and existing medicines and treatments in the NHS in England and Wales. This guidance was developed using the NICE single technology appraisal process. We have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available. Your responsibility This guidance represents the views of NICE and was arrived at after careful consideration of the evidence available. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. However, the guidance does not override the individual responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or guardian or carer. Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties. Copyright © National Institute for Health and Clinical Excellence 2010. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.	{'Guidance': 'Capecitabine in combination with a platinum-based regimen is recommended for the first-line treatment of inoperable advanced gastric cancer.', 'The technology ': 'Capecitabine (Xeloda, Roche Products) is an orally administered pro-drug of fluorouracil. It is converted to fluorouracil by enzymes that are principally located in the liver and tumour tissue. This leads to a higher concentration of fluorouracil in tumour tissue than in normal tissues. Capecitabine has a UK marketing authorisation for the first-line treatment of advanced gastric cancer in combination with a platinum-based regimen.\n\nAccording to the summary of product characteristics (SPC), contraindications include known dihydropyrimidine dehydrogenase deficiency, severe leucopenia, neutropenia or thrombocytopenia, severe hepatic impairment and severe renal impairment. The SPC states that capecitabine has been associated with hand–foot syndrome, diarrhoea, neutropenia, peripheral neuropathy, headache and alopecia. For full details of side effects and contraindications, see the SPC.\n\nCapecitabine is administered orally. The recommended dose of capecitabine is 625 mg/m2 twice daily for 21 days if it is used as part of the epirubicin, cisplatin and capecitabine (ECX) regimen, or the epirubicin, oxaliplatin and capecitabine (EOX) regimen. If it is used as part of a capecitabine and cisplatin (CX) regimen, the recommended dose of capecitabine is 1000 mg/m2 twice daily for 14 days in every 21 days. Treatment should be stopped if the disease gets worse or if there is intolerable toxicity. The cost of\n\n60\xa0150-mg tablets of capecitabine is £40.02 and the cost of 120 500-mg tablets is £265.55 (excluding VAT; Monthly Index of Medical Specialities [MIMS], March 2010). Costs may vary in different settings because of negotiated procurement discounts.', "The manufacturer's submission": "The Appraisal Committee (appendix A) considered evidence submitted by the manufacturer of capecitabine and a review of this submission by the Evidence Review Group (ERG; appendix B).\n\nThe manufacturer's submission considered the use of capecitabine with epirubicin plus cisplatin or oxaliplatin compared with fluorouracil with epirubicin plus cisplatin or oxaliplatin, and capecitabine plus cisplatin compared with fluorouracil plus cisplatin. The population was people with locally advanced (that is, the disease had spread to regional lymph nodes) or metastatic (that is, the disease had spread beyond the regional lymph nodes to other parts of the body) inoperable gastric cancer. This was in line with the scope, which restricted the population to people with inoperable advanced gastric cancer. The manufacturer reported details of two phase III multicentre randomised controlled trials (REAL-2 and ML17032). These trials assessed the non-inferiority of capecitabine compared with fluorouracil for the treatment of advanced gastric cancer. REAL-2 compared ECX and EOX combinations with epirubicin/cisplatin/fluorouracil (ECF) and epirubicin/oxaliplatin/fluorouracil (EOF) combinations. ML17032 compared CX with cisplatin/fluorouracil (CF).\n\nThe REAL-2 trial was an open-label UK multicentre study that enrolled adults with advanced carcinoma of the oesophagus, oesophageal-gastric junction or stomach. People were included in the trial if they had locally advanced or metastatic adenocarcinoma, squamous cell carcinoma or undifferentiated carcinoma. In addition the primary tumour had to be classified as inoperable. People were randomised to receive capecitabine plus platinum-based chemotherapy regimens: ECX regimen (n = 241), ECF regimen (n\xa0=\xa0249), EOX regimen (n\xa0=\xa0239) or EOF regimen (n\xa0=\xa0235). The doses were as specified in the individual SPCs of each drug. In all cases treatment was repeated every 3\xa0weeks for 8 cycles in the absence of progressive disease or unacceptable toxicity. The primary endpoint was to determine non-inferiority of overall survival in people receiving capecitabine compared with those receiving fluorouracil, and non-inferiority of overall survival in people receiving oxaliplatin compared with those receiving cisplatin. The null hypothesis of non-inferiority of the capecitabine regimen was rejected if the upper limit of the 95% confidence interval (CI) around the hazard ratio (HR) for overall survival was more than 1.23.\n\nThe manufacturer reported that REAL-2 met the two primary non-inferiority endpoints, and that there was a trend towards improved survival in favour of both capecitabine over fluorouracil and oxaliplatin over cisplatin. The manufacturer also reported that the trial showed non-inferiority in terms of overall survival for capecitabine; the HR adjusted for performance status, extent of disease and age was 0.89 (95% CI 0.77 to 1.02) in the per-protocol population. This was based on the comparison of ECF and EOF versus ECX and EOX. The manufacturer also reported that for the secondary endpoints, there was no significant difference in progression-free survival between the capecitabine and the fluorouracil arms or between the cisplatin and the oxaliplatin arms. There was minimal quality-of-life data reported in REAL-2 and there were no differences between the mean scores at baseline and 12\xa0weeks between any of the groups on the General Health Status subscale of the European Organization for Research and Treatment of Cancer (EORTC)-30 questionnaire.\n\nML17032 was an open-label study that enrolled people with advanced gastric adenocarcinoma. Adults were included in the trial if they had histologically confirmed gastric adenocarcinoma with advanced and/or metastatic disease and at least one measurable lesion according to Response Evaluation Criteria in Solid Tumors (RECIST) that had not been irradiated and a Karnofsky performance status score of 70% or higher. People were randomised to receive cisplatin (80\xa0mg/m2 intravenously, day 1) plus fluorouracil (800\xa0mg/m2 intravenously, days 1–5 as a continuous infusion) (n = 156) or cisplatin (80\xa0mg/m2 intravenously, day 1) plus capecitabine (1000\xa0mg/m2 orally, twice daily, days 1–14) (n = 160). The primary endpoint was non-inferiority of progression-free survival. The null hypothesis of non-inferiority of the capecitabine regimen was rejected if the upper limit of the 95%\xa0CI around the HR for progression-free survival was more than 1.25.\n\nIn the per-protocol population, there was non-inferiority of progression-free survival in people receiving CX compared with those receiving CF (adjusted HR 0.85, 95% CI 0.65 to 1.11). The manufacturer reported that the results showed a trend towards improved progression-free survival with CX compared with CF in the unadjusted analysis. The median overall survival was 10.5\xa0months for CX compared with 9.3\xa0months for CF (HR 0.85, 95% CI 0.64 to1.13). It was also reported by the manufacturer that the trial demonstrated non-inferiority of capecitabine compared with fluorouracil for the secondary end-points of overall survival, response rate, mean time of response and duration of response. No quality of life data were collected in ML17032.\n\nThe manufacturer also reported a published meta-analysis that combined the individual data from 1318 people taking part in the REAL-2 and ML17032 trials. The aim of the meta-analysis was to test whether capecitabine was superior to fluorouracil within the double and triple combination chemotherapy regimens for people with advanced oesophago-gastric cancer. The primary endpoint was overall survival and the secondary endpoints were progression-free survival and response rate. The median overall survival for the intention-to-treat population was 285\xa0days (95% CI 265 to 305\xa0days) for people treated with fluorouracil (n\xa0=\xa0664) and 322\xa0days (95% CI 300 to 343\xa0days) for people treated with capecitabine (n\xa0=\xa0654). This resulted in an unadjusted HR of 0.87 (95% CI 0.77 to 0.98, p\xa0=\xa00.027) in favour of capecitabine. There was no evidence of any statistically significant heterogeneity of treatment effect according to baseline patient characteristics (such as age, disease site and histology). The meta-analysis reported that superiority of capecitabine over fluorouracil was maintained with multivariate analyses (adjusted HR 0.87, 95% CI 0.77 to 0.98, p\xa0= 0.02).The meta-analysis also reported a non statistically significant trend towards improved progression-free survival in people receiving capecitabine (unadjusted HR 0.91, 95% CI 0.81 to 1.02, p\xa0=\xa00.093).\n\nIn REAL-2, grade 3 and 4 neutropenia was more common in the ECX arm compared with the ECF arm and there was an increased level of fatigue in the EOF arm compared with the EOX arm. Stomatitis occurred more frequently and with greater severity in the CF arm than in the CX arm in ML17032, while hand–foot syndrome was more common in the CX arm. The ML17032 trial also reported that adverse events leading to dose modification were more common in the CX arm (62%) compared with the CF arm (48%).\n\nOn the basis of equivalent clinical effectiveness, similar safety and improved patient convenience, a cost-minimisation model was developed to evaluate the costs for each regimen. The manufacturer reported that this captured all significant incremental direct costs relating to switching from fluorouracil-based therapies to capecitabine-based therapies. The model considered both the drug acquisition and drug administration costs for all the regimens evaluated. People entered the model at the start of treatment when they received either capecitabine or fluorouracil and left the model after 5.5 cycles (21 days per cycle), which was the time horizon of the model. The costs of treatment-related adverse events were not included. The overall tolerability profile of capecitabine was considered by the manufacturer to be similar and at least as good as fluorouracil. The manufacturer also stated that the adverse events associated with the method by which fluorouracil is administered, such as central-line complications, can be expensive to manage. This meant that the costs associated with the management of adverse events with capecitabine were unlikely to be higher than those associated with fluorouracil. Therefore, the non-inclusion of adverse events costs in the model would be expected to favour fluorouracil.\n\nThe manufacturer stated that the economic evaluation of capecitabine was undertaken within its licensed indication for the first-line treatment of advanced gastric cancer in combination with a platinum-based regimen. There were three sets of analyses: a comparison of ECX with ECF, EOX with EOF, and CX with CF. A total of six regimens were therefore analysed in the cost-minimisation model. The dosages in each regimen were analysed according to the SPC for each treatment and no drug wastage was taken into account. The manufacturer also conducted some additional sensitivity analyses that included one-way sensitivity analyses, scenario analyses, a worst case scenario analysis and threshold analyses.\n\nThe base-case results included all the drug acquisition and administration costs for all the regimens considered in the submission. All capecitabine-based regimens were shown to be cost saving compared with equivalent fluorouracil-based regimens. The overall NHS cost saving for switching from ECF to ECX regimens was £1620. The overall NHS cost saving for switching from EOF to EOX regimens was £1572. For the double combination chemotherapy regimens the overall NHS saving of switching from CF to CX was £4210. All the results of the sensitivity and scenario analyses conducted by the manufacturer supported the base case and suggested that capecitabine-based regimens were cost saving compared with fluorouracil-based regimens.\n\nThe ERG considered that the clinical-effectiveness evidence presented by the manufacturer reflected the available relevant evidence. It noted that the ML17032 trial was underpowered since the trial had only 50% power to detect statistically significant non-inferiority. The REAL-2 and the ML17032 trials used appropriate outcomes, but there were limited data on health-related quality of life. The ERG also noted that in clinical practice, fluorouracil and capecitabine would be administered in lower doses in the double combination chemotherapy regimen compared with the doses used in ML17032.\n\nOverall, the ERG considered the manufacturer's approach to the economic evaluation reasonable and that the cost-minimisation analysis used in the submission was acceptable. The ERG stated that there was minimal change to the savings when many of the assumptions used were explored. The ERG pointed out that treatments cannot be considered to be exactly equivalent due to uncertainty in estimating their effectiveness. By conducting a cost-minimisation analysis, the manufacturer did not address the uncertainty around the estimates of efficacy. However, they performed a threshold analysis but the ERG noted that modelling a scenario in which fluorouracil was more effective was unlikely to be relevant to the determination of capecitabine's cost effectiveness. The ERG noted that adverse events had not been included in the cost-minimisation model because the manufacturer assumed that the costs associated with adverse event management were unlikely to be higher for capecitabine than fluorouracil. The ERG highlighted that rare adverse events may not have been identified because of the large sample sizes needed to detect these. Therefore, the ERG felt that some uncertainty remained about treatment-related adverse events associated with capecitabine and fluorouracil regimens. The ERG also noted that number of cycles used in the model did not represent the number used in UK clinical practice: the maximum number of cycles in clinical practice is usually six, but in REAL-2 the median (rather than the maximum) number of cycles received was six.\n\nThe ERG noted some additional areas of uncertainty. In the model, the manufacturer calculated capecitabine costs based on milligrams used. The ERG considered that in clinical practice, this would be rounded to match the available tablets. It also considered that in calculating fluorouracil costs, wastage had not been taken into account. The ERG noted that when calculating epirubicin, cisplatin and oxaliplatin costs, the manufacturer used an average of the NHS list prices. In practice, the NHS is likely to prefer the cheapest product. The ERG also considered that, in practice, the dose of capecitabine may be reduced by 25–50% because of toxicity. The ERG undertook exploratory analyses that took into account many of the above areas of uncertainty. In all analyses capecitabine was cost saving compared with fluorouracil.\n\nFull details of all the evidence are in the manufacturer's submission and the ERG report.", 'Consideration of the evidence': "The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of capecitabine, having considered evidence on the nature of gastric cancer and the value placed on the benefits of capecitabine by people with the condition, those who represent them, and clinical specialists. It also took into account the effective use of NHS resources.\n\n# Clinical effectiveness\n\nThe Committee considered the clinical effectiveness of capecitabine for the treatment of advanced gastric cancer from the two open-label trials that assessed the non-inferiority of capecitabine compared with fluorouracil. The Committee noted that the results of the trials indicated that capecitabine was not inferior to fluorouracil for overall survival (REAL-2 trial) and progression-free survival (ML17032 trial). There was also a trend to improved survival with capecitabine in the published meta-analysis of both trials. The Committee noted the ERG concerns that the ML17032 study was underpowered. The Committee also noted that with non-inferiority trials, it was possible for a treatment to achieve non-inferiority with a worse point estimate than the comparator treatment. Therefore, the Committee carefully considered the estimates from the trials and the published meta-analysis and their confidence intervals. The Committee agreed that the results of the studies showed a trend towards improved survival and concluded that capecitabine was probably at least as effective as intravenously administered fluorouracil.\n\nThe Committee noted that the REAL-2 trial was conducted in UK centres, although it included people with cancer involving the gastro-oesophageal junction and distal oesophagus as well as the stomach, and a small minority with squamous cell carcinoma rather than adenocarcinoma. However, the Committee accepted that the two trials were generalisable to people with advanced, inoperable gastric cancer in the UK. In addition, the Committee noted that the people in both trials were relatively young, with good performance status. The clinical specialists highlighted that even though the people in the trials were younger than the median age of death of people with gastric cancer, the trial population was representative of those in UK clinical practice who would be prescribed a chemotherapy regimen. Therefore the Committee concluded that the trials were sufficiently representative of UK practice.\n\nThe Committee considered current clinical practice for the first-line treatment of inoperable advanced gastric cancer. It heard about the experience of people receiving treatment and whether people preferred oral treatment with capecitabine or intravenous treatment (via an infusion pump) with fluorouracil. The patient expert and clinical specialists explained that oral treatment allows for easier dose adjustment and less frequent visits to hospital, compared with an infusion pump that has to be replaced weekly. Oral treatment also offers an advantage for people in terms of carrying on with daily physical activities without the continuous presence of a pump. In addition, complications related to the presence of an indwelling venous line such as infection and line misplacement are avoided. The clinical specialists explained that the majority of people prefer oral treatment as long as there is no increase in adverse events.\n\nThe Committee considered whether there were issues related to equality to be taken into account in its considerations. It acknowledged that some people with inoperable advanced gastric cancer may not be able to swallow oral capecitabine tablets, because of difficulty with swallowing as a result of the cancer, or because of nausea. However the Committee noted that although capecitabine is preferred in most circumstances, fluorouracil remains an alternative where capecitabine is contraindicated or otherwise unsuitable. Therefore, it concluded that there were no specific issues relating to equality that needed to be taken into account.\n\nThe Committee then discussed hand–foot syndrome, which is a specific adverse event that occurs more frequently with capecitabine therapy than with intravenously administered fluorouracil. The clinical specialists noted that if reported early it can be successfully treated with emollient cream, vitamin B6 and temporary dose reduction. The Committee concluded that oral capecitabine therapy was the preferred first-line treatment option in most people able to tolerate it.\n\n# Cost effectiveness\n\nThe Committee heard evidence on the cost effectiveness of capecitabine for the first-line treatment of inoperable advanced gastric cancer. It agreed that in this case the cost-minimisation analysis was an appropriate approach to the economic evaluation based on the clinical evidence that suggested that capecitabine was at least as effective as fluorouracil. The Committee recognised there were limited quality-of-life data but accepted that there was no reason to anticipate any major differences in quality of life between capecitabine-based and fluorouracil-based regimens.\n\nThe Committee noted that the model assumed that there were no significant differences in the incidence or severity of adverse events between capecitabine and fluorouracil regimens, and so the costs of treatment-related adverse events were not included in the analysis. The Committee agreed that based on the trial data this was acceptable. The Committee then discussed the length of the model. It agreed that the time horizon of 5.5 cycles was a reasonable assumption as this was the mean number of treatment cycles given in the REAL-2 trial and is reflective of UK clinical practice. The Committee concluded that the parameters used in the model were acceptable.\n\nThe Committee noted that the model showed that capecitabine-based regimens were cost saving compared with fluorouracil-based regimens. The Committee heard that the ERG had noted some areas of uncertainty and had undertaken exploratory analyses to assess these. However, in all these analyses, capecitabine was still likely to be cost saving compared with fluorouracil. The Committee therefore agreed that capecitabine would be a cost-effective use of NHS resources. The Committee concluded that capecitabine, in combination with a platinum-based regimen, should be recommended for the first-line treatment of inoperable advanced gastric cancer.\n\n# Summary of the Appraisal Committee's key conclusions\n\nKey conclusion\n\nThe Committee concluded that capecitabine, in combination with a platinum-based regimen, should be recommended for the first-line treatment of inoperable advanced gastric cancer.\n\n\n\nCurrent practice\n\nClinical need\n\n\n\nThe patient expert and clinical specialists explained that oral treatment allows for easier dose adjustment and less frequent visits to the hospital, compared with an infusion pump that has to be replaced weekly. In addition, complications related to the presence of an indwelling venous line such as infection and line misplacement are avoided.\n\n\n\nAvailability of alternative treatments\n\n\n\nThe Committee considered current clinical practice for the first-line treatment of inoperable advanced gastric cancer. It heard about the experience of people receiving treatment and whether people preferred oral treatment with capecitabine or intravenous treatment (via an infusion pump) with fluorouracil. The clinical specialists explained that the majority of people prefer oral treatment as long as there is no increase in adverse events.\n\n\n\nThe position of the treatment in the pathway of care for the condition\n\nCapecitabine has a UK marketing authorisation for the first-line treatment of advanced gastric cancer in combination with a platinum-based regimen.\n\n\n\nThe technology\n\nProposed benefits of the technology from the manufacturer, clinician and patient perspective\n\nThe patient expert and clinical specialists explained that oral treatment allows for easier dose adjustment and less frequent visits to the hospital, compared with an infusion pump that has to be replaced weekly. Oral treatment also offers an advantage for people in terms of carrying on with daily physical activities without the continuous presence of a pump.\n\n\n\nDistinguishing features of the technology\n\nCapecitabine is an orally administered pro-drug of fluorouracil.\n\n\n\nAdverse effects\n\nThe Committee discussed hand–foot syndrome, which is a specific adverse event that occurs more frequently with capecitabine therapy than with intravenously administered fluorouracil. The clinical specialists noted that if reported early it can be successfully treated with emollient cream, vitamin B6 and temporary dose reduction.\n\n\n\nEvidence for clinical effectiveness\n\nAvailability and nature of evidence\n\nThe Committee considered the clinical effectiveness of capecitabine for the treatment of advanced gastric cancer from two open-label trials that assessed the non-inferiority of capecitabine compared with fluorouracil.\n\n\n\nQuality of the evidence\n\n\n\nThe Committee carefully considered the estimates from the trials and the published meta-analysis and their confidence intervals, noting the ERG concerns that one of the studies was underpowered. The Committee agreed that the results of the studies showed a trend towards improved survival and concluded that capecitabine was probably at least as effective as intravenously administered fluorouracil.\n\n\n\nRelevance to general clinical practice in the NHS\n\n\n\nThe Committee accepted that the two trials were generalisable to people with advanced, inoperable gastric cancer in the UK. In addition, the Committee noted that the people in both trials were relatively young, with good performance status. The clinical specialists highlighted that even though the people in the trials were younger than the median age of death of people with gastric cancer, the trial population was representative of those in UK clinical practice who would be prescribed a chemotherapy regimen. Therefore the Committee concluded that trials were sufficiently representative of UK clinical practice.\n\n\n\nUncertainties generated by the evidence\n\n\n\nThe Committee noted the ERG concerns that the ML17032 study was underpowered. The Committee also noted that with non-inferiority trials, it was possible for a treatment to achieve non-inferiority with a worse point estimate than the comparator treatment. Therefore, the Committee carefully considered the estimates from the trials and the published meta-analysis and their confidence intervals.\n\n\n\nAre there any clinically relevant subgroups for which there is evidence of differential effectiveness?\n\nNone\n\n\n\nEvidence for cost effectiveness\n\nAvailability and nature of evidence\n\n\n\nThe Committee heard evidence on the cost effectiveness of capecitabine for the first-line treatment of inoperable advanced gastric cancer. It agreed that in this case the cost-minimisation analysis was an appropriate approach to the economic evaluation based on the clinical evidence that suggested that capecitabine was at least as effective as fluorouracil.\n\n\n\nUncertainties around and plausibility of assumptions and inputs in the economic model\n\nThe Committee noted that the model assumed that there were no significant differences in the incidence or severity of adverse events between capecitabine and fluorouracil regimens, and so the costs of treatment-related adverse events were not included in the analysis. The Committee agreed that based on the trial data this was acceptable. The Committee then discussed the length of the model. It agreed that the time horizon of 5.5\xa0cycles was a reasonable assumption as this was the mean number of treatment cycles given in the REAL-2 trial and is reflective of UK clinical practice. The Committee concluded that the parameters used in the model were acceptable.\n\n\n\nIncorporation of health-related quality-of-life benefits and utility values\n\nThe Committee recognised there were limited quality-of-life data but accepted that there was no reason to anticipate any major differences in the quality of life between capecitabine-based and fluorouracil-based regimens.\n\n\n\nAre there specific groups of people for whom the technology is particularly cost effective?\n\nNone\n\n\n\nMost likely cost-effectiveness estimate (given as an ICER)\n\nThe Committee noted that the model showed that there were likely to be cost savings with capecitabine-based regimens compared with fluorouracil-based regimens.\n\n\n\nAdditional factors taken into account\n\nPatient access scheme\n\n(Pharmaceutical Price Regulation Programme)\n\nNo patient access scheme was submitted for the technology being appraised.\n\n\n\nEnd of life considerations (supplementary advice on end of life)\n\nBecause the most plausible ICER was not more than £30,000 per QALY gained, the supplementary advice was not relevant.\n\n\n\nEqualities considerations, social value judgement\n\nThe Committee considered whether there were issues related to equality to be taken into account in its considerations. It acknowledged that some people with inoperable advanced gastric cancer may not be able to swallow oral capecitabine tablets because of difficulty with swallowing as a result of the cancer, or because of nausea. However the Committee agreed noted that although capecitabine is preferred in most circumstances, fluorouracil remains an alternative where capecitabine is contraindicated or otherwise unsuitable. Therefore, it concluded that there were no specific issues relating to equality that needed to be taken into account.\n\n", 'Related NICE guidance': 'Trastuzumab for the treatment of HER2-positive metastatic gastric cancer. NICE technology appraisal guidance 208 (2010)', 'Review of guidance': 'The guidance on this technology will be considered for review in May 2013. The Guidance Executive will decide whether the technology should be reviewed based on information gathered by NICE, and in consultation with consultees and commentators.\n\nAndrew DillonChief ExecutiveJuly 2010', 'Changes after publication': 'February 2014: minor maintenance\n\nMarch 2012: minor maintenance', 'About this guidance': 'NICE technology appraisal guidance is about the use of new and existing medicines and treatments in the NHS in England and Wales.\n\nThis guidance was developed using the NICE single technology appraisal process.\n\nWe have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available.\n\nYour responsibility\n\nThis guidance represents the views of NICE and was arrived at after careful consideration of the evidence available. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. However, the guidance does not override the individual responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.\n\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.\n\nCopyright\n\n© National Institute for Health and Clinical Excellence 2010. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.'}	https://www.nice.org.uk/guidance/ta191	Evidence-based recommendations on capecitabine for treating advanced gastric cancer in adults.
96b593c2962ace4af3afafc338aba3137d5d6c18	nice	Rituximab for the treatment of relapsed or refractory chronic lymphocytic leukaemia	Rituximab for the treatment of relapsed or refractory chronic lymphocytic leukaemia Evidence-based recommendations on rituximab for treating relapsed or refractory chronic lymphocytic leukaemia in adults. # Guidance Rituximab in combination with fludarabine and cyclophosphamide is recommended as a treatment option for people with relapsed or refractory chronic lymphocytic leukaemia except when the condition: is refractory to fludarabine (that is, it has not responded to fludarabine or has relapsed within 6 months of treatment) or has previously been treated with rituximab, unless: in the context of a clinical trial, at a dose lower than the dose currently licensed for chronic lymphocytic leukaemia or in the context of a clinical trial, in combination with chemotherapy other than fludarabine and cyclophosphamide. Rituximab in combination with fludarabine and cyclophosphamide is recommended only in the context of research for people with relapsed or refractory chronic lymphocytic leukaemia that has previously been treated with rituximab, unless rituximab has been given as specified in section 1.1. Rituximab in combination with chemotherapy other than fludarabine and cyclophosphamide is recommended only in the context of research for people with relapsed or refractory chronic lymphocytic leukaemia. People with chronic lymphocytic leukaemia that is refractory to fludarabine (as defined in section 1.1), who are currently receiving rituximab in combination with fludarabine and cyclophosphamide should have the option to continue treatment until they and their clinicians consider it appropriate to stop. People with chronic lymphocytic leukaemia that has previously been treated with rituximab other than as specified in section 1.1, who are currently receiving rituximab in combination with fludarabine and cyclophosphamide and people who are currently receiving rituximab in combination with other chemotherapy regimens that is not in the context of research, should have the option to continue treatment until they and their clinicians consider it appropriate to stop.# The technology Rituximab (MabThera, Roche) is a chimeric monoclonal antibody that binds selectively to the CD20 antigen expressed on the surface of mature B lymphocytes and tumour cells that express CD20. Rituximab is licensed for the treatment of patients with previously untreated and relapsed/refractory chronic lymphocytic leukaemia. The summary of product characteristics (SPC) states that only limited data are available on efficacy and safety for patients previously treated with monoclonal antibodies including rituximab or patients refractory to previous rituximab plus chemotherapy. Rituximab is administered intravenously, once every 4 weeks for a total of six cycles; a complete course of treatment with rituximab lasts 24 weeks. Dosing is calculated according to body surface area, with an initial dose of 375 mg/m2 followed by 500 mg/m2 for all subsequent doses. Six cycles of rituximab equate to a total dose of 2875 mg/m2. The SPC states that rituximab should be administered under the close supervision of an experienced physician, and in an environment where full resuscitation facilities are immediately available. The most frequently observed adverse events in people receiving rituximab are infusion-related reactions, including cytokine release syndrome. The majority of these reactions occur during the first infusion. Serious but rare adverse events associated with rituximab include neutropenia and leucopenia (including febrile neutropenia), infections (predominantly bacterial and viral) and cardiovascular events (hypotension, hypertension, arrhythmias and angina). Very rare serious adverse events include hepatitis B reactivation and progressive multifocal leucoencephalopathy. For full details of side effects and contraindications, see the SPC. Rituximab is available in 100 mg (10 ml) and 500 mg (50 ml) vials. The cost of a 100 mg vial is £174.63 and a 500 mg vial is £873.15 (excluding VAT; 'British national formulary' edition 58). For a person with a body surface area of 1.86 m2, the cost of rituximab for the first dose is £1222 and for subsequent doses is £1746, including wastage of excess rituximab. The total cost of rituximab is £9954 per course. Costs may vary in different settings because of negotiated procurement discounts.# The manufacturer's submission The Appraisal Committee (appendix A) considered evidence submitted by the manufacturer of rituximab and a review of this submission by the Evidence Review Group (ERG; appendix B). The manufacturer's submission compared the combination of rituximab plus fludarabine and cyclophosphamide with the combination of fludarabine plus cyclophosphamide. This comparison was based on the REACH trial, a phase III, multicentre, open-label, randomised controlled trial in people with previously treated chronic lymphocytic leukaemia. People were enrolled if they had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, a life expectancy greater than 6 months and if they had previously received treatment with chlorambucil monotherapy with or without prednisolone, fludarabine monotherapy (or other nucleoside analogue), or an alkylator-containing combination therapy (such as cyclophosphamide plus doxorubicin, vincristine and prednisolone, or cyclophosphamide plus vincristine and prednisolone). People were excluded from the trial if they had previously received treatment with interferon, rituximab or another monoclonal antibody, or fludarabine and cyclophosphamide, either concurrently or sequentially. People were also excluded if they had chronic lymphocytic leukaemia that was refractory to fludarabine (defined as not achieving at least a partial response for a minimum duration of 6 months). A total of 552 people were randomised to receive either rituximab plus fludarabine and cyclophosphamide or fludarabine and cyclophosphamide alone. The median age of people in the trial was 63 years and 67% were men. Most people (90%) had Binet stage B or C disease. People in the trial were randomised to six cycles of treatment, with an interim assessment of response after three cycles. At this point, people whose disease showed a partial or complete response continued treatment to six cycles, people with progressive disease discontinued treatment and people with stable disease continued treatment at the investigator's discretion. Each treatment cycle of 28 days consisted of fludarabine and cyclophosphamide chemotherapy (fludarabine 25 mg/m2 and cyclophosphamide 250 mg/m2 on days 1, 2 and 3) with or without rituximab (375 mg/m2 on day 0 of cycle 1, 500 mg/m2 on day 1 of cycles 2–6). All treatments were administered intravenously. The primary outcome of the trial was progression-free survival, defined as the time between randomisation and the date of the first documented disease progression, relapse or death by any cause. Secondary outcomes were event-free survival, overall survival, disease-free survival, duration of response, time to new chronic lymphocytic leukaemia treatment and response rates. Quality-of-life data were collected in the first year of the trial using the Functional Assessment of Cancer Therapy – General (FACT-G). Demographic characteristics and disease characteristics, including Binet stage B symptoms and prognostic markers such as cytogenetic abnormalities, were well balanced between the trial groups. Of all people in the trial, 59% had Binet stage B disease, 31% had Binet stage C disease, and 10% had Binet stage A disease. The trial enrolled 42 people (8%) with del(17p), a chromosome mutation associated with a poorer prognosis. The manufacturer's submission stated that most people had previously been treated with single-agent chemotherapy (82%), most commonly an alkylating agent (66%) such as chlorambucil or cyclophosphamide. Of the people in the trial 56% were alkylator sensitive, 26% were alkylator refractory, and 16% had previously received fludarabine. The trial results reported in the manufacturer's submission are based on a median follow-up of 25.3 months. At this point, the median progression-free survival was 30.6 months in the rituximab plus fludarabine and cyclophosphamide group and 20.6 months in the fludarabine and cyclophosphamide group, with a hazard ratio of 0.65 (95% CI 0.51 to 0.82, p = 0.0002). The best overall response rate was 69.9% in the rituximab plus fludarabine and cyclophosphamide group and 58% in the fludarabine and cyclophosphamide group (p = 0.0034). The median overall survival was 51.9 months in the fludarabine and cyclophosphamide group and was not reached in the rituximab plus fludarabine and cyclophosphamide group (hazard ratio 0.83, 95% CI 0.59 to 1.17, p = 0.2871). The manufacturer presented a number of subgroup analyses. For people with the del(17p) mutation, the hazard ratio for progression-free survival was 0.75 (95% CI 0.38 to 1.49). The hazard ratio for progression-free survival for people with Binet stage A disease was 0.75 (95% CI 0.33 to 1.72), Binet stage B disease was 0.65 (95% CI 0.47 to 0.88) and Binet stage C disease was 0.61 (95% CI 0.41 to 0.90). The REACH trial was not powered to detect differences between the treatment groups for any of these subgroups. In the REACH trial, 80% of people in the rituximab plus fludarabine and cyclophosphamide group experienced a grade 3 or 4 adverse event compared with 74% in the fludarabine and cyclophosphamide group. The most common grade 3 or 4 adverse events, with at least a 2% higher incidence in the rituximab plus fludarabine and cyclophosphamide group, were neutropenia, febrile neutropenia, granulocytopenia and hepatitis B infections. In the rituximab plus fludarabine and cyclophosphamide group, there were 19 treatment-related deaths (7%) and 51% of people had their treatment modified or interrupted for safety reasons. In the fludarabine and cyclophosphamide group, there were 14 treatment-related deaths (5%) and 39% of people had their treatment modified or interrupted for safety reasons. The manufacturer provided supporting data from 20 non-comparative studies. These studies examined the efficacy and tolerability of rituximab plus different chemotherapy regimens, and of rituximab-containing regimens in people with fludarabine-refractory chronic lymphocytic leukaemia, and in people previously treated with rituximab (both groups had been excluded from the REACH trial). Of these 20 studies, 19 were uncontrolled, phase II studies and one was a randomised phase II trial of fludarabine, cyclophosphamide and mitoxantrone with or without rituximab in people with previously treated chronic lymphocytic leukaemia (n = 52). However, the small number of people included in each group in the randomised trial did not allow a statistical comparison to be made. Seven of the 20 trials investigated the use of rituximab outside the terms of the marketing authorisation (either rituximab monotherapy or rituximab plus non-chemotherapy regimens). The largest non-comparative study was a single-arm, open-label, phase II study of 177 people with relapsed or refractory chronic lymphocytic leukaemia (median follow-up 28 months) treated at the MD Anderson Cancer Centre (MDACC). Of the people in the study, 82% had previously received treatment with fludarabine monotherapy or combination therapy (of whom 108 people were fludarabine sensitive and 37 were fludarabine refractory) and 18% had received prior alkylating agents only. Twenty-two of the 177 people in the study had received rituximab monotherapy or combination therapy. The overall response rate for all people in the study was 73% and the complete response rate was 25%.The overall and complete response rates were 58% and 6% respectively for the group with fludarabine-refractory chronic lymphocytic leukaemia compared with 77% and 33% for the group with fludarabine-sensitive disease. For the group who had previously received rituximab monotherapy or combination therapy, the overall response rate was 64% and the complete response rate was 18%. During consultation on the appraisal consultation document, the manufacturer provided new data from the MDACC study described above. This included longer term results for a total of 284 people who received rituximab plus fludarabine and cyclophosphamide after previous treatment for chronic lymphocytic leukaemia. One hundred of these people had previously received a rituximab-containing regimen, which may have been rituximab monotherapy or one of various rituximab combination regimens. The number of people receiving each type of treatment was not reported. The overall response rate for all people in the study was 75% and the complete response rate was 31%. For people with fludarabine-refractory chronic lymphocytic leukaemia, the overall and complete response rates were 57% and 8% respectively compared with 80% and 36% for people with fludarabine-sensitive disease. For people who had previously received rituximab, the overall and complete response rates were 73% and 32% respectively compared with 76% and 30% for people who had not previously received rituximab. There was no difference in progression-free survival between people who had previously received rituximab and those who had not (hazard ratio 1.13, p = 0.431). The manufacturer submitted an economic analysis comparing rituximab plus fludarabine and cyclophosphamide with fludarabine and cyclophosphamide. The manufacturer used a three-state Markov model with a cycle length of 1 month and a 25-year time horizon (to represent a lifetime horizon). The health states in the model were 'progression-free survival', 'progressed', and 'death'. People entered the model in the progression-free survival health state. The probability of transition from the progression-free survival to the progressed health state was taken from the groups in the REACH trial. For the transition from the progression-free survival to the death health state, trial data were used and supplemented with Office of National Statistics data to inform the background mortality rate. Transition from the progressed to the progression-free survival health state was not possible. For the transition from the progressed to the death health state, people from both groups of the trial were assumed to have equal risk of death. This assumption was based on a non-significant (p = 0.5596) difference in Kaplan–Meier curves for post-progression survival. In the model, the drug costs were calculated assuming a body surface area of 1.86 m2, which reflected the average body surface area of the people in the REACH trial. The REACH trial used fludarabine and cyclophosphamide administered intravenously, but it is more common to use oral chemotherapy in the UK. In the model it was assumed that the efficacy of fludarabine and cyclophosphamide was the same regardless of the route of administration if the dosage was adjusted to ensure equivalent bioavailability. The costs of fludarabine and cyclophosphamide treatment in the model were adjusted to allow for the difference in the route of administration. In the base case, the drug doses and costs were reduced according to the proportion of people expected to progress or die each month. The average undiscounted drug cost for rituximab was £9078 for all six cycles of treatment. The average undiscounted drug costs of fludarabine were £2569 for people in the rituximab plus fludarabine and cyclophosphamide group and £2510 for people in the fludarabine and cyclophosphamide group. The average undiscounted drug costs of cyclophosphamide were calculated as £21 and £20 for each group respectively. The model included costs for supportive care. Supportive care consisted of quarterly outpatient consultations, blood transfusions and bone marrow transplants in the progression-free survival health state and monthly outpatient consultations and second-line therapies for the progressed health state. The cost for intravenous administration of rituximab was £307 per cycle of treatment and the cost for an appointment to prescribe oral fludarabine and cyclophosphamide chemotherapy was £201. It was assumed that oral chemotherapy could be prescribed in the same appointment as rituximab so no additional cost of prescribing oral chemotherapy was included for the rituximab treatment group. Costs were also added for the pharmacist's time to prepare the infusion and one consultation with a clinical oncologist. The utility values used in the manufacturer's submission were taken from a health technology assessment report that assessed the cost effectiveness of fludarabine as a first-line treatment for chronic lymphocytic leukaemia. A utility value of 0.8 was attached to the progression-free survival health state and 0.6 to the progressed health state. The estimates of utility were not preference based, and were estimated by the authors of the report from condition-specific health-related quality-of-life data. No disutility for adverse events was included in the model. The manufacturer provided an interim analysis of 34 people from an observational study of utility in people with chronic lymphocytic leukaemia. The value for the progression-free survival health state was consistent with that used in the manufacturer's submission. No conclusions could be drawn about the utility value appropriate for the progressed health state because only data for two people were available. The manufacturer provided a base-case estimate of incremental cost effectiveness of rituximab plus fludarabine and cyclophosphamide compared with fludarabine and cyclophosphamide. The incremental quality-adjusted life year (QALY) gain was 0.585 at an incremental cost of £9128, giving an incremental cost-effectiveness ratio (ICER) of £15,593 per QALY gained. The probabilistic sensitivity analysis presented suggested that rituximab plus fludarabine and cyclophosphamide had a 75% probability of being cost effective at £20,000 and a 94% probability of being cost effective at £30,000 when compared with fludarabine and cyclophosphamide. During consultation on the appraisal consultation document, the manufacturer provided an estimate of the cost effectiveness of rituximab plus fludarabine and cyclophosphamide compared with fludarabine and cyclophosphamide, for the subgroup of people who had previously received rituximab. This was calculated using the same model described in section 3.11 with an adjustment to the progression-free survival in the rituximab plus fludarabine and cyclophosphamide group using the hazard ratio (1.13) estimated from the MDACC study. This adjustment to the model resulted in a QALY gain of 0.406 at an incremental cost of £9134, giving an ICER of £22,519 per QALY gained. A sensitivity analysis was presented in the manufacturer's submission using different parametric models for the progression-free survival extrapolation. Additional sensitivity analyses were completed as follows: increasing and decreasing adverse event costs by 50% increasing and decreasing supportive care costs for the health states by 50% assuming utility values for the health states such that the difference in the values between the health states was 0.4 and 0.1 assuming upper and lower quartiles for drug administration costs (from reference costs 2007/08) assuming differential probabilities of death after progression between treatment arms.One-way sensitivity analyses suggested that the results were not sensitive to a variety of parameter assumptions including adverse events costs, monthly supportive care costs, and drug administration costs. The results were also not sensitive to the function used to extrapolate progression-free survival. The results were sensitive to assumptions about utilities and assumptions about the probability of death after progression. The highest ICER reported (using both differential mortality rates between treatment arms and adjusting utilities) was £23,790 per QALY gained. The manufacturer's submission also included a scenario analysis to explore the impact on the ICER of combining rituximab with chemotherapy other than fludarabine and cyclophosphamide. The results of this analysis suggested that the QALY gain from combining rituximab with chemotherapy would need to decrease to about 45% of that in the base case, all else remaining the same, for the ICER for rituximab to increase to over £30,000 per QALY gained. The ERG considered that all the relevant trials had been identified. The ERG noted that the manufacturer's submission was based on only one clinical trial, and this trial was unpublished. The ERG considered this trial had adequate randomisation and allocation concealment. However, it noted that the trial was open label and therefore assessments might be biased. The ERG noted that an independent assessment of response was made during a pre-planned interim analysis of the trial data (conducted when about two thirds of the total 284 events had occurred). It stated that there were differences in progression-free survival between the trial groups when assessed by the blinded independent panel and the unblinded trial investigators (independent panel data were provided as academic-in-confidence). The ERG considered that the trial population was relatively young compared with the UK population who would be eligible for rituximab and 10% of people had mild stage disease (Binet stage A), a stage at which people were not commonly treated in the UK. The ERG also noted that people with fludarabine-refractory chronic lymphocytic leukaemia were excluded from the trial although they could be eligible for rituximab. It considered that the comparator used in the cost-effectiveness analysis (that is, fludarabine and cyclophosphamide) was appropriate. The ERG noted that in the manufacturer's economic model people in the progressed health state could not move back into the progression-free survival health state. They considered that this did not appropriately reflect the disease process because people with chronic lymphocytic leukaemia receive a series of treatments and therefore they may have periods of progression-free survival after relapse and further treatment. The ERG commented that not all adverse events were assigned costs in the model. In particular, hepatitis B, for which there were six cases in the rituximab plus fludarabine and cyclophosphamide group and no cases in the fludarabine and cyclophosphamide group. The ERG completed a series of exploratory analyses. It remodelled rituximab costs so that full costs were incurred at the start of each cycle rather than spread throughout the cycle. This amendment increased the base-case analysis from £15,593 to £18,129 per QALY gained. The ICER of £18,129 was corrected to £16,607 per QALY gained during consultation on the ACD. The ERG conducted an analysis using progression-free survival curves based on the independent assessment of progression (from the interim trial analysis) rather than non-blinded, investigator-assessed progression. This increased the base-case ICER to £17,507 per QALY gained. The ERG also explored the effect on the ICER of assuming no overall survival benefit of treatment with rituximab plus fludarabine and cyclophosphamide. It used two methods for this; it used the mortality rate from the fludarabine and cyclophosphamide group and applied it to the rituximab plus fludarabine and cyclophosphamide group and vice versa. The resulting ICERs were £40,568 and £42,444 per QALY gained for each method respectively compared with £15,593 per QALY gained in the manufacturer's base case. The ERG identified that if it is assumed there is no difference in overall survival between the rituximab plus fludarabine and cyclophosphamide and fludarabine and cyclophosphamide groups, the model outputs become sensitive to the assumed utility differences between the progression-free and the progressed health states. If the difference in utility between the health states is decreased by 0.1 (that is from a difference of 0.2 to 0.1), the ICER increases to between £81,135 and £84,889 per QALY gained. Full details of all the evidence are in the manufacturer's submission and the ERG report.# Consideration of the evidence The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of rituximab, having considered evidence on the nature of relapsed or refractory chronic lymphocytic leukaemia and the value placed on the benefits of rituximab by people with the condition, those who represent them, and clinical specialists. It also took into account the effective use of NHS resources. # Clinical effectiveness The Appraisal Committee discussed current standard clinical management of relapsed or refractory chronic lymphocytic leukaemia. The Committee heard from clinical specialists that the most frequently used first-line treatments are: fludarabine plus cyclophosphamide with or without rituximab; and chlorambucil for people unable to have fludarabine because they have a poor performance status. However, for relapsed or refractory chronic lymphocytic leukaemia there is no single standard treatment option. The choice of treatment depends on a number of factors, including the presence of genetic abnormalities such as del(17p) mutation, previous treatments the person has received, whether a response was achieved from previous treatments, and if so, the duration of response. Clinical specialists noted that for these reasons, they considered it important to have a range of treatment options available. The Committee heard that, for relapsed disease, treatments used previously may be administered again either with or without the addition of another therapeutic agent, or alternatively a different agent may be used. When additional or different treatments were used, these could include fludarabine and cyclophosphamide with the addition of mitoxantrone, alemtuzumab and stem cell transplantation. The Committee noted that the clinical effectiveness evidence for this appraisal was based mainly on a single unpublished randomised controlled trial (the REACH trial). In this trial rituximab plus fludarabine and cyclophosphamide was compared with fludarabine and cyclophosphamide. The Committee heard from clinical specialists that people in the REACH trial were younger and had a better performance status than people with chronic lymphocytic leukaemia seen in routine practice in the NHS in England and Wales. However, the clinical specialists commented that the people in the trial were representative of the people who would be eligible for treatment with fludarabine plus cyclophosphamide. The Committee discussed the inclusion in the trial of people who had Binet stage A chronic lymphocytic leukaemia. It heard from clinical specialists that the decision to treat chronic lymphocytic leukaemia would depend on symptoms and progression of disease rather than specific staging. The Committee discussed the exclusion from the REACH trial of people who were previously treated with fludarabine combination therapy, people who were previously treated with rituximab and people who had chronic lymphocytic leukaemia that was refractory to fludarabine. However, it heard from clinical specialists that, if suitable, people often had fludarabine combination regimens as a first-line treatment. It also heard that the publication of 'Rituximab for the first-line treatment of chronic lymphocytic leukaemia' (NICE technology appraisal guidance 174) recommending rituximab plus fludarabine and cyclophosphamide meant that in the future an increasing number of people with relapsed or refractory disease will have had rituximab and fludarabine combination therapy as a first-line treatment. The Committee considered the exclusion of these groups from the clinical trial was a limitation for decision making because it meant that the trial population did not reflect all the people with relapsed or refractory disease who would be eligible for rituximab plus fludarabine and cyclophosphamide in the NHS. The Committee accepted that the REACH trial demonstrated that the addition of rituximab to fludarabine and cyclophosphamide improved progression-free survival and complete response rates. The Committee noted there was potential for bias in outcome assessment because of the open-label design of the trial. The Committee discussed the results of an interim analysis of the trial data. This was an independent assessment of response that was provided as academic-in-confidence. The Committee noted that there was a difference between the investigator and independent assessments but was aware that the interim analysis was conducted 1 year before the investigator assessment. The Committee heard from clinical specialists that assessment of progression-free survival was subjective and could change depending on familiarity with assessment tools. The Committee considered that the differences in these assessments led to uncertainty in estimating the additional benefit of rituximab. The Committee noted that in the REACH trial median overall survival had not been reached in the rituximab group, and that survival curves for patients in the two treatment groups hardly diverged until 30 months. The Committee heard from clinical specialists and patient experts that it is difficult for studies of chronic lymphocytic leukaemia to demonstrate an effect of treatment on overall survival because of the long natural history of the disease and because people with the disease often receive multiple treatments. It also heard that progression-free survival and response rates were often accepted as surrogates for overall survival. Furthermore, clinical specialists commented that longer term trial evidence is emerging that demonstrates an overall survival benefit of first-line treatment with rituximab plus fludarabine and cyclophosphamide. On balance, the Committee was persuaded that the improvements observed in progression-free survival and response rates were likely to lead to at least some gain in overall survival, although this gain could not be quantified. The Committee noted that in the REACH trial there were slightly more grade 3 or 4 adverse events and treatment-related deaths in the rituximab plus fludarabine and cyclophosphamide group than in the fludarabine and cyclophosphamide group. It heard from clinical specialists that people with chronic lymphocytic leukaemia are aware of the risks of treatments and are willing to accept these risks because of the severity of the condition. The Committee discussed the six cases of hepatitis B seen in the trial in the rituximab plus fludarabine and cyclophosphamide group. However, it heard from clinical specialists that this would be unlikely to happen in the UK because all people with chronic lymphocytic leukaemia are screened for hepatitis B before treatment, and so hepatitis B reactivation would be rare. People who have previously received treatment with rituximab The Committee discussed the use of rituximab plus fludarabine and cyclophosphamide in people who have previously received treatment with rituximab-containing regimens. These people were excluded from the REACH trial, and the Committee heard from clinical specialists that there was uncertainty about the degree of benefit of retreatment with rituximab. However, patient experts indicated that there was anecdotal evidence that people retreated with rituximab may have a good response to treatment. The Committee also noted comments received at consultation that retreatment with rituximab is common in other lymphoproliferative conditions where there has been a good response, and that the same could be expected for chronic lymphocytic leukaemia. It was also aware that over the next few years there would be an increasing number of people who would be treated with rituximab and who would require further treatment following relapse. The Committee considered the evidence from uncontrolled phase II studies reporting the benefits of retreatment with rituximab and noted the methodological limitations of these studies. It discussed the MDACC data provided during consultation, reporting that there was a similar response rate and progression-free survival in people who have previously received rituximab compared with people who have not. However, it noted this study had limitations in its design, for example, it was open label and uncontrolled (and therefore not randomised). The study included 100 people who had previously been treated with a rituximab-containing regimen. However, limited data were provided about these regimens and they included rituximab monotherapy and rituximab plus chemotherapy other than fludarabine and cyclophosphamide. The Committee was not persuaded that the results from this study could be considered reflective of the UK population, of whom an increasing number will have previously received rituximab plus fludarabine and cyclophosphamide. ## People who have previously received treatment with fludarabine The Committee considered the use of rituximab plus fludarabine and cyclophosphamide in people who have previously received treatment with fludarabine. It first discussed people who had previously had a response to treatment with fludarabine (that is, people with fludarabine-sensitive disease). The Committee discussed evidence from the REACH trial which included people whose disease was sensitive to fludarabine monotherapy. It noted that the REACH trial did not include people who had previously received fludarabine combination therapy. However, the Committee considered that the clinical effectiveness was likely to be similar for people who were sensitive to fludarabine monotherapy and for people who were sensitive to fludarabine combination therapy. Therefore the Committee was persuaded that data from the REACH trial could apply to people who were sensitive to fludarabine combination therapy. The Committee then discussed the evidence for the use of rituximab plus fludarabine and cyclophosphamide in people who have chronic lymphocytic leukaemia that is refractory to fludarabine. It noted the methodological limitations of the non-comparative studies provided by the manufacturer. The Committee understood that clinical specialists did not consider that people with fludarabine-refractory disease should be retreated with the same fludarabine-containing regimen. The Committee considered that the results of the MDACC study indicated a lower response to treatment with rituximab plus fludarabine and cyclophosphamide in chronic lymphocytic leukaemia refractory to fludarabine than in disease that was sensitive to fludarabine. The Committee concluded that although people with fludarabine-refractory disease may derive some benefit from retreatment with fludarabine-containing chemotherapy regimens such as rituximab plus fludarabine and cyclophosphamide, the benefit was likely to be less than if the disease was fludarabine sensitive. ## Rituximab plus chemotherapy regimens other than fludarabine plus cyclophosphamide The Committee recognised that the marketing authorisation for rituximab allowed its use with any chemotherapy regimen. It discussed the evidence on rituximab plus chemotherapy regimens other than fludarabine and cyclophosphamide. The Committee discussed comments received on the appraisal consultation document that suggested that people who cannot take fludarabine and people with chronic lymphocytic leukaemia that is refractory to fludarabine may benefit from treatment with rituximab plus other chemotherapy. The Committee was aware of the lack of treatment options available to these people. However, the Committee noted the methodological limitations of the non-comparative evidence provided. It heard from the manufacturer that a study of rituximab plus chlorambucil for first-line treatment was under way and that preliminary data from a cross-trial analysis indicated that response rates were better for people treated with rituximab plus chlorambucil than with chlorambucil alone. Overall, the Committee considered that there was significant uncertainty about the relative benefit of adding rituximab to chemotherapy regimens other than fludarabine and cyclophosphamide and therefore more research was needed. # Cost effectiveness The Committee reviewed the economic model submitted by the manufacturer and the ERG's analysis of the model. It was aware that the model did not allow transition from the progressed health state to the progression-free survival heath state. The Committee considered that this did not appropriately reflect the disease process because people may receive later treatments with further periods of progression-free survival. The Committee was aware that a similar model had been used in the appraisal of 'Rituximab for the first-line treatment of chronic lymphocytic leukaemia' (NICE technology appraisal guidance 174). On balance, the Committee agreed that the model could be used as a basis for considering the cost effectiveness of rituximab. The Committee considered how the costs of rituximab had been incorporated into the economic model. It noted that the ERG considered the assumption that costs were spread throughout the cycle in the base-case analysis inappropriate because rituximab was provided on the first day of each cycle. Therefore, the ERG explored remodelling rituximab costs so that costs were incurred at the start of each treatment cycle. The ERG re-analysis was corrected after consultation on the appraisal consultation document, and concluded that the ICER increased from £15,600 per QALY gained in the base case to £16,600 per QALY gained, which the Committee accepted. The Committee discussed the utilities used in the economic model and noted that the evidence base for these estimates did not reflect the NICE reference case; in particular, preference-based methods were not used. It was aware that a utility study was under way in people with chronic lymphocytic leukaemia in the UK but detailed results from this study for people who had progressed following treatment were not yet available. The Committee heard from patient experts that they considered an assumption of only a small difference in utility between the progressed and progression-free survival health states was not realistic. People greatly value being progression free and asymptomatic – it is associated with a marked improvement in quality of life. The Committee considered the lack of appropriate utility data contributed to uncertainty in the economic model. The Committee discussed whether the modelled gains in overall survival from the economic model appropriately reflected the data from the clinical trial. It noted that the outputs from the manufacturer's economic analysis modelled a difference in overall survival between treatment groups from the start of treatment that did not reflect the trial data. The overall survival curves from the clinical trial provided by the manufacturer showed no difference in overall survival between the treatment groups before around 30 months, although, beyond this time, the extrapolated curves began to diverge. The Committee considered that there was little evidence from the REACH trial to support the validity of the analysis provided by the manufacturer and that the manufacturer's base-case analysis was likely to have overestimated the benefits associated with rituximab. The Committee considered the estimates of cost effectiveness provided by the manufacturer and the additional exploratory analyses performed by the ERG that examined the impact on the ICER of reducing the survival advantage of treatment with rituximab. It noted that using an assumption of no overall survival advantage had the effect of increasing the cost-effectiveness estimates from £15,600 per QALY gained in the base case to £41,000 per QALY gained. Furthermore it recognised that when there was no modelled gain in overall survival the results became very sensitive to the difference between the utility values used for the progression-free survival health state and those used for the progressed health state which were uncertain. However, based on comments from the clinical specialists, the Committee was persuaded that it was appropriate to assume at least some gain in overall survival in the economic model. Overall, the Committee considered that the most plausible ICER was likely to be at the upper end of the range of £20,000 to £30,000 per QALY gained, which was higher than the ERG's corrected base case of £16,600 per QALY gained. On balance, the Committee was persuaded that even taking into account the uncertainty about utility values and the uncertainty about a gain in overall survival from treatment with rituximab, the use of rituximab plus fludarabine and cyclophosphamide was a cost-effective use of NHS resources for the population represented in the REACH trial; that is, people who have not previously received rituximab or fludarabine combination therapy and those whose disease is not refractory to fludarabine monotherapy. Additionally, the Committee was persuaded that the cost effectiveness of rituximab plus fludarabine and cyclophosphamide could be generalised from people whose chronic lymphocytic leukaemia was sensitive to fludarabine monotherapy to those whose disease was sensitive to fludarabine combination therapy (section 4.10). ## People who have previously received treatment with rituximab The Committee was not persuaded of the clinical effectiveness of rituximab plus fludarabine and cyclophosphamide for people who have already been treated with rituximab. Nevertheless, the Committee discussed the cost-effectiveness estimate provided by the manufacturer during consultation of £22,500 per QALY gained for people who had previously received rituximab. It noted that this did not include the correction for the timing of rituximab costs. It recognised that there was considerable uncertainty in the manufacturer's original base-case ICER because of the uncertainties in the gains in overall survival and the limitations in the health-related quality of life data available. The Committee noted that even for the REACH trial population the most plausible ICER was likely to be at the upper end of the range of £20,000 to £30,000 per QALY gained. It considered that in the rituximab-pretreated population, for which there was little research, the manufacturer's estimated ICER could not provide a basis for decision making. The Committee concluded that rituximab plus fludarabine and cyclophosphamide could not be recommended as an appropriate use of NHS resources for everyone who had previously been treated with rituximab. However, because of the uncertainty about the benefits of retreatment with rituximab, the Committee concluded that rituximab plus fludarabine and cyclophosphamide should be recommended in the context of research for people with relapsed or refractory chronic lymphocytic leukaemia that has previously been treated with rituximab. The Committee was aware of comments from consultees that some people in clinical trials had received rituximab in combination with treatments other than fludarabine and cyclophosphamide and at doses of rituximab lower than the licensed dose. The Committee considered that this technology appraisal guidance should not adversely affect recruitment to future or ongoing clinical trials. Therefore the Committee concluded that rituximab plus fludarabine and cyclophosphamide could be recommended for people with relapsed or refractory chronic lymphocytic leukaemia when rituximab had previously been given in the context of a clinical trial, either at a dose lower than currently licensed for chronic lymphocytic leukaemia, or in combination with chemotherapy other than fludarabine and cyclophosphamide. ## People who have previously received treatment with fludarabine After concluding that rituximab plus fludarabine and cyclophosphamide was cost effective for people with chronic lymphocytic leukaemia that was sensitive to fludarabine (section 4.18), the Committee then considered its use in people with fludarabine-refractory disease. It noted the lower clinical response in people who were refractory to fludarabine than in people who were sensitive to it (section 4.10), and that clinical practice was not to retreat these people with the same fludarabine regimen. It also noted that the manufacturer had not provided an estimate of the cost effectiveness of rituximab plus fludarabine and cyclophosphamide in this population. The Committee heard from the manufacturer that there were difficulties identifying baseline event rate data and that the relative efficacy of rituximab therapy in this group was uncertain. On this basis the Committee considered that the use of rituximab plus fludarabine and cyclophosphamide for the treatment of people who had already had fludarabine could only be considered a cost-effective use of NHS resources when the chronic lymphocytic leukaemia remained fludarabine sensitive and not when it was fludarabine refractory. ## Rituximab plus chemotherapy regimens other than fludarabine and cyclophosphamide The Committee understood the potential need for other rituximab combinations for people whose disease is refractory to fludarabine or is not suitable for treatment with fludarabine. However, it concluded that there was significant uncertainty about the relative benefit of adding rituximab to chemotherapy regimens other than fludarabine and cyclophosphamide and therefore more research was needed. Furthermore, the Committee noted there was no current basis for estimating the cost effectiveness of such combinations, or for considering them to be cost effective. The Committee was aware that people with chronic lymphocytic leukaemia that is not suitable for treatment with fludarabine plus cyclophosphamide might be treated with rituximab plus other chemotherapy. It was also aware that this group might be older and include people with poor performance status or comorbidities. The Committee considered whether equalities legislation and the requirement for fairness meant that it should make a positive recommendation for rituximab plus other chemotherapy for this group. However, given the lack of evidence for both the clinical and cost effectiveness of this treatment, the Committee concluded that rituximab plus chemotherapy other than fludarabine and cyclophosphamide should only be used for the treatment of relapsed or refractory chronic lymphocytic leukaemia in the context of research.# Recommendations for further research The Committee considered that the following research would be of value: Studies investigating the effectiveness of rituximab plus fludarabine and cyclophosphamide in people with relapsed and refractory chronic lymphocytic leukaemia that has previously been treated with rituximab. Studies investigating the effectiveness of rituximab plus chemotherapy other than fludarabine and cyclophosphamide in people with relapsed and refractory chronic lymphocytic leukaemia. Studies investigating the health-related quality of life of people with chronic lymphocytic leukaemia that include data collected using a generic preference-based measure.# Related NICE guidance Rituximab for the first-line treatment of chronic lymphocytic leukaemia. NICE technology appraisal guidance 174 (2009). Fludarabine monotherapy for the first-line treatment of chronic lymphocytic leukaemia. NICE technology appraisal guidance 119 (2007). Improving outcomes in haematological cancers. NICE cancer service guidance (2003). Ofatumumab for the treatment of chronic lymphocytic leukaemia refractory to fludarabine and alemtuzumab. NICE technology appraisal guidance 202 (2010)# Review of guidance The guidance on this technology will be considered for review in 2012. The Guidance Executive will decide whether the technology should be reviewed based on information gathered by NICE, and in consultation with consultees and commentators. Andrew DillonChief ExecutiveJuly 2010# Changes after publication February 2014: implementation section updated to clarify that rituximab is recommended as an option for treating relapsed or refractory chronic lymphocytic leukaemia. Additional minor maintenance update also carried out. March 2012: minor maintenance# About this guidance NICE technology appraisal guidance is about the use of new and existing medicines and treatments in the NHS in England and Wales. This guidance was developed using the NICE single technology appraisal process. We have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available. Your responsibility This guidance represents the views of NICE and was arrived at after careful consideration of the evidence available. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. However, the guidance does not override the individual responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or guardian or carer. Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties. Copyright © National Institute for Health and Clinical Excellence 2010. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.	{'Guidance': 'Rituximab in combination with fludarabine and cyclophosphamide is recommended as a treatment option for people with relapsed or refractory chronic lymphocytic leukaemia except when the condition:\n\nis refractory to fludarabine (that is, it has not responded to fludarabine or has relapsed within 6\xa0months of treatment) or\n\nhas previously been treated with rituximab, unless:\n\n\n\nin the context of a clinical trial, at a dose lower than the dose currently licensed for chronic lymphocytic leukaemia or\n\nin the context of a clinical trial, in combination with chemotherapy other than fludarabine and cyclophosphamide.\n\n\n\nRituximab in combination with fludarabine and cyclophosphamide is recommended only in the context of research for people with relapsed or refractory chronic lymphocytic leukaemia that has previously been treated with rituximab, unless rituximab has been given as specified in section 1.1.\n\nRituximab in combination with chemotherapy other than fludarabine and cyclophosphamide is recommended only in the context of research for people with relapsed or refractory chronic lymphocytic leukaemia.\n\nPeople with chronic lymphocytic leukaemia that is refractory to fludarabine (as defined in section 1.1), who are currently receiving rituximab in combination with fludarabine and cyclophosphamide should have the option to continue treatment until they and their clinicians consider it appropriate to stop.\n\nPeople with chronic lymphocytic leukaemia that has previously been treated with rituximab other than as specified in section 1.1, who are currently receiving rituximab in combination with fludarabine and cyclophosphamide and people who are currently receiving rituximab in combination with other chemotherapy regimens that is not in the context of research, should have the option to continue treatment until they and their clinicians consider it appropriate to stop.', 'The technology ': "Rituximab (MabThera, Roche) is a chimeric monoclonal antibody that binds selectively to the CD20 antigen expressed on the surface of mature B lymphocytes and tumour cells that express CD20. Rituximab is licensed for the treatment of patients with previously untreated and relapsed/refractory chronic lymphocytic leukaemia. The summary of product characteristics (SPC) states that only limited data are available on efficacy and safety for patients previously treated with monoclonal antibodies including rituximab or patients refractory to previous rituximab plus chemotherapy. Rituximab is administered intravenously, once every 4\xa0weeks for a total of six cycles; a complete course of treatment with rituximab lasts 24\xa0weeks. Dosing is calculated according to body surface area, with an initial dose of 375\xa0mg/m2 followed by 500\xa0mg/m2 for all subsequent doses. Six cycles of rituximab equate to a total dose of 2875\xa0mg/m2. The SPC states that rituximab should be administered under the close supervision of an experienced physician, and in an environment where full resuscitation facilities are immediately available.\n\nThe most frequently observed adverse events in people receiving rituximab are infusion-related reactions, including cytokine release syndrome. The majority of these reactions occur during the first infusion. Serious but rare adverse events associated with rituximab include neutropenia and leucopenia (including febrile neutropenia), infections (predominantly bacterial and viral) and cardiovascular events (hypotension, hypertension, arrhythmias and angina). Very rare serious adverse events include hepatitis B reactivation and progressive multifocal leucoencephalopathy. For full details of side effects and contraindications, see the SPC.\n\nRituximab is available in 100\xa0mg (10\xa0ml) and 500\xa0mg (50\xa0ml) vials. The cost of a 100\xa0mg vial is £174.63 and a 500\xa0mg vial is £873.15 (excluding VAT; 'British national formulary' [BNF] edition 58). For a person with a body surface area of 1.86\xa0m2, the cost of rituximab for the first dose is £1222 and for subsequent doses is £1746, including wastage of excess rituximab. The total cost of rituximab is £9954 per course. Costs may vary in different settings because of negotiated procurement discounts.", "The manufacturer's submission": "The Appraisal Committee (appendix A) considered evidence submitted by the manufacturer of rituximab and a review of this submission by the Evidence Review Group (ERG; appendix B).\n\nThe manufacturer's submission compared the combination of rituximab plus fludarabine and cyclophosphamide with the combination of fludarabine plus cyclophosphamide. This comparison was based on the REACH trial, a phase III, multicentre, open-label, randomised controlled trial in people with previously treated chronic lymphocytic leukaemia. People were enrolled if they had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, a life expectancy greater than 6\xa0months and if they had previously received treatment with chlorambucil monotherapy with or without prednisolone, fludarabine monotherapy (or other nucleoside analogue), or an alkylator-containing combination therapy (such as cyclophosphamide plus doxorubicin, vincristine and prednisolone, or cyclophosphamide plus vincristine and prednisolone). People were excluded from the trial if they had previously received treatment with interferon, rituximab or another monoclonal antibody, or fludarabine and cyclophosphamide, either concurrently or sequentially. People were also excluded if they had chronic lymphocytic leukaemia that was refractory to fludarabine (defined as not achieving at least a partial response for a minimum duration of 6\xa0months). A total of 552 people were randomised to receive either rituximab plus fludarabine and cyclophosphamide or fludarabine and cyclophosphamide alone. The median age of people in the trial was 63\xa0years and 67% were men. Most people (90%) had Binet stage B or C disease.\n\nPeople in the trial were randomised to six cycles of treatment, with an interim assessment of response after three cycles. At this point, people whose disease showed a partial or complete response continued treatment to six cycles, people with progressive disease discontinued treatment and people with stable disease continued treatment at the investigator's discretion. Each treatment cycle of 28\xa0days consisted of fludarabine and cyclophosphamide chemotherapy (fludarabine 25\xa0mg/m2 and cyclophosphamide 250\xa0mg/m2 on days\xa01, 2 and 3) with or without rituximab (375\xa0mg/m2 on day 0 of cycle 1, 500\xa0mg/m2 on day\xa01 of cycles\xa02–6). All treatments were administered intravenously.\n\nThe primary outcome of the trial was progression-free survival, defined as the time between randomisation and the date of the first documented disease progression, relapse or death by any cause. Secondary outcomes were event-free survival, overall survival, disease-free survival, duration of response, time to new chronic lymphocytic leukaemia treatment and response rates. Quality-of-life data were collected in the first year of the trial using the Functional Assessment of Cancer Therapy – General (FACT-G).\n\nDemographic characteristics and disease characteristics, including Binet stage B symptoms and prognostic markers such as cytogenetic abnormalities, were well balanced between the trial groups. Of all people in the trial, 59% had Binet stage B disease, 31% had Binet stage C disease, and 10% had Binet stage A disease. The trial enrolled 42 people (8%) with del(17p), a chromosome mutation associated with a poorer prognosis. The manufacturer's submission stated that most people had previously been treated with single-agent chemotherapy (82%), most commonly an alkylating agent (66%) such as chlorambucil or cyclophosphamide. Of the people in the trial 56% were alkylator sensitive, 26% were alkylator refractory, and 16% had previously received fludarabine.\n\nThe trial results reported in the manufacturer's submission are based on a median follow-up of 25.3\xa0months. At this point, the median progression-free survival was 30.6\xa0months in the rituximab plus fludarabine and cyclophosphamide group and 20.6\xa0months in the fludarabine and cyclophosphamide group, with a hazard ratio of 0.65 (95%\xa0CI 0.51 to 0.82, p\xa0=\xa00.0002). The best overall response rate was 69.9% in the rituximab plus fludarabine and cyclophosphamide group and 58% in the fludarabine and cyclophosphamide group (p\xa0=\xa00.0034). The median overall survival was 51.9\xa0months in the fludarabine and cyclophosphamide group and was not reached in the rituximab plus fludarabine and cyclophosphamide group (hazard ratio 0.83, 95%\xa0CI 0.59 to 1.17, p\xa0=\xa00.2871).\n\nThe manufacturer presented a number of subgroup analyses. For people with the del(17p) mutation, the hazard ratio for progression-free survival was 0.75 (95%\xa0CI 0.38 to 1.49). The hazard ratio for progression-free survival for people with Binet stage A disease was 0.75 (95%\xa0CI 0.33 to 1.72), Binet stage B disease was 0.65 (95%\xa0CI 0.47 to 0.88) and Binet stage C disease was 0.61 (95%\xa0CI 0.41 to 0.90). The REACH trial was not powered to detect differences between the treatment groups for any of these subgroups.\n\nIn the REACH trial, 80% of people in the rituximab plus fludarabine and cyclophosphamide group experienced a grade 3 or 4 adverse event compared with 74% in the fludarabine and cyclophosphamide group. The most common grade 3 or 4 adverse events, with at least a 2% higher incidence in the rituximab plus fludarabine and cyclophosphamide group, were neutropenia, febrile neutropenia, granulocytopenia and hepatitis B infections. In the rituximab plus fludarabine and cyclophosphamide group, there were 19 treatment-related deaths (7%) and 51% of people had their treatment modified or interrupted for safety reasons. In the fludarabine and cyclophosphamide group, there were 14 treatment-related deaths (5%) and 39% of people had their treatment modified or interrupted for safety reasons.\n\nThe manufacturer provided supporting data from 20 non-comparative studies. These studies examined the efficacy and tolerability of rituximab plus different chemotherapy regimens, and of rituximab-containing regimens in people with fludarabine-refractory chronic lymphocytic leukaemia, and in people previously treated with rituximab (both groups had been excluded from the REACH trial). Of these 20 studies, 19 were uncontrolled, phase II studies and one was a randomised phase II trial of fludarabine, cyclophosphamide and mitoxantrone with or without rituximab in people with previously treated chronic lymphocytic leukaemia (n\xa0=\xa052). However, the small number of people included in each group in the randomised trial did not allow a statistical comparison to be made. Seven of the 20 trials investigated the use of rituximab outside the terms of the marketing authorisation (either rituximab monotherapy or rituximab plus non-chemotherapy regimens).\n\nThe largest non-comparative study was a single-arm, open-label, phase II study of 177 people with relapsed or refractory chronic lymphocytic leukaemia (median follow-up 28\xa0months) treated at the MD Anderson Cancer Centre (MDACC). Of the people in the study, 82% had previously received treatment with fludarabine monotherapy or combination therapy (of whom 108 people were fludarabine sensitive and 37 were fludarabine refractory) and 18% had received prior alkylating agents only. Twenty-two of the 177 people in the study had received rituximab monotherapy or combination therapy. The overall response rate for all people in the study was 73% and the complete response rate was 25%.The overall and complete response rates were 58% and 6% respectively for the group with fludarabine-refractory chronic lymphocytic leukaemia compared with 77% and 33% for the group with fludarabine-sensitive disease. For the group who had previously received rituximab monotherapy or combination therapy, the overall response rate was 64% and the complete response rate was 18%.\n\nDuring consultation on the appraisal consultation document, the manufacturer provided new data from the MDACC study described above. This included longer term results for a total of 284 people who received rituximab plus fludarabine and cyclophosphamide after previous treatment for chronic lymphocytic leukaemia. One hundred of these people had previously received a rituximab-containing regimen, which may have been rituximab monotherapy or one of various rituximab combination regimens. The number of people receiving each type of treatment was not reported. The overall response rate for all people in the study was 75% and the complete response rate was 31%. For people with fludarabine-refractory chronic lymphocytic leukaemia, the overall and complete response rates were 57% and 8% respectively compared with 80% and 36% for people with fludarabine-sensitive disease. For people who had previously received rituximab, the overall and complete response rates were 73% and 32% respectively compared with 76% and 30% for people who had not previously received rituximab. There was no difference in progression-free survival between people who had previously received rituximab and those who had not (hazard ratio 1.13, p\xa0=\xa00.431).\n\nThe manufacturer submitted an economic analysis comparing rituximab plus fludarabine and cyclophosphamide with fludarabine and cyclophosphamide. The manufacturer used a three-state Markov model with a cycle length of 1\xa0month and a 25-year time horizon (to represent a lifetime horizon). The health states in the model were 'progression-free survival', 'progressed', and 'death'. People entered the model in the progression-free survival health state. The probability of transition from the progression-free survival to the progressed health state was taken from the groups in the REACH trial. For the transition from the progression-free survival to the death health state, trial data were used and supplemented with Office of National Statistics data to inform the background mortality rate. Transition from the progressed to the progression-free survival health state was not possible. For the transition from the progressed to the death health state, people from both groups of the trial were assumed to have equal risk of death. This assumption was based on a non-significant (p\xa0=\xa00.5596) difference in Kaplan–Meier curves for post-progression survival.\n\nIn the model, the drug costs were calculated assuming a body surface area of 1.86\xa0m2, which reflected the average body surface area of the people in the REACH trial. The REACH trial used fludarabine and cyclophosphamide administered intravenously, but it is more common to use oral chemotherapy in the UK. In the model it was assumed that the efficacy of fludarabine and cyclophosphamide was the same regardless of the route of administration if the dosage was adjusted to ensure equivalent bioavailability. The costs of fludarabine and cyclophosphamide treatment in the model were adjusted to allow for the difference in the route of administration. In the base case, the drug doses and costs were reduced according to the proportion of people expected to progress or die each month. The average undiscounted drug cost for rituximab was £9078 for all six cycles of treatment. The average undiscounted drug costs of fludarabine were £2569 for people in the rituximab plus fludarabine and cyclophosphamide group and £2510 for people in the fludarabine and cyclophosphamide group. The average undiscounted drug costs of cyclophosphamide were calculated as £21 and £20 for each group respectively.\n\nThe model included costs for supportive care. Supportive care consisted of quarterly outpatient consultations, blood transfusions and bone marrow transplants in the progression-free survival health state and monthly outpatient consultations and second-line therapies for the progressed health state. The cost for intravenous administration of rituximab was £307 per cycle of treatment and the cost for an appointment to prescribe oral fludarabine and cyclophosphamide chemotherapy was £201. It was assumed that oral chemotherapy could be prescribed in the same appointment as rituximab so no additional cost of prescribing oral chemotherapy was included for the rituximab treatment group. Costs were also added for the pharmacist's time to prepare the infusion and one consultation with a clinical oncologist.\n\nThe utility values used in the manufacturer's submission were taken from a health technology assessment report that assessed the cost effectiveness of fludarabine as a first-line treatment for chronic lymphocytic leukaemia. A utility value of 0.8 was attached to the progression-free survival health state and 0.6 to the progressed health state. The estimates of utility were not preference based, and were estimated by the authors of the report from condition-specific health-related quality-of-life data. No disutility for adverse events was included in the model. The manufacturer provided an interim analysis of 34 people from an observational study of utility in people with chronic lymphocytic leukaemia. The value for the progression-free survival health state was consistent with that used in the manufacturer's submission. No conclusions could be drawn about the utility value appropriate for the progressed health state because only data for two people were available.\n\nThe manufacturer provided a base-case estimate of incremental cost effectiveness of rituximab plus fludarabine and cyclophosphamide compared with fludarabine and cyclophosphamide. The incremental quality-adjusted life year (QALY) gain was 0.585 at an incremental cost of £9128, giving an incremental cost-effectiveness ratio (ICER) of £15,593 per QALY gained. The probabilistic sensitivity analysis presented suggested that rituximab plus fludarabine and cyclophosphamide had a 75% probability of being cost effective at £20,000 and a 94% probability of being cost effective at £30,000 when compared with fludarabine and cyclophosphamide.\n\nDuring consultation on the appraisal consultation document, the manufacturer provided an estimate of the cost effectiveness of rituximab plus fludarabine and cyclophosphamide compared with fludarabine and cyclophosphamide, for the subgroup of people who had previously received rituximab. This was calculated using the same model described in section 3.11 with an adjustment to the progression-free survival in the rituximab plus fludarabine and cyclophosphamide group using the hazard ratio (1.13) estimated from the MDACC study. This adjustment to the model resulted in a QALY gain of 0.406 at an incremental cost of £9134, giving an ICER of £22,519 per QALY gained.\n\nA sensitivity analysis was presented in the manufacturer's submission using different parametric models for the progression-free survival extrapolation. Additional sensitivity analyses were completed as follows:\n\nincreasing and decreasing adverse event costs by 50%\n\nincreasing and decreasing supportive care costs for the health states by 50%\n\nassuming utility values for the health states such that the difference in the values between the health states was 0.4 and 0.1\n\nassuming upper and lower quartiles for drug administration costs (from reference costs 2007/08)\n\nassuming differential probabilities of death after progression between treatment arms.One-way sensitivity analyses suggested that the results were not sensitive to a variety of parameter assumptions including adverse events costs, monthly supportive care costs, and drug administration costs. The results were also not sensitive to the function used to extrapolate progression-free survival. The results were sensitive to assumptions about utilities and assumptions about the probability of death after progression. The highest ICER reported (using both differential mortality rates between treatment arms and adjusting utilities) was £23,790 per QALY gained.\n\nThe manufacturer's submission also included a scenario analysis to explore the impact on the ICER of combining rituximab with chemotherapy other than fludarabine and cyclophosphamide. The results of this analysis suggested that the QALY gain from combining rituximab with chemotherapy would need to decrease to about 45% of that in the base case, all else remaining the same, for the ICER for rituximab to increase to over £30,000 per QALY gained.\n\nThe ERG considered that all the relevant trials had been identified. The ERG noted that the manufacturer's submission was based on only one clinical trial, and this trial was unpublished. The ERG considered this trial had adequate randomisation and allocation concealment. However, it noted that the trial was open label and therefore assessments might be biased. The ERG noted that an independent assessment of response was made during a pre-planned interim analysis of the trial data (conducted when about two thirds of the total 284 events had occurred). It stated that there were differences in progression-free survival between the trial groups when assessed by the blinded independent panel and the unblinded trial investigators (independent panel data were provided as academic-in-confidence). The ERG considered that the trial population was relatively young compared with the UK population who would be eligible for rituximab and 10% of people had mild stage disease (Binet stage A), a stage at which people were not commonly treated in the UK. The ERG also noted that people with fludarabine-refractory chronic lymphocytic leukaemia were excluded from the trial although they could be eligible for rituximab. It considered that the comparator used in the cost-effectiveness analysis (that is, fludarabine and cyclophosphamide) was appropriate.\n\nThe ERG noted that in the manufacturer's economic model people in the progressed health state could not move back into the progression-free survival health state. They considered that this did not appropriately reflect the disease process because people with chronic lymphocytic leukaemia receive a series of treatments and therefore they may have periods of progression-free survival after relapse and further treatment. The ERG commented that not all adverse events were assigned costs in the model. In particular, hepatitis B, for which there were six cases in the rituximab plus fludarabine and cyclophosphamide group and no cases in the fludarabine and cyclophosphamide group.\n\nThe ERG completed a series of exploratory analyses. It remodelled rituximab costs so that full costs were incurred at the start of each cycle rather than spread throughout the cycle. This amendment increased the base-case analysis from £15,593 to £18,129 per QALY gained. The ICER of £18,129 was corrected to £16,607 per QALY gained during consultation on the ACD. The ERG conducted an analysis using progression-free survival curves based on the independent assessment of progression (from the interim trial analysis) rather than non-blinded, investigator-assessed progression. This increased the base-case ICER to £17,507 per QALY gained. The ERG also explored the effect on the ICER of assuming no overall survival benefit of treatment with rituximab plus fludarabine and cyclophosphamide. It used two methods for this; it used the mortality rate from the fludarabine and cyclophosphamide group and applied it to the rituximab plus fludarabine and cyclophosphamide group and vice versa. The resulting ICERs were £40,568 and £42,444 per QALY gained for each method respectively compared with £15,593 per QALY gained in the manufacturer's base case.\n\nThe ERG identified that if it is assumed there is no difference in overall survival between the rituximab plus fludarabine and cyclophosphamide and fludarabine and cyclophosphamide groups, the model outputs become sensitive to the assumed utility differences between the progression-free and the progressed health states. If the difference in utility between the health states is decreased by 0.1 (that is from a difference of 0.2 to 0.1), the ICER increases to between £81,135 and £84,889 per QALY gained.\n\nFull details of all the evidence are in the manufacturer's submission and the ERG report.", 'Consideration of the evidence': "The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of rituximab, having considered evidence on the nature of relapsed or refractory chronic lymphocytic leukaemia and the value placed on the benefits of rituximab by people with the condition, those who represent them, and clinical specialists. It also took into account the effective use of NHS resources.\n\n# Clinical effectiveness\n\nThe Appraisal Committee discussed current standard clinical management of relapsed or refractory chronic lymphocytic leukaemia. The Committee heard from clinical specialists that the most frequently used first-line treatments are: fludarabine plus cyclophosphamide with or without rituximab; and chlorambucil for people unable to have fludarabine because they have a poor performance status. However, for relapsed or refractory chronic lymphocytic leukaemia there is no single standard treatment option. The choice of treatment depends on a number of factors, including the presence of genetic abnormalities such as del(17p) mutation, previous treatments the person has received, whether a response was achieved from previous treatments, and if so, the duration of response. Clinical specialists noted that for these reasons, they considered it important to have a range of treatment options available. The Committee heard that, for relapsed disease, treatments used previously may be administered again either with or without the addition of another therapeutic agent, or alternatively a different agent may be used. When additional or different treatments were used, these could include fludarabine and cyclophosphamide with the addition of mitoxantrone, alemtuzumab and stem cell transplantation.\n\nThe Committee noted that the clinical effectiveness evidence for this appraisal was based mainly on a single unpublished randomised controlled trial (the REACH trial). In this trial rituximab plus fludarabine and cyclophosphamide was compared with fludarabine and cyclophosphamide. The Committee heard from clinical specialists that people in the REACH trial were younger and had a better performance status than people with chronic lymphocytic leukaemia seen in routine practice in the NHS in England and Wales. However, the clinical specialists commented that the people in the trial were representative of the people who would be eligible for treatment with fludarabine plus cyclophosphamide. The Committee discussed the inclusion in the trial of people who had Binet stage A chronic lymphocytic leukaemia. It heard from clinical specialists that the decision to treat chronic lymphocytic leukaemia would depend on symptoms and progression of disease rather than specific staging.\n\nThe Committee discussed the exclusion from the REACH trial of people who were previously treated with fludarabine combination therapy, people who were previously treated with rituximab and people who had chronic lymphocytic leukaemia that was refractory to fludarabine. However, it heard from clinical specialists that, if suitable, people often had fludarabine combination regimens as a first-line treatment. It also heard that the publication of 'Rituximab for the first-line treatment of chronic lymphocytic leukaemia' (NICE technology appraisal guidance 174) recommending rituximab plus fludarabine and cyclophosphamide meant that in the future an increasing number of people with relapsed or refractory disease will have had rituximab and fludarabine combination therapy as a first-line treatment. The Committee considered the exclusion of these groups from the clinical trial was a limitation for decision making because it meant that the trial population did not reflect all the people with relapsed or refractory disease who would be eligible for rituximab plus fludarabine and cyclophosphamide in the NHS.\n\nThe Committee accepted that the REACH trial demonstrated that the addition of rituximab to fludarabine and cyclophosphamide improved progression-free survival and complete response rates. The Committee noted there was potential for bias in outcome assessment because of the open-label design of the trial. The Committee discussed the results of an interim analysis of the trial data. This was an independent assessment of response that was provided as academic-in-confidence. The Committee noted that there was a difference between the investigator and independent assessments but was aware that the interim analysis was conducted 1\xa0year before the investigator assessment. The Committee heard from clinical specialists that assessment of progression-free survival was subjective and could change depending on familiarity with assessment tools. The Committee considered that the differences in these assessments led to uncertainty in estimating the additional benefit of rituximab.\n\nThe Committee noted that in the REACH trial median overall survival had not been reached in the rituximab group, and that survival curves for patients in the two treatment groups hardly diverged until 30\xa0months. The Committee heard from clinical specialists and patient experts that it is difficult for studies of chronic lymphocytic leukaemia to demonstrate an effect of treatment on overall survival because of the long natural history of the disease and because people with the disease often receive multiple treatments. It also heard that progression-free survival and response rates were often accepted as surrogates for overall survival. Furthermore, clinical specialists commented that longer term trial evidence is emerging that demonstrates an overall survival benefit of first-line treatment with rituximab plus fludarabine and cyclophosphamide. On balance, the Committee was persuaded that the improvements observed in progression-free survival and response rates were likely to lead to at least some gain in overall survival, although this gain could not be quantified.\n\nThe Committee noted that in the REACH trial there were slightly more grade 3 or 4 adverse events and treatment-related deaths in the rituximab plus fludarabine and cyclophosphamide group than in the fludarabine and cyclophosphamide group. It heard from clinical specialists that people with chronic lymphocytic leukaemia are aware of the risks of treatments and are willing to accept these risks because of the severity of the condition. The Committee discussed the six cases of hepatitis B seen in the trial in the rituximab plus fludarabine and cyclophosphamide group. However, it heard from clinical specialists that this would be unlikely to happen in the UK because all people with chronic lymphocytic leukaemia are screened for hepatitis B before treatment, and so hepatitis B reactivation would be rare.\n\nPeople who have previously received treatment with rituximab\n\nThe Committee discussed the use of rituximab plus fludarabine and cyclophosphamide in people who have previously received treatment with rituximab-containing regimens. These people were excluded from the REACH trial, and the Committee heard from clinical specialists that there was uncertainty about the degree of benefit of retreatment with rituximab. However, patient experts indicated that there was anecdotal evidence that people retreated with rituximab may have a good response to treatment. The Committee also noted comments received at consultation that retreatment with rituximab is common in other lymphoproliferative conditions where there has been a good response, and that the same could be expected for chronic lymphocytic leukaemia. It was also aware that over the next few years there would be an increasing number of people who would be treated with rituximab and who would require further treatment following relapse.\n\nThe Committee considered the evidence from uncontrolled phase II studies reporting the benefits of retreatment with rituximab and noted the methodological limitations of these studies. It discussed the MDACC data provided during consultation, reporting that there was a similar response rate and progression-free survival in people who have previously received rituximab compared with people who have not. However, it noted this study had limitations in its design, for example, it was open label and uncontrolled (and therefore not randomised). The study included 100 people who had previously been treated with a rituximab-containing regimen. However, limited data were provided about these regimens and they included rituximab monotherapy and rituximab plus chemotherapy other than fludarabine and cyclophosphamide. The Committee was not persuaded that the results from this study could be considered reflective of the UK population, of whom an increasing number will have previously received rituximab plus fludarabine and cyclophosphamide.\n\n## People who have previously received treatment with fludarabine\n\nThe Committee considered the use of rituximab plus fludarabine and cyclophosphamide in people who have previously received treatment with fludarabine. It first discussed people who had previously had a response to treatment with fludarabine (that is, people with fludarabine-sensitive disease). The Committee discussed evidence from the REACH trial which included people whose disease was sensitive to fludarabine monotherapy. It noted that the REACH trial did not include people who had previously received fludarabine combination therapy. However, the Committee considered that the clinical effectiveness was likely to be similar for people who were sensitive to fludarabine monotherapy and for people who were sensitive to fludarabine combination therapy. Therefore the Committee was persuaded that data from the REACH trial could apply to people who were sensitive to fludarabine combination therapy.\n\nThe Committee then discussed the evidence for the use of rituximab plus fludarabine and cyclophosphamide in people who have chronic lymphocytic leukaemia that is refractory to fludarabine. It noted the methodological limitations of the non-comparative studies provided by the manufacturer. The Committee understood that clinical specialists did not consider that people with fludarabine-refractory disease should be retreated with the same fludarabine-containing regimen. The Committee considered that the results of the MDACC study indicated a lower response to treatment with rituximab plus fludarabine and cyclophosphamide in chronic lymphocytic leukaemia refractory to fludarabine than in disease that was sensitive to fludarabine. The Committee concluded that although people with fludarabine-refractory disease may derive some benefit from retreatment with fludarabine-containing chemotherapy regimens such as rituximab plus fludarabine and cyclophosphamide, the benefit was likely to be less than if the disease was fludarabine sensitive.\n\n## Rituximab plus chemotherapy regimens other than fludarabine plus cyclophosphamide\n\nThe Committee recognised that the marketing authorisation for rituximab allowed its use with any chemotherapy regimen. It discussed the evidence on rituximab plus chemotherapy regimens other than fludarabine and cyclophosphamide. The Committee discussed comments received on the appraisal consultation document that suggested that people who cannot take fludarabine and people with chronic lymphocytic leukaemia that is refractory to fludarabine may benefit from treatment with rituximab plus other chemotherapy. The Committee was aware of the lack of treatment options available to these people. However, the Committee noted the methodological limitations of the non-comparative evidence provided. It heard from the manufacturer that a study of rituximab plus chlorambucil for first-line treatment was under way and that preliminary data from a cross-trial analysis indicated that response rates were better for people treated with rituximab plus chlorambucil than with chlorambucil alone. Overall, the Committee considered that there was significant uncertainty about the relative benefit of adding rituximab to chemotherapy regimens other than fludarabine and cyclophosphamide and therefore more research was needed.\n\n# Cost effectiveness\n\nThe Committee reviewed the economic model submitted by the manufacturer and the ERG's analysis of the model. It was aware that the model did not allow transition from the progressed health state to the progression-free survival heath state. The Committee considered that this did not appropriately reflect the disease process because people may receive later treatments with further periods of progression-free survival. The Committee was aware that a similar model had been used in the appraisal of 'Rituximab for the first-line treatment of chronic lymphocytic leukaemia' (NICE technology appraisal guidance 174). On balance, the Committee agreed that the model could be used as a basis for considering the cost effectiveness of rituximab.\n\nThe Committee considered how the costs of rituximab had been incorporated into the economic model. It noted that the ERG considered the assumption that costs were spread throughout the cycle in the base-case analysis inappropriate because rituximab was provided on the first day of each cycle. Therefore, the ERG explored remodelling rituximab costs so that costs were incurred at the start of each treatment cycle. The ERG re-analysis was corrected after consultation on the appraisal consultation document, and concluded that the ICER increased from £15,600 per QALY gained in the base case to £16,600 per QALY gained, which the Committee accepted.\n\nThe Committee discussed the utilities used in the economic model and noted that the evidence base for these estimates did not reflect the NICE reference case; in particular, preference-based methods were not used. It was aware that a utility study was under way in people with chronic lymphocytic leukaemia in the UK but detailed results from this study for people who had progressed following treatment were not yet available. The Committee heard from patient experts that they considered an assumption of only a small difference in utility between the progressed and progression-free survival health states was not realistic. People greatly value being progression free and asymptomatic – it is associated with a marked improvement in quality of life. The Committee considered the lack of appropriate utility data contributed to uncertainty in the economic model.\n\nThe Committee discussed whether the modelled gains in overall survival from the economic model appropriately reflected the data from the clinical trial. It noted that the outputs from the manufacturer's economic analysis modelled a difference in overall survival between treatment groups from the start of treatment that did not reflect the trial data. The overall survival curves from the clinical trial provided by the manufacturer showed no difference in overall survival between the treatment groups before around 30\xa0months, although, beyond this time, the extrapolated curves began to diverge. The Committee considered that there was little evidence from the REACH trial to support the validity of the analysis provided by the manufacturer and that the manufacturer's base-case analysis was likely to have overestimated the benefits associated with rituximab.\n\nThe Committee considered the estimates of cost effectiveness provided by the manufacturer and the additional exploratory analyses performed by the ERG that examined the impact on the ICER of reducing the survival advantage of treatment with rituximab. It noted that using an assumption of no overall survival advantage had the effect of increasing the cost-effectiveness estimates from £15,600 per QALY gained in the base case to £41,000 per QALY gained. Furthermore it recognised that when there was no modelled gain in overall survival the results became very sensitive to the difference between the utility values used for the progression-free survival health state and those used for the progressed health state which were uncertain. However, based on comments from the clinical specialists, the Committee was persuaded that it was appropriate to assume at least some gain in overall survival in the economic model. Overall, the Committee considered that the most plausible ICER was likely to be at the upper end of the range of £20,000 to £30,000 per QALY gained, which was higher than the ERG's corrected base case of £16,600 per QALY gained.\n\nOn balance, the Committee was persuaded that even taking into account the uncertainty about utility values and the uncertainty about a gain in overall survival from treatment with rituximab, the use of rituximab plus fludarabine and cyclophosphamide was a cost-effective use of NHS resources for the population represented in the REACH trial; that is, people who have not previously received rituximab or fludarabine combination therapy and those whose disease is not refractory to fludarabine monotherapy. Additionally, the Committee was persuaded that the cost effectiveness of rituximab plus fludarabine and cyclophosphamide could be generalised from people whose chronic lymphocytic leukaemia was sensitive to fludarabine monotherapy to those whose disease was sensitive to fludarabine combination therapy (section 4.10).\n\n## People who have previously received treatment with rituximab\n\nThe Committee was not persuaded of the clinical effectiveness of rituximab plus fludarabine and cyclophosphamide for people who have already been treated with rituximab. Nevertheless, the Committee discussed the cost-effectiveness estimate provided by the manufacturer during consultation of £22,500 per QALY gained for people who had previously received rituximab. It noted that this did not include the correction for the timing of rituximab costs. It recognised that there was considerable uncertainty in the manufacturer's original base-case ICER because of the uncertainties in the gains in overall survival and the limitations in the health-related quality of life data available. The Committee noted that even for the REACH trial population the most plausible ICER was likely to be at the upper end of the range of £20,000 to £30,000 per QALY gained. It considered that in the rituximab-pretreated population, for which there was little research, the manufacturer's estimated ICER could not provide a basis for decision making. The Committee concluded that rituximab plus fludarabine and cyclophosphamide could not be recommended as an appropriate use of NHS resources for everyone who had previously been treated with rituximab. However, because of the uncertainty about the benefits of retreatment with rituximab, the Committee concluded that rituximab plus fludarabine and cyclophosphamide should be recommended in the context of research for people with relapsed or refractory chronic lymphocytic leukaemia that has previously been treated with rituximab. The Committee was aware of comments from consultees that some people in clinical trials had received rituximab in combination with treatments other than fludarabine and cyclophosphamide and at doses of rituximab lower than the licensed dose. The Committee considered that this technology appraisal guidance should not adversely affect recruitment to future or ongoing clinical trials. Therefore the Committee concluded that rituximab plus fludarabine and cyclophosphamide could be recommended for people with relapsed or refractory chronic lymphocytic leukaemia when rituximab had previously been given in the context of a clinical trial, either at a dose lower than currently licensed for chronic lymphocytic leukaemia, or in combination with chemotherapy other than fludarabine and cyclophosphamide.\n\n## People who have previously received treatment with fludarabine\n\nAfter concluding that rituximab plus fludarabine and cyclophosphamide was cost effective for people with chronic lymphocytic leukaemia that was sensitive to fludarabine (section 4.18), the Committee then considered its use in people with fludarabine-refractory disease. It noted the lower clinical response in people who were refractory to fludarabine than in people who were sensitive to it (section 4.10), and that clinical practice was not to retreat these people with the same fludarabine regimen. It also noted that the manufacturer had not provided an estimate of the cost effectiveness of rituximab plus fludarabine and cyclophosphamide in this population. The Committee heard from the manufacturer that there were difficulties identifying baseline event rate data and that the relative efficacy of rituximab therapy in this group was uncertain. On this basis the Committee considered that the use of rituximab plus fludarabine and cyclophosphamide for the treatment of people who had already had fludarabine could only be considered a cost-effective use of NHS resources when the chronic lymphocytic leukaemia remained fludarabine sensitive and not when it was fludarabine refractory.\n\n## Rituximab plus chemotherapy regimens other than fludarabine and cyclophosphamide\n\nThe Committee understood the potential need for other rituximab combinations for people whose disease is refractory to fludarabine or is not suitable for treatment with fludarabine. However, it concluded that there was significant uncertainty about the relative benefit of adding rituximab to chemotherapy regimens other than fludarabine and cyclophosphamide and therefore more research was needed. Furthermore, the Committee noted there was no current basis for estimating the cost effectiveness of such combinations, or for considering them to be cost effective. The Committee was aware that people with chronic lymphocytic leukaemia that is not suitable for treatment with fludarabine plus cyclophosphamide might be treated with rituximab plus other chemotherapy. It was also aware that this group might be older and include people with poor performance status or comorbidities. The Committee considered whether equalities legislation and the requirement for fairness meant that it should make a positive recommendation for rituximab plus other chemotherapy for this group. However, given the lack of evidence for both the clinical and cost effectiveness of this treatment, the Committee concluded that rituximab plus chemotherapy other than fludarabine and cyclophosphamide should only be used for the treatment of relapsed or refractory chronic lymphocytic leukaemia in the context of research.", 'Recommendations for further research ': 'The Committee considered that the following research would be of value:\n\nStudies investigating the effectiveness of rituximab plus fludarabine and cyclophosphamide in people with relapsed and refractory chronic lymphocytic leukaemia that has previously been treated with rituximab.\n\nStudies investigating the effectiveness of rituximab plus chemotherapy other than fludarabine and cyclophosphamide in people with relapsed and refractory chronic lymphocytic leukaemia.\n\nStudies investigating the health-related quality of life of people with chronic lymphocytic leukaemia that include data collected using a generic preference-based measure.', 'Related NICE guidance': 'Rituximab for the first-line treatment of chronic lymphocytic leukaemia. NICE technology appraisal guidance 174 (2009).\n\nFludarabine monotherapy for the first-line treatment of chronic lymphocytic leukaemia. NICE technology appraisal guidance 119 (2007).\n\nImproving outcomes in haematological cancers. NICE cancer service guidance (2003).\n\nOfatumumab for the treatment of chronic lymphocytic leukaemia refractory to fludarabine and alemtuzumab. NICE technology appraisal guidance 202 (2010)', 'Review of guidance': 'The guidance on this technology will be considered for review in 2012. The Guidance Executive will decide whether the technology should be reviewed based on information gathered by NICE, and in consultation with consultees and commentators.\n\nAndrew DillonChief ExecutiveJuly 2010', 'Changes after publication': 'February 2014: implementation section updated to clarify that rituximab is recommended as an option for treating relapsed or refractory chronic lymphocytic leukaemia. Additional minor maintenance update also carried out.\n\nMarch 2012: minor maintenance', 'About this guidance': 'NICE technology appraisal guidance is about the use of new and existing medicines and treatments in the NHS in England and Wales.\n\nThis guidance was developed using the NICE single technology appraisal process.\n\nWe have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available.\n\nYour responsibility\n\nThis guidance represents the views of NICE and was arrived at after careful consideration of the evidence available. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. However, the guidance does not override the individual responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.\n\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.\n\nCopyright\n\n© National Institute for Health and Clinical Excellence 2010. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.'}	https://www.nice.org.uk/guidance/ta193	Evidence-based recommendations on rituximab for treating relapsed or refractory chronic lymphocytic leukaemia in adults.
cb57b1a7146ae42e0bb28463517d6e8e8468beb4	nice	Gefitinib for the first-line treatment of locally advanced or metastatic non-small-cell lung cancer	Gefitinib for the first-line treatment of locally advanced or metastatic non-small-cell lung cancer Evidence-based recommendations on gefitinib (Iressa) for untreated locally advanced or metastatic non-small-cell lung cancer in adults. # Guidance Gefitinib is recommended as an option for the first-line treatment of people with locally advanced or metastatic non-small-cell lung cancer (NSCLC) if: they test positive for the epidermal growth factor receptor tyrosine kinase (EGFR-TK) mutation and the manufacturer provides gefitinib at the fixed price agreed under the patient access scheme.# The technology Gefitinib (Iressa, AstraZeneca) is a selective inhibitor of epidermal growth factor receptor tyrosine kinase (EGFR-TK) which blocks the signal pathways involved in cell proliferation. By blocking EGFR-TK, gefitinib helps to slow the growth and spread of the cancer. Gefitinib has a UK marketing authorisation for the treatment of adult patients with locally advanced or metastatic non-small-cell lung cancer (NSCLC) with activating mutations of EGFR-TK. The summary of product characteristics (SPC) states that when assessing the EGFR-TK mutation status of a patient, it is important that a well-validated and robust method is chosen to avoid false-negative and false-positive determinations. The SPC lists the following conditions that may be associated with gefitinib treatment: interstitial lung disease, hepatotoxicity and liver impairment. For full details of adverse effects and contraindications, see the SPC. Gefitinib is administered orally as 250-mg film-coated tablets. The recommended dosage is 250 mg daily to be taken until the disease progresses or the clinician advises otherwise. The cost for a pack of 250-mg tablets (30 tablets per pack) is £2167.71 (excluding VAT, 'British national formulary' edition 59). The manufacturer has agreed with the Department of Health a patient access scheme in which gefitinib for first-line treatment of NSCLC will be available at a single fixed cost of £12,200 per patient irrespective of the duration of treatment. The manufacturer will not invoice the NHS until the third monthly pack of gefitinib is supplied. This means that patients who need less than 3 months of treatment will not incur a charge. The Department of Health considered that this patient access scheme does not constitute an excessive administrative burden on the NHS.# The manufacturer's submission The Appraisal Committee (appendix A) considered evidence submitted by the manufacturer of gefitinib and a review of this submission by the Evidence Review Group (ERG; appendix B). The manufacturer's decision problem compared gefitinib with gemcitabine and carboplatin, paclitaxel and carboplatin, vinorelbine and cisplatin, and gemcitabine and cisplatin. The decision problem defined the population as patients with locally advanced or metastatic NSCLC who are previously untreated and who test positive for an EGFR-TK mutation (EGFR-TK mutation-positive patients). Outcomes were defined as overall survival, progression-free survival, objective tumour response rates, health-related quality of life and adverse events associated with treatment. In the economic evaluation the incremental cost per quality-adjusted life year (QALY) gained was presented. A lifetime horizon was used, and costs were considered from the perspective of the NHS and personal social services (PSS). The manufacturer's submission presented clinical effectiveness data from the Iressa Pan Asian Study (IPASS), a randomised controlled trial (RCT) set in East Asia. IPASS was a multicentre, open-label RCT in clinically selected patients older than 18 years who had the following characteristics: histologically or cytologically confirmed stage IIIb (locally advanced disease such as pleural effusion not amenable to local therapy) or stage IV (metastatic) NSCLC with adenocarcinoma histology (including bronchoalveolar carcinoma), had never smoked (or had smoked fewer than 100 cigarettes per lifetime) or had been light smokers (stopped smoking at least 15 years previously and had smoked no more than 10 pack-years), had no prior chemotherapy, biological or immunological therapy, and had a WHO performance status of 0, 1 or 2 (on a scale of 0 to 4, with low values reflecting better health). IPASS included 1217 patients from 87 East Asian centres. Patients were randomised to receive 250 mg of gefitinib once daily or paclitaxel (200 mg/m2 body surface area) immediately followed by carboplatin (at a dose corresponding to an area under the curve of concentration versus time of 5.0–6.0 minute.mg/ml) in 3-weekly cycles. Treatment was continued until disease progression (according to Response Evaluation Criteria in Solid Tumours , which used tumour measurement rather than investigator assessment), unacceptable adverse events, a patient or clinician request to discontinue, severe non-adherence to the protocol, or until six chemotherapy cycles were reached. Following disease progression, all patients in the gefitinib arm were offered treatment with paclitaxel and carboplatin; if the patient declined or the combination was considered unsuitable, the clinician chose an approved therapy. Following disease progression on paclitaxel and carboplatin treatment, choice of treatment was at the clinician's discretion. The manufacturer's submission focused on a subgroup of 261 EGFR-TK mutation-positive patients from the overall IPASS population. This subgroup accounted for 21% of the IPASS population. Of these patients, 80.8% were women. Most patients (94.3%) had never smoked, 5.4% had been light smokers and 0.4% were ex-smokers. On a scale of 0 (good) to 4 (poor), most patients (65.9%) had a WHO performance status of 1; 26.4% had a WHO performance status of 0 and 7.7% had a WHO performance status of 2. Most patients had tumours with histology indicating adenocarcinoma (94.6%); 5.4% had histology indicating bronchocarcinoma and none had unknown histology. At study entry most patients had metastatic disease (81.6%); 18.4% had stage IIIb locally advanced disease. Baseline characteristics in the subgroup were similar between both treatment arms. The primary outcome examined in IPASS was progression-free survival, which was assessed from the date of randomisation to disease progression (determined by RECIST) or death from any cause. Secondary outcomes included overall survival, objective tumour response rate, health-related quality of life, symptomatic improvement, safety and tolerability. Estimates of overall survival in the overall population were based on an interim analysis after 450 deaths (37% of study participants), as well as modelled values reflecting median overall survival. The final analyses are due in the second quarter of 2010. Health-related quality of life was assessed by the Functional Assessment of Cancer Therapy–Lung (FACT–L) and the Trial Outcome Index (TOI), calculated from the domain scores from FACT–L representing physical and functional wellbeing, and lung cancer symptoms (LCS). To assess the non-inferiority of gefitinib compared with paclitaxel and carboplatin, analysis of progression-free survival used a Cox proportional hazard model adjusting for baseline covariates in the intention-to-treat population. In the overall study population, patients randomised to receive gefitinib had a statistically significantly longer progression-free survival compared with patients randomised to receive paclitaxel and carboplatin. The hazard ratio (HR) for progression-free survival (gefitinib compared with paclitaxel and carboplatin) was 0.74 (95% confidence interval 0.65 to 0.85, p < 0.0001). The objective tumour response rate was statistically significantly higher for gefitinib compared with paclitaxel and carboplatin (43.0% versus 32.2%; odds ratio 1.59, 95% CI 1.25 to 2.01, p = 0.0001). The estimates of overall survival in the overall study population were similar for both groups (HR for gefitinib compared with paclitaxel and carboplatin 0.91, 95% CI 0.76 to 1.10). In the subgroup of EGFR-TK mutation-positive patients (n = 261), progression-free survival in patients randomised to receive gefitinib was statistically significantly longer than for patients randomised to receive paclitaxel and carboplatin (HR 0.48, 95% CI 0.36 to 0.64, p < 0.0001). Median progression-free survival was 9.5 months for patients randomised to receive gefitinib and 6.3 months for patients randomised to receive paclitaxel and carboplatin. The objective tumour response rate was statistically significantly higher for patients randomised to receive gefitinib compared with patients randomised to receive paclitaxel and carboplatin (71.2% versus 47.3%; OR 2.75, 95% CI 1.65 to 4.60, p = 0.0001). There was no statistically significant difference in the estimates of overall survival for patients randomised to receive gefitinib compared with patients randomised to receive paclitaxel and carboplatin (HR 0.78, 95% CI 0.50 to 1.20). In the subgroup of EGFR-TK mutation-negative patients (n = 176), progression-free survival in patients randomised to receive gefitinib was statistically significantly shorter than for patients randomised to receive paclitaxel and carboplatin (HR 2.85, 95% CI 2.05 to 3.98, p < 0.0001). Median progression-free survival was 1.5 months for patients randomised to receive gefitinib and 5.5 months for patients randomised to receive paclitaxel and carboplatin (that is, EGFR-TK-negative patients randomised to receive gefitinib had shorter progression-free survival than patients randomised to receive conventional chemotherapy). The objective tumour response rate was statistically significantly lower with gefitinib than with paclitaxel and carboplatin (1.1% versus 23.5%; OR 0.04, 95% CI 0.01 to 0.27, p = 0.0013). There was no statistically significant difference in the estimates of overall survival for patients randomised to receive gefitinib compared with those randomised to receive paclitaxel and carboplatin (HR 1.38, 95% CI 0.92 to 2.09). In the overall study population, statistically significantly more patients randomised to receive gefitinib experienced a clinically relevant improvement in health-related quality of life and disease symptoms, assessed by the FACT–L and TOI, than patients randomised to receive paclitaxel and carboplatin (FACT–L – OR 1.34, 95% CI 1.06 to 1.69, p = 0.0148; TOI – OR 1.78, 95% CI 1.40 to 2.26, p < 0.0001). Rates of symptomatic improvement were measured using the lung cancer symptoms (LCS) domain of the FACT–L and were similar for patients randomised to receive gefitinib and patients randomised receive to paclitaxel and carboplatin. Similarly in the subgroup of EGFR-TK mutation-positive patients, statistically significantly more patients randomised to receive gefitinib experienced a clinically relevant improvement in health-related quality of life and disease symptoms than patients randomised to receive paclitaxel and carboplatin (FACT–L – OR 3.01, 95% CI 1.79 to 5.07, p < 0.0001; TOI – OR 3.96, 95% CI 2.33 to 6.71, p < 0.0001; LCS – OR 2.70, 95% CI 1.58 to 4.62, p = 0.0003). Time to worsening of health-related quality of life and disease-related symptoms was longer for patients randomised to receive gefitinib than for patients randomised to receive paclitaxel and carboplatin (median range 11.3–16.6 months for gefitinib and 2.9–3.0 months for paclitaxel and carboplatin). In the subgroup of EFGR-TK mutation-negative patients, statistically significantly more patients randomised to receive paclitaxel and carboplatin had a clinically relevant improvement in health-related quality of life and disease-related symptoms than patients randomised to receive gefitinib (FACT–L – OR 0.31, 95% CI 0.15 to 0.65, p = 0.0021; TOI – OR 0.35, 95% CI 0.16 to 0.79, p = 0.00111; LCS – OR 0.28, 95% CI 0.14 to 0.55, p = 0.0002). Time to worsening of health-related quality of life and disease-related symptoms was similar or shorter for patients randomised to receive gefitinib compared with patients randomised to receive paclitaxel and carboplatin (median 1.4 months for gefitinib versus 1.4–4.2 months for paclitaxel and carboplatin). The manufacturer's submission did not provide an analysis of adverse events according to EGFR-TK mutation status. The manufacturer's submission stated that in the overall populations gefitinib was associated with fewer grade 3 or 4 adverse events than paclitaxel and carboplatin (28.7% versus 61.0%). The manufacturer identified two additional trials (First-SIGNAL and the North East Japan Gefitinib Study Group trial ) that compared gefitinib with chemotherapy for the treatment of chemotherapy-naive patients with predominantly adenocarcinoma histology and EGFR-TK mutations. The manufacturer considered including these studies in a meta-analysis along with data from IPASS. However, the manufacturer excluded the First-SIGNAL study on the basis that it examined only a small number of EGFR-TK mutation-positive patients (n = 42) and because the comparator (gemcitabine and cisplatin) differed from IPASS. The NEJGSG trial, which compared gefitinib with paclitaxel and carboplatin, was considered suitable by the manufacturer for inclusion in the meta-analysis and used as supporting evidence for IPASS. In the NEJGSG trial, patients randomised to receive gefitinib had a statistically significant longer progression-free survival than those randomised to receive paclitaxel and carboplatin (HR 0.357, 95% CI 0.25 to 0.51, p < 0.001). The meta-analysis incorporating progression-free survival from the IPASS and the NEJGSG trial demonstrated a statistically significant improvement in progression-free survival for EGFR-TK mutation-positive patients who were randomised to receive gefitinib compared with mutation-positive patients who were randomised to received paclitaxel and carboplatin (fixed effects model: HR 0.43, 95% CI 0.34 to 0.53, p < 0.001). The manufacturer carried out a systematic review and mixed-treatment comparison of RCTs comparing chemotherapy in chemotherapy-naive patients with NSCLC. The manufacturer chose paclitaxel and carboplatin as a baseline comparator for all analyses. The systematic review identified 29 trials, and 28 studies were included in the network that formed the basis for the mixed-treatment comparison. In response to a request from the ERG for clarification, the manufacturer provided an updated mixed-treatment comparison, which included treatment with pemetrexed and cisplatin as a comparator (29 studies in the updated mixed-treatment comparison). The manufacturer extracted and analysed data for clinical efficacy (progression-free survival, overall survival and objective tumour response) and tolerability (anaemia, diarrhoea, fatigue, febrile neutropenia, nausea and vomiting) for use in the economic evaluation. The manufacturer calculated the relative effect of alternative chemotherapy (other than paclitaxel and carboplatin) compared with paclitaxel and carboplatin in an unselected population with NSCLC (that is, without regard to EGFR mutation). The manufacturer then applied the relative estimates for clinical efficacy to a baseline event rate in EGFR-TK mutation-positive patients who had been randomised to receive paclitaxel and carboplatin in IPASS. The manufacturer used a Markov economic model to assess the cost effectiveness of gefitinib compared with chemotherapy in the first-line treatment of EGFR-TK mutation-positive patients with NSCLC. Patients entered the model with stable disease. The model had four distinct health states: response to treatment, stable disease, disease progression and death. The model had a cycle length of 21 days and a 5-year time horizon (assumed to be a lifetime horizon). The manufacturer obtained data for effectiveness from a variety of sources. The hazard ratio for progression-free survival for EGFR-TK mutation-positive patients for gefitinib relative to paclitaxel and carboplatin was derived from the manufacturer's meta-analysis (HR 0.43) The hazard ratio for overall survival for EGFR-TK mutation-positive patients for gefitinib relative to paclitaxel and carboplatin was estimated from IPASS; estimates of hazard ratios for progression-free survival and overall survival for the chemotherapy regimens were derived from the manufacturer's mixed-treatment comparison. The manufacturer chose a Weibull model for extrapolating costs and outcomes beyond the IPASS follow-up period. Covariates in the model included: mutation status, gender, performance status (0 or 1 versus > 1) and smoking history (never-smoker or ever-smoker). The characteristics of the population modelled in the manufacturer's economic evaluation were based on the IPASS population, which comprised chemotherapy-naive EGFR-TK mutation-positive patients who were eligible to receive chemotherapy. The comparator technologies were paclitaxel and carboplatin, gemcitabine and cisplatin, gemcitabine and carboplatin, and vinorelbine and cisplatin. Utility estimates in the manufacturer's model were adopted from a single UK study in which utility values were derived from a survey of 105 members of the general public who were asked to value descriptions of health states of second-line chemotherapy for patients with NSCLC. This study did not provide utility estimates associated with the mode of delivery of treatment (oral versus intravenous), so the manufacturer used utility values previously applied in NICE technology appraisal guidance 162 ('Erlotinib for the treatment of relapsed non-small cell lung cancer'), which examined second-line chemotherapy for patients with NSCLC and included utilities related to oral (erlotinib) and intravenous treatment. Resource use in the model included: medication, delivery of chemotherapy, EGFR-TK mutation testing, patient monitoring, NHS transport service, management of grade 3 or 4 adverse events, best supportive care and active treatment after progression. Resource use was estimated from a range of secondary sources (such as references costs, British national formulary, previous NICE technology appraisal submissions and the ERG reports for NICE technology appraisal guidance 162). The manufacturer's model incorporated details of a patient access scheme. In the manufacturer's base case, the incremental cost-effectiveness ratios (ICERs) for EGFR-TK mutation-positive patients ranged from £19,402 per QALY gained (gefitinib compared with paclitaxel and carboplatin) to £35,992 per QALY gained (gefitinib compared with vinorelbine and cisplatin) using a 16.6% prevalence for EGFR-TK mutation. The manufacturer undertook a range of one-way sensitivity analyses and noted that the results of the cost-effectiveness analysis were sensitive to five key parameters: the overall survival for EGFR-TK mutation-positive patients randomised to receive gefitinib; the overall survival for EGFR-TK mutation-positive patients randomised to receive gemcitabine and carboplatin; the progression-free survival for EGFR-TK mutation-positive patients randomised to receive gemcitabine and carboplatin; the progression-free survival for EGFR-TK mutation-positive patients randomised to receive gefitinib; and the maximum number of chemotherapy cycles, which varied from four to eight. The manufacturer also carried out a number of scenario analyses, and none led to any substantial change in the ICER. The manufacturer's probabilistic sensitivity analysis showed that vinorelbine and cisplatin was the most cost-effective regimen for the first-line treatment of EGFR-TK mutation-positive patients up to a threshold of £35,100 per QALY gained. Beyond this threshold, gefitinib was the most cost-effective option for the first-line treatment of EGFR-TK mutation-positive patients. At a threshold of £30,000 per QALY gained the probabilities of each treatment being the most cost effective in EGFR-TK mutation-positive patients were: vinorelbine and cisplatin (75%); gefitinib (18%); gemcitabine and carboplatin (4%); gemcitabine and cisplatin (3%); and paclitaxel and carboplatin (0%). The ERG considered that the evidence of clinical effectiveness presented in the manufacturer's submission was derived from a high-quality trial that used robust randomisation techniques and was suitably powered to demonstrate the primary objectives of the trial for the overall population. The ERG stated that the trial provided convincing evidence of the efficacy and benefits to health-related quality of life of gefitinib in EGFR-TK mutation-positive patients compared with paclitaxel and carboplatin. The ERG highlighted several areas of concern about the clinical evidence submitted by the manufacturer. The ERG was concerned about the generalisability of the clinical results from IPASS to the UK population given the characteristics of the people in the trial (predominantly women, East Asians, non-smokers), the histological type of NSCLC (adenocarcinoma accounts for approximately 25% of the population with NSCLC in the UK), and the comparator used (it is estimated that 5% of patients in the UK receive paclitaxel and carboplatin for the first-line treatment of NSCLC). The ERG noted that the licensed indication for gefitiib was in locally advanced or metastatic NSCLC in patients with activating mutations of EGFR-TK, and questioned the feasibility of conducting EGFR-TK mutation testing within the NHS given that this is not routinely carried out. The ERG was concerned that making the service operational throughout England and Wales may require substantial investment in time and resources. The ERG highlighted that in IPASS the measurement of the primary outcome of progression-free survival may be unreliable because it was assessed without blinding. The ERG was also concerned that the hazard ratios for this outcome may have been inappropriately calculated using the Cox proportional hazards method. This was because this method is valid only if the hazard ratio for the two groups being compared remains constant over time, and the ERG believed that this criterion was not met in the manufacturer's intention-to-treat analysis of IPASS. The ERG had major concerns about the immaturity of the overall survival data (that is, that relatively few deaths had occurred) because the interim analysis in the manufacturer's submission was based on 450 deaths of 1217 participants (death of 37% of participants). The ERG highlighted that confounding may have occurred in IPASS because of crossover of treatment after disease progression. Therefore, any changes in overall survival may not result from the treatment to which trial participants were originally assigned. The ERG highlighted that the manufacturer's meta-analysis could have appropriately included the First-SIGNAL trial because the comparator used in the First-SIGNAL trial (gemcitabine and cisplatin) was not substantially different in terms of clinical benefit and tolerability from the comparator used in IPASS. The ERG noted that an indirect comparison or mixed-treatment comparison including all three studies (IPASS, NEJGSG and First-SIGNAL) would have been more appropriate. The ERG emphasised a number of weaknesses in the manufacturer's mixed-treatment comparison, such as the extraction of unreported outcome statistics for some studies from two published meta-analyses. Different methods were used to estimate the unreported hazard ratios and this may have led to bias regarding the selection of studies included in the mixed-treatment comparison. The ERG was also concerned that the mixed-treatment comparison assumed that EGFR-TK mutation status did not affect outcomes in patients receiving chemotherapy. The ERG noted that assessment of gefitinib is more complex than a simple comparison of two treatment options as presented in the manufacturer's submission, because it involves both a specific diagnostic test to identify the presence of EGFR-TK mutations and the consequent choice of treatment following the test result (gefitinib or chemotherapy). The accuracy (that is, analytical validity) of the amplification-refractory mutation system (ARMS) test for identifying EGFR-TK mutations is very high, but the power of the test result to predict a good response to treatment with gefitinib is lower. The ERG suggested that the average benefit for patients receiving gefitinib in IPASS involved a trade-off between those who would get a good outcome (EGFR-TK mutation-positive patients who correctly tested positive for the mutation) and those who would get no benefit at all (EGFR-TK mutation-negative patients who tested positive for the mutation). The ERG also noted that performance characteristics of the diagnostic test should have been incorporated by the manufacturer within the model. The ERG expressed concern that the prevalence of EGFR-TK mutations (that is, the proportion of EGFR-TK mutation-positive patients within the tested population) would determine the volume and cost of EGFR-TK tests, and that this would contribute to the incremental cost of adopting a 'test and treat' policy. The ERG highlighted that the results from the manufacturer's economic model for EGFR-TK mutation-positive patients receiving gefitinib were dependent on the prevalence of EGFR-TK mutations. The ERG noted that varying the prevalence of EGFR-TK mutations from the 16.6% stated in the manufacturer's submission (producing an ICER of £20,010 per QALY gained based on a 6-year time horizon) to between 5.0% and 25.0% produced ICERs ranging from £32,685 to £18,174 per QALY gained. The results of the economic model varied depending on the combination of a specific test (ARMS) and gefitinib treatment, and might not be valid if tests other than ARMS were used. The ERG believed that the time horizon in the manufacturer's model should have been 6 years instead of 5 years because this more closely approximated the length of life for EGFR-TK mutation-postive patients with locally advanced or metastatic NSCLC. The ERG also highlighted that the chemotherapy costs used in the model were not accurate. The ERG made adjustments to the costs of first-line chemotherapy comparators, which had a modest impact on cost effectiveness. However, the reduction in dose level of comparator chemotherapy because of the higher proportion of female patients in the population of EGFR-TK mutation-positive patients compared with the general lung cancer population, combined with lower BNF prices for generic paclitaxel, led to an increase in the ICER of gefitinib compared with paclitaxel and carboplatin from £20,010 per QALY gained (based on the 6-year time horizon) to £38,063 per QALY gained. The ERG was concerned that IPASS allowed a maximum of six chemotherapy cycles whereas in their view patients in the UK usually receive four cycles with up to a maximum of six allowed if their disease responds well. This adjustment to the model by the ERG increased the ICER to more than £32,000 per QALY gained when gefitinib was compared with gemcitabine and carboplatin or paclitaxel and carboplatin, and to £44,000 per QALY gained when gefitinib was compared with vinorelbine and cisplatin or gemcitabine and cisplatin. Furthermore, the ERG noted that the economic model assumed that all patients received prescribed medication up to a maximum of six cycles and that this overestimated the mean number of cycles of chemotherapy administered per patient. When corrected, the ICER for gefitinib increased from £20,010 to £25,427 per QALY gained compared with paclitaxel and carboplatin, which was broadly representative of all chemotherapy regimens. The ERG expressed concern about the manufacturer's method of extrapolating survival data beyond the period of IPASS. This involved a two-parameter Weibull formulation for modelling both progression-free survival and overall survival. The ERG digitised the Kaplan–Meier curves for EGFR-TK mutation-positive patients in IPASS and used these to estimate the cumulative hazard for each outcome. The ERG highlighted that in a Weibull survival model the cumulative hazard of an event increases exponentially over time, but that the results from IPASS did not support this. The ERG noted that the parametric model corresponded poorly to the IPASS data, particularly at the beginning and end of the trial. The ERG stated that it obtained a better fit to the data by fitting a linear regression line to obtain a 'spline' model (that is, in this case, two exponential models spliced together at a time when the risk profile of patients changes). The ERG stated that this method reflected the IPASS data accurately across the whole period of the study and with greater accuracy than the Weibull models, which overestimate progression-free survival for both treatment arms. The reanalysis by the ERG reduced estimates of progression-free survival and increased estimates of overall survival, but in both cases reduced the incremental gain attributable to gefitinib by approximately 1 month. This represented a reduction in modelled outcome gains of approximately 25% from those reported in the manufacturer's submission. The ERG noted that the manufacturer's economic analysis used differential hazard ratios for the four chemotherapy regimens derived from the mixed-treatment comparison. However, the ERG felt that the four chemotherapy regimens were equally clinically effective. Furthermore, the mixed-treatment comparison depended upon the assumption of proportional hazards, and data from IPASS indicated that this may not be a valid assumption because the hazard ratios within IPASS varied over time. Because the hazard ratios for gefitinib compared with paclitaxel and carboplatin are the main factors determining outcomes in the model and affect results for all comparators as a result of their use in the mixed-treatment comparison, the ERG expressed concern about all the estimates of cost-effectiveness generated by the manufacturer's model. The ERG identified several technical errors in the manufacturer's model and carried out amendments and corrections to address these issues. The ERG also incorporated docetaxel and cisplatin, and pemetrexed and cisplatin (using results for pemetrexed and cisplatin from the manufacturer's updated mixed-treatment comparison) into the economic analysis. The ERG's revised base-case analysis indicated that ICERs ranged from £59,016 to £72,908 per QALY gained depending on the comparator used. The ERG highlighted that it appeared from this analysis that gefitinib was dominated by pemetrexed and cisplatin (that is, gefitinib was both more expensive and less effective). # Revised economic analyses following consultation Additional analyses were provided by the manufacturer in response to NICE's request for further clarification on the clinical and cost effectiveness of gefitinib presented in the appraisal consultation document. The manufacturer responded to most concerns raised by the Committee about: alternative probability distributions (models) for the extrapolation of survival data beyond the IPASS; how the models related to observational evidence on long-term survival; independent survival curves and approaches to applying the hazard ratio to incorporate other comparators (with gefitinib or paclitaxel and carboplatin as the baseline); and updated analyses to include amendments to the number and cost of chemotherapy cycles, lower first-line chemotherapy dosing in female patients, and variations in the prevalence of EGFR-TK mutations and costs for EGFR-TK mutation testing. The manufacturer provided additional analyses examining alternative probability distributions, with consideration given to model fit to the early trial data and the shape of the curves at the tail of the distribution. The manufacturer examined five distributions – Weibull, log-normal, log-logistic, Gompertz and exponential. The models were fitted to data from IPASS (taken predominantly from EGFR-TK mutation-positive patients) in three ways: to each treatment arm separately (stratified); to the whole population using a stratified model but in the absence of other covariates; and to the whole population using an unstratified model (which assumed proportional hazards between treatments for distributions with this property, that is, the Weibull, Gompertz and exponential models). The manufacturer evaluated the model fit using the Akaike Information Criterion (AIC) and Cox–Snell residuals. The manufacturer's analyses showed that for progression-free survival and overall survival the Weibull models consistently provided the best fit according to AIC, although the log-logistic distribution also provided a good fit to the overall survival data. The manufacturer provided evidence that the proportional hazards assumption was satisfied (that is, there was a constant ratio of the hazards between the two treatments across all points in time) and stated the 'spline' model proposed by the ERG was therefore not appropriate. The manufacturer provided, as academic in confidence, unpublished observational evidence on long-term survival of patients with NSCLC from the NEJGSG study, and published evidence, which showed that for overall survival the data supported the choice of the Weibull or log-logistic distributions. The ERG considered that the manufacturer had provided data to address most of the Committee's concerns raised in the appraisal consultation document. However, the ERG noted that the manufacturer had not carried out sensitivity analyses to determine the robustness of the ICERs to alternative survival distributions. Furthermore, the ERG considered that there were several limitations with the manufacturer's submitted analyses because four of the requested amendments to the modelling (a mid-cycle correction, corrected costs for first- and second-line chemotherapy, and adjusted costs to take account of patient drug exposure) had not, in the ERG's view, been implemented correctly in the manufacturer's revised analyses. The ERG therefore carried out an additional analysis to adjust for this. The ERG's additional analysis resulted in ICERs for gefitinib ranging from £30,368 per QALY gained compared with six cycles of gemcitabine and carboplatin to £40,048 per QALY gained compared with four cycles of gemcitabine and carboplatin. The ERG also adjusted the manufacturer's two-way sensitivity analyses that varied the prevalence of the EGFR-TK mutation (from 5% to 17%) and the assumed costs of EGFR-TK mutation testing (from £157.50 per test to £210.00 per test). This resulted in ICERs ranging from £27,457 to £49,323 per QALY gained for gefitinib compared with gemcitabine and carboplatin (based on six cycles of chemotherapy). Assuming a cost of £157.50 for EGFR-TK mutation testing in line with advice from consultees and the clinical specialists resulted in ICERs ranging from £31,800 per QALY gained (with a 10% prevalence of EGFR-TK mutation) to £27,500 per QALY gained (with a 17% prevalence of EGFR-TK mutation) for gefitinib compared with gemcitabine and carboplatin (based on six cycles of chemotherapy). Applying the ERG's corrections to the manufacturer's additional analyses also showed that, when using paclitaxel plus carboplatin as the baseline, the ICER for gefitinib compared with pemetrexed plus cisplatin was £23,615 per QALY gained for a maximum of six cycles (mean 5.4) and £64,481 per QALY gained for a maximum of five cycles (mean 4.6). When using gefitinib as the baseline, gefitinib dominated pemetrexed plus cisplatin (that is, pemetrexed plus cisplatin was both more expensive and less effective than gefitinib) regardless of whether the model assumed a maximum of five or six cycles. The ERG identified an anomaly in the manufacturer's updated economic model relating to Kaplan–Meier estimates of survival in IPASS. However, following clarification with the manufacturer it was established that this anomaly reflected a typographical error and did not affect the manufacturer's cost-effectiveness calculations. Full details of all the evidence are in the manufacturer's submission and the ERG report.# Consideration of the evidence The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of gefitinib for locally advanced or metastatic NSCLC, having considered evidence on the nature of locally advanced or metastatic NSCLC and the value placed on the benefits of gefitinib by people with the condition, those who represent them, and clinical specialists. It also took into account the effective use of NHS resources. # Management of locally advanced or metastatic NSCLC in UK clinical practice The Committee discussed the clinical need of patients with locally advanced or metastatic NSCLC. It heard from the clinical specialists that the main aim of treatment is to extend progression-free and overall survival with the fewest adverse events and with the best quality of life possible for the remaining months of life. The Committee heard from clinical specialists that up to the end of 2009 UK clinical practice was to combine gemcitabine with a platinum drug, usually cisplatin or carboplatin, but that no particular regimen of combination chemotherapy was considered more effective than another. The regimen chosen for an individual patient depended on the ease of administration and the associated adverse effects. The Committee also heard that chemotherapy with carboplatin in combination with vinorelbine or paclitaxel is not used very often because of the adverse effects associated with these agents. The clinical specialists also highlighted that following NICE guidance recommending pemetrexed and cisplatin for the first-line treatment of locally advanced or metastatic NSCLC (TA181), this therapy is becoming more widely used and is likely to become the standard treatment for patients with non-squamous NSCLC. The Committee accepted that current standard practice in England and Wales is platinum combination therapy, but concluded that pemetrexed plus cisplatin is the most appropriate principal comparator for the first-line treatment of non-squamous NSCLC. The Committee was aware that the licensed indication for gefitinib is treatment of locally advanced or metastatic NSCLC in patients with activating mutations of EGFR-TK. The Committee accepted that the manufacturer's decision problem focused on EGFR-TK mutation-positive patients and therefore the subsequent discussion focused on this population only. The Committee heard from the clinical specialists that gefitinib is the first oral therapy for the first-line treatment of locally advanced or metastatic NSCLC, and that gefitinib's biological mechanism of action results in targeted therapy with fewer adverse events and improvements in health-related quality of life for EGFR-TK mutation-positive patients. The Committee agreed that treatment which is administered orally, such as gefitinib, offers an advantage because it can be taken at home, and would allow patients to carry on with normal daily activities. Furthermore, the Committee heard from the clinical specialists that targeting therapy at EGFR-TK mutation-positive patients represents an innovative approach to treatment in terms of increasing the response rate over what is normally seen in lung cancer treatment. The clinical specialists explained that, until recently, pathologists in the UK did not routinely carry out histological subtyping of NSCLC because treatment did not depend on the histological subtype. However, following NICE guidance (TA181) recommending pemetrexed and cisplatin as a treatment option for patients with confirmed adenocarcinoma or large-cell carcinoma, it is now rapidly becoming standard practice to determine the histological subtype of NSCLC. The Committee heard from the clinical specialists that EGFR-TK mutation testing is not routinely carried out in UK clinical practice at present because it has not been needed to date. However, the clinical specialists expressed the view that the emergence of therapy targeted to EGFR-TK mutation status will lead to the introduction of testing in the NHS, and that the NHS has the capacity and expertise to undertake testing. The Committee was persuaded that the need for testing for the EGFR-TK mutation would not limit treatment and that it should be seen as analogous to testing for human epidermal growth factor receptor 2 (HER2), which has been successfully implemented in a short timeframe within the NHS. # Clinical effectiveness The Committee considered that the clinical effectiveness evidence presented in the manufacturer's submission was derived from a large, high-quality trial (IPASS) that used robust randomisation techniques, and was suitably powered to demonstrate the primary objectives of the trial for the overall population. However, it noted that evidence from IPASS related mainly to East-Asian women who did not smoke and who had adenocarcinoma histology. The Committee considered how this evidence would relate to the target population of EGFR-TK mutation-positive patients with locally advanced or metastatic NSCLC treated in England and Wales. It accepted advice from the clinical specialists that the efficacy of gefitinib depended on EGFR-TK mutation status and that there was no reason to assume that efficacy would differ according to gender, ethnicity, histological subtype or smoking status. The Committee considered the results from the IPASS study presented by the manufacturer. It noted that the primary outcome of progression-free survival in IPASS was assessed by unblinded investigators. Evidence from this study showed that in EGFR-TK mutation-positive patients, gefitinib increased the median progression-free survival by 3.2 months compared with paclitaxel and carboplatin. The Committee was aware that the analysis of overall survival was an interim analysis of immature data based on 450 deaths (that is, 37% of patients having died) and that a final analysis from follow-up was due in the second quarter of 2010. The Committee noted that a longer progression-free survival may correlate with improved overall survival in NSCLC, but there was uncertainty around this. It also noted the ERG's concerns that crossover observed in IPASS may have influenced the length of overall survival observed. The Committee accepted the ERG's view that EGFR-TK mutation-positive patients who were randomised to receive gefitinib had a clinically relevant improvement in health-related quality of life and disease symptoms compared with patients randomised to receive paclitaxel and carboplatin. The Committee concluded that the evidence from IPASS demonstrated that gefitinib improved progression-free survival and health-related quality of life in EGFR-TK mutation-positive patients. By contrast, the Committee noted that for EGFR-TK mutation-negative patients gefitinib was associated with worse outcomes when compared with chemotherapy. The Committee discussed the adverse events experienced by patients receiving treatment for locally advanced or metastatic NSCLC and noted that, in IPASS, treatment with gefitinib was associated with fewer grade 3 or 4 adverse events than chemotherapy with paclitaxel and carboplatin. The clinical specialists confirmed that gefitinib had been shown to be well tolerated in clinical practice and that this is an important aspect of treatment with this drug. The Committee concluded that gefitinib was associated with an improved adverse effects profile compared with platinum-based chemotherapy. The Committee noted the ERG's concerns that the manufacturer assumed a prevalence of EGFR-TK mutations of 16.6% in the UK population (representing patients with adenocarcinoma histology). The Committee heard from the clinical specialists that the prevalence of EGFR-TK mutations in patients with NSCLC may range from 5.0% to 17.0% depending on the subpopulation, and that in patients with adenocarcinoma histology the prevalence is more likely to be around 10%. This was also supported by consultees who advised that the prevalence of EGFR-TK mutations is between 10% and 15%. The Committee was therefore satisfied that the prevalence of the EGFR-TK mutation was likely to be between 10% and 15% in the target population. The Committee noted the ERG's concerns about the accuracy and performance of the EGFR-TK mutation test and particularly the risk that patients may be wrongly identified as mutation positive and consequently receive a treatment (gefitinib) which has been shown in EGFR-TK mutation-negative patients to lead to worse outcomes than standard chemotherapy. However, the Committee heard from the clinical specialists that the EGFR-TK mutation test is qualitative rather than quantitative and shows either the presence or absence of an EGFR-TK mutation. The clinical specialists stated that it would be unlikely that patients would be wrongly identified as having a mutation when they did not have one. The Committee accepted that there was little reason to assume that patients would be incorrectly identified. The Committee discussed the mixed-treatment comparison carried out by the manufacturer which included standard combination therapy with a platinum drug and paclitaxel, docetaxel, gemcitabine or vinorelbine. The Committee noted that this analysis supported the clinical view of similar efficacy between these treatment options, with a marginal preference for gemcitabine-containing therapy. The Committee further noted that, following feedback from NICE as part of the initial clarification process, the manufacturer included pemetrexed and cisplatin in the mixed-treatment comparison. The results of the updated mixed-treatment comparison suggested that pemetrexed and cisplatin had a greater effect on overall survival (for patients with NSCLC of non-squamous type) than the other platinum combination therapies, that gefitinib showed similar effects in terms of overall survival to pemetrexed in combination with cisplatin, and that gefitinib showed longer progression-free survival than pemetrexed and cisplatin. The Committee accepted that there was uncertainty in these comparisons but concluded that it was likely that gefitinib was no less efficacious than pemetrexed and cisplatin, and that pemetrexed in combination with cisplatin was the relevant comparator for gefitinib. # Cost effectiveness The Committee considered the manufacturer's economic model, and the critique and exploratory sensitivity analyses performed by the ERG. It noted that the manufacturer used a Markov economic model to evaluate the cost effectiveness of gefitinib compared with four different double chemotherapy combinations. The clinical data used were derived from a variety of sources, and although the evaluation was primarily trial-based, the manufacturer had carried out modelling to extrapolate the health effects beyond the duration of the IPASS. The Committee noted that the manufacturer's base-case analyses incorporated a patient access scheme. It noted that the patient access scheme involved a fixed cost being charged for each patient treated with gefitinib regardless of the length of treatment. The Committee agreed that the updated scheme submitted by the manufacturer following consultation (whereby the NHS will not be invoiced until the supply of the third monthly pack of gefitinib) was probably relatively simple to administer in the NHS and that it involved less uncertainty than the original scheme. The Committee understood that the NHS would not be charged for gefitinib if patients needed two or fewer months of treatment. The Committee discussed the incorporation of benefits to health-related quality of life and utility in the manufacturer's economic model. The Committee noted that the values of health-related quality of life derived from gefitinib's adverse event profile were included in the economic model. The Committee accepted that measurements of quality of life specific for patients with lung cancer rather than the EQ–5D were included in IPASS, because the EQ–5D is not widely used in Asia. The Committee was aware that the manufacturer used utility estimates from a study examining second-line chemotherapy for patients with NSCLC, which had included the mode of delivery of treatment (oral versus intravenous); these estimates were also used in 'Erlotinib for the treatment of relapsed non-small cell lung cancer' (NICE technology appraisal guidance 162). Acknowledging that patients receiving second-line treatment may have had more severe disease and slightly worse utility than patients receiving gefitinib for first-line therapy, the Committee agreed that the methods used by the manufacturer were appropriate in the absence of other data. The Committee agreed that treatment with gefitinib may reduce the amount of time spent in hospital towards the end of life, which it heard from the clinical specialists and patient experts was an important benefit for patients, and noted that this may not have been fully captured in the manufacturer's economic model. The Committee concluded that these quality-of-life benefits were an important aspect of treatment with gefitinib and that taking these into account would reduce the ICERs for gefitinib. The Committee noted that the ICERs for gefitinib estimated in the manufacturer's original base case were between £19,400 and £36,000 per QALY gained depending on the comparator chosen, and it was aware that the ICERs depended on the manufacturer having extrapolated progression-free survival and overall survival by fitting a Weibull probability distribution. The Committee considered the four alternative probability distributions presented in the manufacturer's additional analyses following its request for further clarification in the appraisal consultation document. The Committee accepted that for progression-free survival the fitted distributions for both the stratified and unstratified models appeared similar and that the manufacturer's selection of the unstratified Weibull model was appropriate because it appeared to provide the best fit to the progression-free survival data and because it met the proportional hazards assumption (that is, a constant ratio of the hazards between the two treatments across all points in time). The Committee noted that for overall survival the tails of the stratified Weibull and log-logistic models crossed after day 930. The Committee considered the final overall survival data from the NEJGSG study, submitted in confidence by the manufacturer, and accepted the manufacturer's explanation that there was no plausible clinical reason for crossing of the survival curves. The Committee was persuaded that, for both progression-free survival and overall survival, the unstratified Weibull distribution was appropriate for extrapolating the data beyond the duration of the IPASS because it appeared to fit the data better than other distributions and was consistent with long-term historical survival data in similar populations. The Committee considered the ERG's critique of the manufacturer's economic modelling. It was aware of the ERG's concern that there was an anomaly in the manufacturer's updated economic model relating to Kaplan–Meier estimates of survival in IPASS. However, the Committee accepted that the anomaly reflected a typographical error and did not affect the manufacturer's cost-effectiveness calculations. In addition, the Committee was aware of concerns raised by the ERG that the costs of chemotherapy in the manufacturer's original model may not have been appropriate. The Committee heard from the ERG that EGFR-TK mutation-positive patients may differ from the general population with NSCLC and that the manufacturer's model did not take into account this variability. For example, a higher proportion of patients who test positive for the EGFR-TK mutation are women who, on average, have a smaller body surface area and a lower dosage of standard chemotherapy. The Committee acknowledged that this would reduce the cost of the comparator chemotherapy and increase the ICER of gefitinib. The Committee was also aware of the ERG's concerns that the maximum number of cycles of chemotherapy (six) assumed in the manufacturer's original model may not be appropriate. However, it accepted the views of the clinical specialists that, because of the availability of better anti-emetics and improved tolerability, there is an upward trend in the number of cycles given and that patients increasingly receive up to six cycles if their disease responds well, with five cycles being the average. The Committee considered the manufacturer's additional analyses following its request for further clarification in the appraisal consultation document. These additional analyses incorporated amended costs for first-line chemotherapy and a sensitivity analysis varying the number of first-line chemotherapy cycles between four and six. The Committee accepted the ERG's view that four of the requested amendments to the modelling (a mid-cycle correction, corrected costs for first- and second-line chemotherapy, and adjusted costs to take account of patient drug exposure) had not been implemented correctly in the manufacturer's revised analysis. It further accepted that the ERG's additional analysis to adjust for this resulted in ICERs for gefitinib ranging from £30,400 per QALY gained compared with six cycles of gemcitabine and carboplatin to £40,000 per QALY gained compared with four cycles of gemcitabine and carboplatin (see section 3.39). The Committee discussed the impact of the prevalence of the EGFR-TK mutation (10% to 15% for patients with NSCLC of adenocarcinoma histology, see section 4.7) on the cost effectiveness of gefitinib. The Committee was aware that the cost of testing was linked to the prevalence of EGFR-TK mutations and the volume of tests and heard from the clinical specialists and consultees that the cost was likely to be in the region of £150. The Committee noted that, following its request for further clarification in the appraisal consultation document, the manufacturer had provided two-way sensitivity analyses, varying both the prevalence of EGFR-TK mutations and the costs of EGFR testing. The Committee further noted that applying the ERG's corrections to the manufacturer's additional analyses (see section 3.40), and assuming a cost for EGFR-TK mutation testing of £157.50 and six cycles of chemotherapy, resulted in ICERs ranging from £31,800 per QALY gained (with a 10% prevalence of EGFR-TK mutation) to £27,500 per QALY gained (with a 17% prevalence of EGFR-TK mutation) for gefitinib compared with gemcitabine plus carboplatin. The Committee concluded that varying the prevalence of EGFR-TK mutations between 10% and 15% did not dramatically alter the ICERs for gefitinib. The Committee discussed additional analyses performed by the ERG which expanded the manufacturer's economic model to include docetaxel plus cisplatin, and pemetrexed plus cisplatin. The Committee noted that pemetrexed and cisplatin treatment was dominated by gefitinib (that is, pemetrexed and cisplatin treatment was more expensive and less effective than gefitinib) using the manufacturer's assumptions, but not when using the spline modelling and other assumptions used by the ERG. The Committee understood that this was because of different approaches used by the manufacturer and the ERG to modelling survival for the different comparators. The Committee noted that, following its request for further clarification in the appraisal consultation document, the manufacturer had provided additional analyses comparing gefitinib with pemetrexed plus cisplatin using either paclitaxel plus carboplatin or gefitinib as the baseline (that is, the baseline rates of survival to which the hazard ratios were applied). The Committee noted that taking into account the ERG's corrections to the manufacturer's additional analyses (see section 3.41) and using paclitaxel plus carboplatin as the baseline resulted in ICERs of £23,600 per QALY gained for a maximum of six cycles (mean 5.4 cycles) and £64,500 per QALY gained for a maximum of five cycles (mean 4.6 cycles). When using gefitinib as the baseline, gefitinib dominated pemetrexed plus cisplatin (that is, pemetrexed plus cisplatin was both more expensive and less effective than gefitinib) regardless of whether the model assumed a maximum or five or six cycles. The Committee considered that it was not possible to make a judgement about the most appropriate method for applying the hazard ratios and noted the differences in the ICERs depending on the method used. Taking into account this uncertainty, together with advice received on the variation in the number of chemotherapy cycles received by patients (see section 4.14), and the probable underestimation in the modelling of quality-of-life benefits associated with gefitinib (see section 4.12) the Committee agreed that the results of the ERG's additional analyses comparing gefitinib with pemetrexed plus cisplatin suggested, on balance, that gefitinib would be a cost-effective use of NHS resources. The Committee concluded that at the fixed price agreed under the patient access scheme, gefitinib should be recommended for the first-line treatment of locally advanced or metastatic NSCLC in EGFR-TK mutation-positive patients. The Committee considered whether its recommendations were associated with any potiental issues related to equality. The Committee was aware that selecting patients with a higher probability of being positive when testing for EGFR-TK mutations (on the basis of their gender or ethnicity) could reduce the cost to the NHS, but that this could raise issues related to equality. The Committee heard from the clinical specialists that although EGFR-TK mutation-positive patients were more likely to have certain characteristics (that is, to be Asian women who have never smoked and have tumours with adenocarcinoma histology), they would not feel comfortable limiting testing to these patients. The Committee accepted the views of the clinical specialists that testing should be carried out on all eligible patients irrespective of gender, ethnicity, and smoking status to ensure that all eligible patients who could benefit would be identified. The Committee had initially considered whether it should follow the supplementary advice from NICE that should be taken into account when appraising treatments which may extend the life of patients with a short life expectancy and which are licensed for indications that affect small numbers of people with incurable illnesses. However, the Committee agreed that, following the additional information submitted by the manufacturer, this consideration was no longer necessary given that the most plausible ICERs, as outlined in section 4.18, fell below the threshold normally considered to be a cost-effective use of NHS resources. # Summary of Appraisal Committee's key conclusions TA192 (STA) Appraisal title: Gefitinib for the first-line treatment of locally advanced or metastatic non-small-cell lung cancer FAD section Key conclusion Gefitinib is recommended as an option for the first-line treatment of people with locally advanced or metastatic non-small-cell lung cancer (NSCLC) if: they test positive for the epidermal growth factor receptor tyrosine kinase (EGFR-TK) mutation and the manufacturer provides gefitinib at the fixed price agreed under the patient access scheme. Current practice Clinical need of patients The main aim of treatment is to extend progression-free and overall survival with the fewest adverse events and with the best quality of life possible for the remaining months of life. Availability of alternative treatments Up to the end of 2009 standard practice in England and Wales was platinum combination therapy with no particular combination chemotherapy regimen considered more effective than another. Pemetrexed plus cisplatin is increasingly used for the treatment of non-squamous NSCLC and is likely to become the standard treatment for non-squamous NSCLC in the future. The technology Proposed benefits of the technology from the manufacturer, clinician and patient perspective Gefitinib is the first oral therapy for the first-line treatment of locally advanced or metastatic NSCLC. This offers an advantage for patients because it means gefitinib can be taken at home, and would allow patients to carry on with their normal daily activities. How innovative is the technology? The Committee agreed that gefitinib's mechanism of action allows targeting of therapy at EGFR-TK mutation-positive patients. This is an innovative approach to treatment which allows an increase in response rate over what is normally seen in lung cancer treatment. The marketing authorisation requires the implementation of a specific test for the EGFR-TK mutation before gefitinib treatment. Although mutation testing is not routinely carried out in UK clinical practice at present, the Committee considered that the emergence of targeted therapy such as gefitinib is likely to lead to the introduction of such testing in the NHS, and that the NHS has the capacity and expertise to undertake testing. Adverse events Gefitinib is associated with fewer adverse events and an improved safety profile compared with platinum-based chemotherapy. This is an important feature for patients and their carers. Evidence for clinical effectiveness Quality of the evidence The evidence for clinical effectiveness was derived from a large, high-quality trial that used robust randomisation techniques, and was suitably powered to demonstrate the primary objectives of the trial for the overall population. Availability and nature of evidence The trial provided convincing evidence that, compared with standard platinum combination therapy, gefitinib improves progression-free survival and health-related quality of life in EGFR-TK mutation-positive patients. These outcomes were worse for EGFR-TK mutation-negative patients. The Committee agreed that although there was uncertainty around the comparison with pemetrexed plus cisplatin, it was likely that gefitinib is no less efficacious than pemetrexed plus cisplatin, and that pemetrexed plus cisplatin was the relevant comparator for gefitinib. Relevance to general clinical practice in the NHS The evidence for clinical effectiveness was derived mainly from a trial of gefitinib in East-Asian women, who were non-smokers and had tumours with adenocarcinoma histology. However, the efficacy of gefitinib depends on the EGFR-TK mutation status of the patient, but EGFR-TK mutation-positive patients are likely to respond to gefitinib irrespective of their gender, ethnicity, smoking status or the histological subtype of their tumour. Uncertainties generated by the evidence There is uncertainty about the prevalence of EGFR-TK mutations among patients with NSCLC in England and Wales, but it would be unlikely that patients would be wrongly identified as having a mutation when they did not have one. Evidence for cost effectiveness Availability and nature of evidence The manufacturer used a Markov economic model to evaluate the cost effectiveness of gefitinib compared with four different double chemotherapy combinations; using clinical data derived from a variety of sources, and including modelling to extrapolate the health effects beyond the duration of the clinical trial. The ERG undertook exploratory sensitivity analyses and included two additional comparators. Uncertainties around and plausibility of assumptions and inputs in the economic model There is considerable uncertainty around both the manufacturer's and the ERG's methods of extrapolating overall survival data. However, the Committee was persuaded that, for both progression-free survival and overall survival, the unstratified Weibull distribution used by the manufacturer was appropriate to extrapolate survival data beyond the period of the IPASS because it appeared to fit the data better than other distributions and was consistent with long-term historical survival data in similar populations. The Committee also accepted that the anomaly identified in the manufacturer's updated economic model reflects a typographical error and does not affect the manufacturer's cost-effectiveness calculations. There was uncertainty about the costs of first-line chemotherapy and the number of cycles of first-line chemotherapy used in the model. However, the Committee accepted evidence from the clinical specialists that, because of the availability of better anti-emetics and improved tolerability, there is an upward trend in the number of cycles given and that patients increasingly receive up to six cycles if their disease responds well, with five cycles being the average. There was uncertainty around the sensitivity of the ICER for gefitinib to the prevalence of EGFR-TK mutations (which the manufacturer varied between 5% and 17%), the number of EGFR-TK mutation tests and the associated cost. The Committee accepted the views of the clinical specialists and consultees that the prevalence of EGFR-TK mutations was likely to be between 10% and 15% in the target population and that the cost of mutation testing was likely to be approximately £150. The Committee concluded that varying the prevalence of EGFR-TK mutations between 10% and 15% did not dramatically alter the ICERs for gefitinib. Incorporation of health-related quality of life benefits and utility values The benefits derived from gefitinib's favourable adverse events profile were included in the economic model. Treatment with gefitinib may reduce the amount of time spent in hospital towards the end of life, which is likely to be important for patients' quality of life and for their carers. The Committee concluded that these benefits were not fully captured in the utility values used in the economic model. The Committee concluded that these quality of life benefits were an important aspect of treatment with gefitinib and that taking these into account would have reduced the ICERs for gefitinib. Most likely cost-effectiveness estimate (given as an ICER) The Committee concluded that it was not possible to make a judgement about the most appropriate method for applying the hazard ratios and noted the differences in the ICERs depending on the method used. Taking into account this uncertainty, together with advice received on the variation in the number of chemotherapy cycles received by patients, and the probable underestimation in the modelling of quality-of-life benefits associated with gefitinib, the Committee agreed that the results of the ERG's additional analyses comparing gefitinib with pemetrexed plus cisplatin suggested, on balance, that gefitinib would be cost effective. The Committee concluded that based on the available evidence and the fixed price agreed under the patient access scheme, gefitinib is a cost-effective use of NHS resources for the first-line treatment of locally advanced or metastatic NSCLC in EGFR-TK mutation-positive patients. Additional factors taken into account Patient access scheme The Committee agreed that the updated patient access scheme submitted by the manufacturer after consultation was likely to be relatively simple to administer in the NHS and that it involved less uncertainty than the original scheme. End-of-life considerations The Committee had initially considered whether it should follow the supplementary advice from NICE that should be taken into account when appraising treatments which may extend the life of patients with a short life expectancy and which are licensed for indications that affect small numbers of people with incurable illnesses. However, the Committee agreed that this consideration was no longer necessary because, following consultation and the revised analyses, the most plausible ICERs were considered to fall below the threshold normally considered to be a cost-effective use of NHS resources. Equalities considerations, social value judgements Testing for EGFR mutations should be carried out on all eligible patients irrespective of their gender, ethnicity, and smoking status to ensure that all patients who could benefit from gefitinib are identified. # Related NICE guidance # Published Pemetrexed for the first-line treatment of locally advanced or metastatic non-small cell lung cancer. NICE technology appraisal guidance 181 (2009). Bevacizumab for the treatment of non-small-cell lung cancer (terminated appraisal).NICE technology appraisal guidance 148 (2008). The diagnosis and treatment of lung cancer. NICE clinical guideline 24 (2005). # Under development NICE is developing the following guidance (details available from the NICE website): Cetuximab for the treatment of advanced non-small cell lung cancer. NICE technology appraisal guidance. Publication date to be confirmed.# Review of guidance The guidance on this technology will be considered for review in April 2013. NICE welcomes comment on this proposed date. The Guidance Executive will decide whether the technology should be reviewed based on information gathered by NICE, and in consultation with consultees and commentators. Andrew DillonChief ExecutiveJuly 2010# Changes after publication February 2014: implementation section updated to clarify that gefitinib is recommended as an option for treating locally advanced or metastatic non-small-cell lung cancer. Additional minor maintenance update also carried out. March 2012: minor maintenance# About this guidance NICE technology appraisal guidance is about the use of new and existing medicines and treatments in the NHS in England and Wales. This guidance was developed using the NICE single technology appraisal process. We have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available. Your responsibility This guidance represents the views of NICE and was arrived at after careful consideration of the evidence available. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. However, the guidance does not override the individual responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or guardian or carer. Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties. Copyright © National Institute for Health and Clinical Excellence 2010. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.	{'Guidance': 'Gefitinib is recommended as an option for the first-line treatment of people with locally advanced or metastatic non-small-cell lung cancer (NSCLC) if:\n\nthey test positive for the epidermal growth factor receptor tyrosine kinase (EGFR-TK) mutation and\n\nthe manufacturer provides gefitinib at the fixed price agreed under the patient access scheme.', 'The technology ': "Gefitinib (Iressa, AstraZeneca) is a selective inhibitor of epidermal growth factor receptor tyrosine kinase (EGFR-TK) which blocks the signal pathways involved in cell proliferation. By blocking EGFR-TK, gefitinib helps to slow the growth and spread of the cancer. Gefitinib has a UK marketing authorisation for the treatment of adult patients with locally advanced or metastatic non-small-cell lung cancer (NSCLC) with activating mutations of EGFR-TK.\n\nThe summary of product characteristics (SPC) states that when assessing the EGFR-TK mutation status of a patient, it is important that a well-validated and robust method is chosen to avoid false-negative and false-positive determinations. The SPC lists the following conditions that may be associated with gefitinib treatment: interstitial lung disease, hepatotoxicity and liver impairment. For full details of adverse effects and contraindications, see the SPC.\n\nGefitinib is administered orally as 250-mg film-coated tablets. The recommended dosage is 250\xa0mg daily to be taken until the disease progresses or the clinician advises otherwise.\n\nThe cost for a pack of 250-mg tablets (30 tablets per pack) is £2167.71 (excluding VAT, 'British national formulary' [BNF] edition 59). The manufacturer has agreed with the Department of Health a patient access scheme in which gefitinib for first-line treatment of NSCLC will be available at a single fixed cost of £12,200 per patient irrespective of the duration of treatment. The manufacturer will not invoice the NHS until the third monthly pack of gefitinib is supplied. This means that patients who need less than 3\xa0months of treatment will not incur a charge. The Department of Health considered that this patient access scheme does not constitute an excessive administrative burden on the NHS.", "The manufacturer's submission": "The Appraisal Committee (appendix A) considered evidence submitted by the manufacturer of gefitinib and a review of this submission by the Evidence Review Group (ERG; appendix B).\n\nThe manufacturer's decision problem compared gefitinib with gemcitabine and carboplatin, paclitaxel and carboplatin, vinorelbine and cisplatin, and gemcitabine and cisplatin. The decision problem defined the population as patients with locally advanced or metastatic NSCLC who are previously untreated and who test positive for an EGFR-TK mutation (EGFR-TK mutation-positive patients). Outcomes were defined as overall survival, progression-free survival, objective tumour response rates, health-related quality of life and adverse events associated with treatment. In the economic evaluation the incremental cost per quality-adjusted life year (QALY) gained was presented. A lifetime horizon was used, and costs were considered from the perspective of the NHS and personal social services (PSS).\n\nThe manufacturer's submission presented clinical effectiveness data from the Iressa Pan Asian Study (IPASS), a randomised controlled trial (RCT) set in East Asia. IPASS was a multicentre, open-label RCT in clinically selected patients older than 18\xa0years who had the following characteristics: histologically or cytologically confirmed stage IIIb (locally advanced disease such as pleural effusion not amenable to local therapy) or stage IV (metastatic) NSCLC with adenocarcinoma histology (including bronchoalveolar carcinoma), had never smoked (or had smoked fewer than 100 cigarettes per lifetime) or had been light smokers (stopped smoking at least 15 years previously and had smoked no more than 10 pack-years), had no prior chemotherapy, biological or immunological therapy, and had a WHO performance status of 0, 1 or 2 (on a scale of 0 to 4, with low values reflecting better health).\n\nIPASS included 1217 patients from 87 East Asian centres. Patients were randomised to receive 250\xa0mg of gefitinib once daily or paclitaxel (200\xa0mg/m2 body surface area) immediately followed by carboplatin (at a dose corresponding to an area under the curve [AUC] of concentration versus time of 5.0–6.0\xa0minute.mg/ml) in 3-weekly cycles. Treatment was continued until disease progression (according to Response Evaluation Criteria in Solid Tumours [RECIST], which used tumour measurement rather than investigator assessment), unacceptable adverse events, a patient or clinician request to discontinue, severe non-adherence to the protocol, or until six chemotherapy cycles were reached. Following disease progression, all patients in the gefitinib arm were offered treatment with paclitaxel and carboplatin; if the patient declined or the combination was considered unsuitable, the clinician chose an approved therapy. Following disease progression on paclitaxel and carboplatin treatment, choice of treatment was at the clinician's discretion.\n\nThe manufacturer's submission focused on a subgroup of 261 EGFR-TK mutation-positive patients from the overall IPASS population. This subgroup accounted for 21% of the IPASS population. Of these patients, 80.8% were women. Most patients (94.3%) had never smoked, 5.4% had been light smokers and 0.4% were ex-smokers. On a scale of 0 (good) to 4 (poor), most patients (65.9%) had a WHO performance status of 1; 26.4% had a WHO performance status of 0 and 7.7% had a WHO performance status of 2. Most patients had tumours with histology indicating adenocarcinoma (94.6%); 5.4% had histology indicating bronchocarcinoma and none had unknown histology. At study entry most patients had metastatic disease (81.6%); 18.4% had stage IIIb locally advanced disease. Baseline characteristics in the subgroup were similar between both treatment arms.\n\nThe primary outcome examined in IPASS was progression-free survival, which was assessed from the date of randomisation to disease progression (determined by RECIST) or death from any cause. Secondary outcomes included overall survival, objective tumour response rate, health-related quality of life, symptomatic improvement, safety and tolerability. Estimates of overall survival in the overall population were based on an interim analysis after 450 deaths (37% of study participants), as well as modelled values reflecting median overall survival. The final analyses are due in the second quarter of 2010. Health-related quality of life was assessed by the Functional Assessment of Cancer Therapy–Lung (FACT–L) and the Trial Outcome Index (TOI), calculated from the domain scores from FACT–L representing physical and functional wellbeing, and lung cancer symptoms (LCS).\n\nTo assess the non-inferiority of gefitinib compared with paclitaxel and carboplatin, analysis of progression-free survival used a Cox proportional hazard model adjusting for baseline covariates in the intention-to-treat population.\n\nIn the overall study population, patients randomised to receive gefitinib had a statistically significantly longer progression-free survival compared with patients randomised to receive paclitaxel and carboplatin. The hazard ratio (HR) for progression-free survival (gefitinib compared with paclitaxel and carboplatin) was 0.74 (95% confidence interval [CI] 0.65 to 0.85, p\xa0<\xa00.0001). The objective tumour response rate was statistically significantly higher for gefitinib compared with paclitaxel and carboplatin (43.0% versus 32.2%; odds ratio [OR] 1.59, 95% CI 1.25 to 2.01, p\xa0=\xa00.0001). The estimates of overall survival in the overall study population were similar for both groups (HR for gefitinib compared with paclitaxel and carboplatin 0.91, 95% CI 0.76 to 1.10).\n\nIn the subgroup of EGFR-TK mutation-positive patients (n\xa0=\xa0261), progression-free survival in patients randomised to receive gefitinib was statistically significantly longer than for patients randomised to receive paclitaxel and carboplatin (HR 0.48, 95% CI 0.36 to 0.64, p\xa0<\xa00.0001). Median progression-free survival was 9.5\xa0months for patients randomised to receive gefitinib and 6.3\xa0months for patients randomised to receive paclitaxel and carboplatin. The objective tumour response rate was statistically significantly higher for patients randomised to receive gefitinib compared with patients randomised to receive paclitaxel and carboplatin (71.2% versus 47.3%; OR 2.75, 95% CI 1.65 to 4.60, p\xa0=\xa00.0001). There was no statistically significant difference in the estimates of overall survival for patients randomised to receive gefitinib compared with patients randomised to receive paclitaxel and carboplatin (HR 0.78, 95% CI 0.50 to 1.20).\n\nIn the subgroup of EGFR-TK mutation-negative patients (n\xa0=\xa0176), progression-free survival in patients randomised to receive gefitinib was statistically significantly shorter than for patients randomised to receive paclitaxel and carboplatin (HR 2.85, 95% CI 2.05 to 3.98, p\xa0<\xa00.0001). Median progression-free survival was 1.5\xa0months for patients randomised to receive gefitinib and 5.5\xa0months for patients randomised to receive paclitaxel and carboplatin (that is, EGFR-TK-negative patients randomised to receive gefitinib had shorter progression-free survival than patients randomised to receive conventional chemotherapy). The objective tumour response rate was statistically significantly lower with gefitinib than with paclitaxel and carboplatin (1.1% versus 23.5%; OR 0.04, 95% CI 0.01 to 0.27, p\xa0=\xa00.0013). There was no statistically significant difference in the estimates of overall survival for patients randomised to receive gefitinib compared with those randomised to receive paclitaxel and carboplatin (HR 1.38, 95% CI 0.92 to 2.09).\n\nIn the overall study population, statistically significantly more patients randomised to receive gefitinib experienced a clinically relevant improvement in health-related quality of life and disease symptoms, assessed by the FACT–L and TOI, than patients randomised to receive paclitaxel and carboplatin (FACT–L – OR 1.34, 95% CI 1.06 to 1.69, p\xa0=\xa00.0148; TOI – OR 1.78, 95% CI 1.40 to 2.26, p\xa0<\xa00.0001). Rates of symptomatic improvement were measured using the lung cancer symptoms (LCS) domain of the FACT–L and were similar for patients randomised to receive gefitinib and patients randomised receive to paclitaxel and carboplatin.\n\nSimilarly in the subgroup of EGFR-TK mutation-positive patients, statistically significantly more patients randomised to receive gefitinib experienced a clinically relevant improvement in health-related quality of life and disease symptoms than patients randomised to receive paclitaxel and carboplatin (FACT–L – OR 3.01, 95% CI 1.79 to 5.07, p\xa0<\xa00.0001; TOI – OR 3.96, 95% CI 2.33 to 6.71, p\xa0<\xa00.0001; LCS – OR 2.70, 95% CI 1.58 to 4.62, p\xa0=\xa00.0003). Time to worsening of health-related quality of life and disease-related symptoms was longer for patients randomised to receive gefitinib than for patients randomised to receive paclitaxel and carboplatin (median range 11.3–16.6\xa0months for gefitinib and 2.9–3.0\xa0months for paclitaxel and carboplatin).\n\nIn the subgroup of EFGR-TK mutation-negative patients, statistically significantly more patients randomised to receive paclitaxel and carboplatin had a clinically relevant improvement in health-related quality of life and disease-related symptoms than patients randomised to receive gefitinib (FACT–L – OR 0.31, 95%\xa0CI 0.15 to 0.65, p\xa0=\xa00.0021; TOI – OR 0.35, 95% CI 0.16 to 0.79, p\xa0=\xa00.00111; LCS – OR 0.28, 95% CI 0.14 to 0.55, p\xa0=\xa00.0002). Time to worsening of health-related quality of life and disease-related symptoms was similar or shorter for patients randomised to receive gefitinib compared with patients randomised to receive paclitaxel and carboplatin (median 1.4\xa0months for gefitinib versus 1.4–4.2\xa0months for paclitaxel and carboplatin).\n\nThe manufacturer's submission did not provide an analysis of adverse events according to EGFR-TK mutation status. The manufacturer's submission stated that in the overall populations gefitinib was associated with fewer grade 3 or 4 adverse events than paclitaxel and carboplatin (28.7% versus 61.0%).\n\nThe manufacturer identified two additional trials (First-SIGNAL [n\xa0=\xa042] and the North East Japan Gefitinib Study Group [NEJGSG] trial [n\xa0=\xa0198]) that compared gefitinib with chemotherapy for the treatment of chemotherapy-naive patients with predominantly adenocarcinoma histology and EGFR-TK mutations. The manufacturer considered including these studies in a meta-analysis along with data from IPASS. However, the manufacturer excluded the First-SIGNAL study on the basis that it examined only a small number of EGFR-TK mutation-positive patients (n\xa0=\xa042) and because the comparator (gemcitabine and cisplatin) differed from IPASS. The NEJGSG trial, which compared gefitinib with paclitaxel and carboplatin, was considered suitable by the manufacturer for inclusion in the meta-analysis and used as supporting evidence for IPASS. In the NEJGSG trial, patients randomised to receive gefitinib had a statistically significant longer progression-free survival than those randomised to receive paclitaxel and carboplatin (HR 0.357, 95% CI 0.25 to 0.51, p\xa0<\xa00.001). The meta-analysis incorporating progression-free survival from the IPASS and the NEJGSG trial demonstrated a statistically significant improvement in progression-free survival for EGFR-TK mutation-positive patients who were randomised to receive gefitinib compared with mutation-positive patients who were randomised to received paclitaxel and carboplatin (fixed effects model: HR 0.43, 95% CI 0.34 to 0.53, p\xa0<\xa00.001).\n\nThe manufacturer carried out a systematic review and mixed-treatment comparison of RCTs comparing chemotherapy in chemotherapy-naive patients with NSCLC. The manufacturer chose paclitaxel and carboplatin as a baseline comparator for all analyses. The systematic review identified 29 trials, and 28 studies were included in the network that formed the basis for the mixed-treatment comparison. In response to a request from the ERG for clarification, the manufacturer provided an updated mixed-treatment comparison, which included treatment with pemetrexed and cisplatin as a comparator (29 studies in the updated mixed-treatment comparison). The manufacturer extracted and analysed data for clinical efficacy (progression-free survival, overall survival and objective tumour response) and tolerability (anaemia, diarrhoea, fatigue, febrile neutropenia, nausea and vomiting) for use in the economic evaluation. The manufacturer calculated the relative effect of alternative chemotherapy (other than paclitaxel and carboplatin) compared with paclitaxel and carboplatin in an unselected population with NSCLC (that is, without regard to EGFR mutation). The manufacturer then applied the relative estimates for clinical efficacy to a baseline event rate in EGFR-TK mutation-positive patients who had been randomised to receive paclitaxel and carboplatin in IPASS.\n\nThe manufacturer used a Markov economic model to assess the cost effectiveness of gefitinib compared with chemotherapy in the first-line treatment of EGFR-TK mutation-positive patients with NSCLC. Patients entered the model with stable disease. The model had four distinct health states: response to treatment, stable disease, disease progression and death. The model had a cycle length of 21\xa0days and a 5-year time horizon (assumed to be a lifetime horizon).\n\nThe manufacturer obtained data for effectiveness from a variety of sources. The hazard ratio for progression-free survival for EGFR-TK mutation-positive patients for gefitinib relative to paclitaxel and carboplatin was derived from the manufacturer's meta-analysis (HR 0.43) The hazard ratio for overall survival for EGFR-TK mutation-positive patients for gefitinib relative to paclitaxel and carboplatin was estimated from IPASS; estimates of hazard ratios for progression-free survival and overall survival for the chemotherapy regimens were derived from the manufacturer's mixed-treatment comparison. The manufacturer chose a Weibull model for extrapolating costs and outcomes beyond the IPASS follow-up period. Covariates in the model included: mutation status, gender, performance status (0 or 1 versus > 1) and smoking history (never-smoker or ever-smoker).\n\nThe characteristics of the population modelled in the manufacturer's economic evaluation were based on the IPASS population, which comprised chemotherapy-naive EGFR-TK mutation-positive patients who were eligible to receive chemotherapy. The comparator technologies were paclitaxel and carboplatin, gemcitabine and cisplatin, gemcitabine and carboplatin, and vinorelbine and cisplatin.\n\nUtility estimates in the manufacturer's model were adopted from a single UK study in which utility values were derived from a survey of 105 members of the general public who were asked to value descriptions of health states of second-line chemotherapy for patients with NSCLC. This study did not provide utility estimates associated with the mode of delivery of treatment (oral versus intravenous), so the manufacturer used utility values previously applied in NICE technology appraisal guidance 162 ('Erlotinib for the treatment of relapsed non-small cell lung cancer'), which examined second-line chemotherapy for patients with NSCLC and included utilities related to oral (erlotinib) and intravenous treatment.\n\nResource use in the model included: medication, delivery of chemotherapy, EGFR-TK mutation testing, patient monitoring, NHS transport service, management of grade 3 or 4 adverse events, best supportive care and active treatment after progression. Resource use was estimated from a range of secondary sources (such as references costs, British national formulary, previous NICE technology appraisal submissions and the ERG reports for NICE technology appraisal guidance 162). The manufacturer's model incorporated details of a patient access scheme.\n\nIn the manufacturer's base case, the incremental cost-effectiveness ratios (ICERs) for EGFR-TK mutation-positive patients ranged from £19,402 per QALY gained (gefitinib compared with paclitaxel and carboplatin) to £35,992 per QALY gained (gefitinib compared with vinorelbine and cisplatin) using a 16.6% prevalence for EGFR-TK mutation.\n\nThe manufacturer undertook a range of one-way sensitivity analyses and noted that the results of the cost-effectiveness analysis were sensitive to five key parameters: the overall survival for EGFR-TK mutation-positive patients randomised to receive gefitinib; the overall survival for EGFR-TK mutation-positive patients randomised to receive gemcitabine and carboplatin; the progression-free survival for EGFR-TK mutation-positive patients randomised to receive gemcitabine and carboplatin; the progression-free survival for EGFR-TK mutation-positive patients randomised to receive gefitinib; and the maximum number of chemotherapy cycles, which varied from four to eight.\n\nThe manufacturer also carried out a number of scenario analyses, and none led to any substantial change in the ICER. The manufacturer's probabilistic sensitivity analysis showed that vinorelbine and cisplatin was the most cost-effective regimen for the first-line treatment of EGFR-TK mutation-positive patients up to a threshold of £35,100 per QALY gained. Beyond this threshold, gefitinib was the most cost-effective option for the first-line treatment of EGFR-TK mutation-positive patients. At a threshold of £30,000 per QALY gained the probabilities of each treatment being the most cost effective in EGFR-TK mutation-positive patients were: vinorelbine and cisplatin (75%); gefitinib (18%); gemcitabine and carboplatin (4%); gemcitabine and cisplatin (3%); and paclitaxel and carboplatin (0%).\n\nThe ERG considered that the evidence of clinical effectiveness presented in the manufacturer's submission was derived from a high-quality trial that used robust randomisation techniques and was suitably powered to demonstrate the primary objectives of the trial for the overall population. The ERG stated that the trial provided convincing evidence of the efficacy and benefits to health-related quality of life of gefitinib in EGFR-TK mutation-positive patients compared with paclitaxel and carboplatin.\n\nThe ERG highlighted several areas of concern about the clinical evidence submitted by the manufacturer. The ERG was concerned about the generalisability of the clinical results from IPASS to the UK population given the characteristics of the people in the trial (predominantly women, East Asians, non-smokers), the histological type of NSCLC (adenocarcinoma accounts for approximately 25% of the population with NSCLC in the UK), and the comparator used (it is estimated that 5% of patients in the UK receive paclitaxel and carboplatin for the first-line treatment of NSCLC).\n\nThe ERG noted that the licensed indication for gefitiib was in locally advanced or metastatic NSCLC in patients with activating mutations of EGFR-TK, and questioned the feasibility of conducting EGFR-TK mutation testing within the NHS given that this is not routinely carried out. The ERG was concerned that making the service operational throughout England and Wales may require substantial investment in time and resources.\n\nThe ERG highlighted that in IPASS the measurement of the primary outcome of progression-free survival may be unreliable because it was assessed without blinding. The ERG was also concerned that the hazard ratios for this outcome may have been inappropriately calculated using the Cox proportional hazards method. This was because this method is valid only if the hazard ratio for the two groups being compared remains constant over time, and the ERG believed that this criterion was not met in the manufacturer's intention-to-treat analysis of IPASS. The ERG had major concerns about the immaturity of the overall survival data (that is, that relatively few deaths had occurred) because the interim analysis in the manufacturer's submission was based on 450 deaths of 1217 participants (death of 37% of participants). The ERG highlighted that confounding may have occurred in IPASS because of crossover of treatment after disease progression. Therefore, any changes in overall survival may not result from the treatment to which trial participants were originally assigned.\n\nThe ERG highlighted that the manufacturer's meta-analysis could have appropriately included the First-SIGNAL trial because the comparator used in the First-SIGNAL trial (gemcitabine and cisplatin) was not substantially different in terms of clinical benefit and tolerability from the comparator used in IPASS. The ERG noted that an indirect comparison or mixed-treatment comparison including all three studies (IPASS, NEJGSG and First-SIGNAL) would have been more appropriate. The ERG emphasised a number of weaknesses in the manufacturer's mixed-treatment comparison, such as the extraction of unreported outcome statistics for some studies from two published meta-analyses. Different methods were used to estimate the unreported hazard ratios and this may have led to bias regarding the selection of studies included in the mixed-treatment comparison. The ERG was also concerned that the mixed-treatment comparison assumed that EGFR-TK mutation status did not affect outcomes in patients receiving chemotherapy.\n\nThe ERG noted that assessment of gefitinib is more complex than a simple comparison of two treatment options as presented in the manufacturer's submission, because it involves both a specific diagnostic test to identify the presence of EGFR-TK mutations and the consequent choice of treatment following the test result (gefitinib or chemotherapy). The accuracy (that is, analytical validity) of the amplification-refractory mutation system (ARMS) test for identifying EGFR-TK mutations is very high, but the power of the test result to predict a good response to treatment with gefitinib is lower. The ERG suggested that the average benefit for patients receiving gefitinib in IPASS involved a trade-off between those who would get a good outcome (EGFR-TK mutation-positive patients who correctly tested positive for the mutation) and those who would get no benefit at all (EGFR-TK mutation-negative patients who tested positive for the mutation). The ERG also noted that performance characteristics of the diagnostic test should have been incorporated by the manufacturer within the model.\n\nThe ERG expressed concern that the prevalence of EGFR-TK mutations (that is, the proportion of EGFR-TK mutation-positive patients within the tested population) would determine the volume and cost of EGFR-TK tests, and that this would contribute to the incremental cost of adopting a 'test and treat' policy. The ERG highlighted that the results from the manufacturer's economic model for EGFR-TK mutation-positive patients receiving gefitinib were dependent on the prevalence of EGFR-TK mutations. The ERG noted that varying the prevalence of EGFR-TK mutations from the 16.6% stated in the manufacturer's submission (producing an ICER of £20,010 per QALY gained based on a 6-year time horizon) to between 5.0% and 25.0% produced ICERs ranging from £32,685 to £18,174 per QALY gained. The results of the economic model varied depending on the combination of a specific test (ARMS) and gefitinib treatment, and might not be valid if tests other than ARMS were used.\n\nThe ERG believed that the time horizon in the manufacturer's model should have been 6\xa0years instead of 5\xa0years because this more closely approximated the length of life for EGFR-TK mutation-postive patients with locally advanced or metastatic NSCLC. The ERG also highlighted that the chemotherapy costs used in the model were not accurate. The ERG made adjustments to the costs of first-line chemotherapy comparators, which had a modest impact on cost effectiveness. However, the reduction in dose level of comparator chemotherapy because of the higher proportion of female patients in the population of EGFR-TK mutation-positive patients compared with the general lung cancer population, combined with lower BNF prices for generic paclitaxel, led to an increase in the ICER of gefitinib compared with paclitaxel and carboplatin from £20,010 per QALY gained (based on the 6-year time horizon) to £38,063 per QALY gained.\n\nThe ERG was concerned that IPASS allowed a maximum of six chemotherapy cycles whereas in their view patients in the UK usually receive four cycles with up to a maximum of six allowed if their disease responds well. This adjustment to the model by the ERG increased the ICER to more than £32,000 per QALY gained when gefitinib was compared with gemcitabine and carboplatin or paclitaxel and carboplatin, and to £44,000 per QALY gained when gefitinib was compared with vinorelbine and cisplatin or gemcitabine and cisplatin. Furthermore, the ERG noted that the economic model assumed that all patients received prescribed medication up to a maximum of six cycles and that this overestimated the mean number of cycles of chemotherapy administered per patient. When corrected, the ICER for gefitinib increased from £20,010 to £25,427 per QALY gained compared with paclitaxel and carboplatin, which was broadly representative of all chemotherapy regimens.\n\nThe ERG expressed concern about the manufacturer's method of extrapolating survival data beyond the period of IPASS. This involved a two-parameter Weibull formulation for modelling both progression-free survival and overall survival. The ERG digitised the Kaplan–Meier curves for EGFR-TK mutation-positive patients in IPASS and used these to estimate the cumulative hazard for each outcome. The ERG highlighted that in a Weibull survival model the cumulative hazard of an event increases exponentially over time, but that the results from IPASS did not support this. The ERG noted that the parametric model corresponded poorly to the IPASS data, particularly at the beginning and end of the trial. The ERG stated that it obtained a better fit to the data by fitting a linear regression line to obtain a 'spline' model (that is, in this case, two exponential models spliced together at a time when the risk profile of patients changes). The ERG stated that this method reflected the IPASS data accurately across the whole period of the study and with greater accuracy than the Weibull models, which overestimate progression-free survival for both treatment arms. The reanalysis by the ERG reduced estimates of progression-free survival and increased estimates of overall survival, but in both cases reduced the incremental gain attributable to gefitinib by approximately 1\xa0month. This represented a reduction in modelled outcome gains of approximately 25% from those reported in the manufacturer's submission.\n\nThe ERG noted that the manufacturer's economic analysis used differential hazard ratios for the four chemotherapy regimens derived from the mixed-treatment comparison. However, the ERG felt that the four chemotherapy regimens were equally clinically effective. Furthermore, the mixed-treatment comparison depended upon the assumption of proportional hazards, and data from IPASS indicated that this may not be a valid assumption because the hazard ratios within IPASS varied over time. Because the hazard ratios for gefitinib compared with paclitaxel and carboplatin are the main factors determining outcomes in the model and affect results for all comparators as a result of their use in the mixed-treatment comparison, the ERG expressed concern about all the estimates of cost-effectiveness generated by the manufacturer's model.\n\nThe ERG identified several technical errors in the manufacturer's model and carried out amendments and corrections to address these issues. The ERG also incorporated docetaxel and cisplatin, and pemetrexed and cisplatin (using results for pemetrexed and cisplatin from the manufacturer's updated mixed-treatment comparison) into the economic analysis.\n\nThe ERG's revised base-case analysis indicated that ICERs ranged from £59,016 to £72,908 per QALY gained depending on the comparator used. The ERG highlighted that it appeared from this analysis that gefitinib was dominated by pemetrexed and cisplatin (that is, gefitinib was both more expensive and less effective).\n\n# Revised economic analyses following consultation\n\nAdditional analyses were provided by the manufacturer in response to NICE's request for further clarification on the clinical and cost effectiveness of gefitinib presented in the appraisal consultation document. The manufacturer responded to most concerns raised by the Committee about: alternative probability distributions (models) for the extrapolation of survival data beyond the IPASS; how the models related to observational evidence on long-term survival; independent survival curves and approaches to applying the hazard ratio to incorporate other comparators (with gefitinib or paclitaxel and carboplatin as the baseline); and updated analyses to include amendments to the number and cost of chemotherapy cycles, lower first-line chemotherapy dosing in female patients, and variations in the prevalence of EGFR-TK mutations and costs for EGFR-TK mutation testing.\n\nThe manufacturer provided additional analyses examining alternative probability distributions, with consideration given to model fit to the early trial data and the shape of the curves at the tail of the distribution. The manufacturer examined five distributions – Weibull, log-normal, log-logistic, Gompertz and exponential. The models were fitted to data from IPASS (taken predominantly from EGFR-TK mutation-positive patients) in three ways: to each treatment arm separately (stratified); to the whole population using a stratified model but in the absence of other covariates; and to the whole population using an unstratified model (which assumed proportional hazards between treatments for distributions with this property, that is, the Weibull, Gompertz and exponential models). The manufacturer evaluated the model fit using the Akaike Information Criterion (AIC) and Cox–Snell residuals. The manufacturer's analyses showed that for progression-free survival and overall survival the Weibull models consistently provided the best fit according to AIC, although the log-logistic distribution also provided a good fit to the overall survival data. The manufacturer provided evidence that the proportional hazards assumption was satisfied (that is, there was a constant ratio of the hazards between the two treatments across all points in time) and stated the 'spline' model proposed by the ERG was therefore not appropriate. The manufacturer provided, as academic in confidence, unpublished observational evidence on long-term survival of patients with NSCLC from the NEJGSG study, and published evidence, which showed that for overall survival the data supported the choice of the Weibull or log-logistic distributions.\n\nThe ERG considered that the manufacturer had provided data to address most of the Committee's concerns raised in the appraisal consultation document. However, the ERG noted that the manufacturer had not carried out sensitivity analyses to determine the robustness of the ICERs to alternative survival distributions. Furthermore, the ERG considered that there were several limitations with the manufacturer's submitted analyses because four of the requested amendments to the modelling (a mid-cycle correction, corrected costs for first- and second-line chemotherapy, and adjusted costs to take account of patient drug exposure) had not, in the ERG's view, been implemented correctly in the manufacturer's revised analyses. The ERG therefore carried out an additional analysis to adjust for this. The ERG's additional analysis resulted in ICERs for gefitinib ranging from £30,368 per QALY gained compared with six cycles of gemcitabine and carboplatin to £40,048 per QALY gained compared with four cycles of gemcitabine and carboplatin.\n\nThe ERG also adjusted the manufacturer's two-way sensitivity analyses that varied the prevalence of the EGFR-TK mutation (from 5% to 17%) and the assumed costs of EGFR-TK mutation testing (from £157.50 per test to £210.00 per test). This resulted in ICERs ranging from £27,457 to £49,323 per QALY gained for gefitinib compared with gemcitabine and carboplatin (based on six cycles of chemotherapy). Assuming a cost of £157.50 for EGFR-TK mutation testing in line with advice from consultees and the clinical specialists resulted in ICERs ranging from £31,800 per QALY gained (with a 10% prevalence of EGFR-TK mutation) to £27,500 per QALY gained (with a 17% prevalence of EGFR-TK mutation) for gefitinib compared with gemcitabine and carboplatin (based on six cycles of chemotherapy).\n\nApplying the ERG's corrections to the manufacturer's additional analyses also showed that, when using paclitaxel plus carboplatin as the baseline, the ICER for gefitinib compared with pemetrexed plus cisplatin was £23,615 per QALY gained for a maximum of six cycles (mean 5.4) and £64,481 per QALY gained for a maximum of five cycles (mean 4.6). When using gefitinib as the baseline, gefitinib dominated pemetrexed plus cisplatin (that is, pemetrexed plus cisplatin was both more expensive and less effective than gefitinib) regardless of whether the model assumed a maximum of five or six cycles.\n\nThe ERG identified an anomaly in the manufacturer's updated economic model relating to Kaplan–Meier estimates of survival in IPASS. However, following clarification with the manufacturer it was established that this anomaly reflected a typographical error and did not affect the manufacturer's cost-effectiveness calculations.\n\nFull details of all the evidence are in the manufacturer's submission and the ERG report.", 'Consideration of the evidence': "The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of gefitinib for locally advanced or metastatic NSCLC, having considered evidence on the nature of locally advanced or metastatic NSCLC and the value placed on the benefits of gefitinib by people with the condition, those who represent them, and clinical specialists. It also took into account the effective use of NHS resources.\n\n# Management of locally advanced or metastatic NSCLC in UK clinical practice\n\nThe Committee discussed the clinical need of patients with locally advanced or metastatic NSCLC. It heard from the clinical specialists that the main aim of treatment is to extend progression-free and overall survival with the fewest adverse events and with the best quality of life possible for the remaining months of life.\n\nThe Committee heard from clinical specialists that up to the end of 2009 UK clinical practice was to combine gemcitabine with a platinum drug, usually cisplatin or carboplatin, but that no particular regimen of combination chemotherapy was considered more effective than another. The regimen chosen for an individual patient depended on the ease of administration and the associated adverse effects. The Committee also heard that chemotherapy with carboplatin in combination with vinorelbine or paclitaxel is not used very often because of the adverse effects associated with these agents. The clinical specialists also highlighted that following NICE guidance recommending pemetrexed and cisplatin for the first-line treatment of locally advanced or metastatic NSCLC (TA181), this therapy is becoming more widely used and is likely to become the standard treatment for patients with non-squamous NSCLC. The Committee accepted that current standard practice in England and Wales is platinum combination therapy, but concluded that pemetrexed plus cisplatin is the most appropriate principal comparator for the first-line treatment of non-squamous NSCLC.\n\nThe Committee was aware that the licensed indication for gefitinib is treatment of locally advanced or metastatic NSCLC in patients with activating mutations of EGFR-TK. The Committee accepted that the manufacturer's decision problem focused on EGFR-TK mutation-positive patients and therefore the subsequent discussion focused on this population only. The Committee heard from the clinical specialists that gefitinib is the first oral therapy for the first-line treatment of locally advanced or metastatic NSCLC, and that gefitinib's biological mechanism of action results in targeted therapy with fewer adverse events and improvements in health-related quality of life for EGFR-TK mutation-positive patients. The Committee agreed that treatment which is administered orally, such as gefitinib, offers an advantage because it can be taken at home, and would allow patients to carry on with normal daily activities. Furthermore, the Committee heard from the clinical specialists that targeting therapy at EGFR-TK mutation-positive patients represents an innovative approach to treatment in terms of increasing the response rate over what is normally seen in lung cancer treatment. The clinical specialists explained that, until recently, pathologists in the UK did not routinely carry out histological subtyping of NSCLC because treatment did not depend on the histological subtype. However, following NICE guidance (TA181) recommending pemetrexed and cisplatin as a treatment option for patients with confirmed adenocarcinoma or large-cell carcinoma, it is now rapidly becoming standard practice to determine the histological subtype of NSCLC. The Committee heard from the clinical specialists that EGFR-TK mutation testing is not routinely carried out in UK clinical practice at present because it has not been needed to date. However, the clinical specialists expressed the view that the emergence of therapy targeted to EGFR-TK mutation status will lead to the introduction of testing in the NHS, and that the NHS has the capacity and expertise to undertake testing. The Committee was persuaded that the need for testing for the EGFR-TK mutation would not limit treatment and that it should be seen as analogous to testing for human epidermal growth factor receptor 2 (HER2), which has been successfully implemented in a short timeframe within the NHS.\n\n# Clinical effectiveness\n\nThe Committee considered that the clinical effectiveness evidence presented in the manufacturer's submission was derived from a large, high-quality trial (IPASS) that used robust randomisation techniques, and was suitably powered to demonstrate the primary objectives of the trial for the overall population. However, it noted that evidence from IPASS related mainly to East-Asian women who did not smoke and who had adenocarcinoma histology. The Committee considered how this evidence would relate to the target population of EGFR-TK mutation-positive patients with locally advanced or metastatic NSCLC treated in England and Wales. It accepted advice from the clinical specialists that the efficacy of gefitinib depended on EGFR-TK mutation status and that there was no reason to assume that efficacy would differ according to gender, ethnicity, histological subtype or smoking status.\n\nThe Committee considered the results from the IPASS study presented by the manufacturer. It noted that the primary outcome of progression-free survival in IPASS was assessed by unblinded investigators. Evidence from this study showed that in EGFR-TK mutation-positive patients, gefitinib increased the median progression-free survival by 3.2\xa0months compared with paclitaxel and carboplatin. The Committee was aware that the analysis of overall survival was an interim analysis of immature data based on 450 deaths (that is, 37% of patients having died) and that a final analysis from follow-up was due in the second quarter of 2010. The Committee noted that a longer progression-free survival may correlate with improved overall survival in NSCLC, but there was uncertainty around this. It also noted the ERG's concerns that crossover observed in IPASS may have influenced the length of overall survival observed. The Committee accepted the ERG's view that EGFR-TK mutation-positive patients who were randomised to receive gefitinib had a clinically relevant improvement in health-related quality of life and disease symptoms compared with patients randomised to receive paclitaxel and carboplatin. The Committee concluded that the evidence from IPASS demonstrated that gefitinib improved progression-free survival and health-related quality of life in EGFR-TK mutation-positive patients. By contrast, the Committee noted that for EGFR-TK mutation-negative patients gefitinib was associated with worse outcomes when compared with chemotherapy.\n\nThe Committee discussed the adverse events experienced by patients receiving treatment for locally advanced or metastatic NSCLC and noted that, in IPASS, treatment with gefitinib was associated with fewer grade 3 or 4 adverse events than chemotherapy with paclitaxel and carboplatin. The clinical specialists confirmed that gefitinib had been shown to be well tolerated in clinical practice and that this is an important aspect of treatment with this drug. The Committee concluded that gefitinib was associated with an improved adverse effects profile compared with platinum-based chemotherapy.\n\nThe Committee noted the ERG's concerns that the manufacturer assumed a prevalence of EGFR-TK mutations of 16.6% in the UK population (representing patients with adenocarcinoma histology). The Committee heard from the clinical specialists that the prevalence of EGFR-TK mutations in patients with NSCLC may range from 5.0% to 17.0% depending on the subpopulation, and that in patients with adenocarcinoma histology the prevalence is more likely to be around 10%. This was also supported by consultees who advised that the prevalence of EGFR-TK mutations is between 10% and 15%. The Committee was therefore satisfied that the prevalence of the EGFR-TK mutation was likely to be between 10% and 15% in the target population.\n\nThe Committee noted the ERG's concerns about the accuracy and performance of the EGFR-TK mutation test and particularly the risk that patients may be wrongly identified as mutation positive and consequently receive a treatment (gefitinib) which has been shown in EGFR-TK mutation-negative patients to lead to worse outcomes than standard chemotherapy. However, the Committee heard from the clinical specialists that the EGFR-TK mutation test is qualitative rather than quantitative and shows either the presence or absence of an EGFR-TK mutation. The clinical specialists stated that it would be unlikely that patients would be wrongly identified as having a mutation when they did not have one. The Committee accepted that there was little reason to assume that patients would be incorrectly identified.\n\nThe Committee discussed the mixed-treatment comparison carried out by the manufacturer which included standard combination therapy with a platinum drug and paclitaxel, docetaxel, gemcitabine or vinorelbine. The Committee noted that this analysis supported the clinical view of similar efficacy between these treatment options, with a marginal preference for gemcitabine-containing therapy. The Committee further noted that, following feedback from NICE as part of the initial clarification process, the manufacturer included pemetrexed and cisplatin in the mixed-treatment comparison. The results of the updated mixed-treatment comparison suggested that pemetrexed and cisplatin had a greater effect on overall survival (for patients with NSCLC of non-squamous type) than the other platinum combination therapies, that gefitinib showed similar effects in terms of overall survival to pemetrexed in combination with cisplatin, and that gefitinib showed longer progression-free survival than pemetrexed and cisplatin. The Committee accepted that there was uncertainty in these comparisons but concluded that it was likely that gefitinib was no less efficacious than pemetrexed and cisplatin, and that pemetrexed in combination with cisplatin was the relevant comparator for gefitinib.\n\n# Cost effectiveness\n\nThe Committee considered the manufacturer's economic model, and the critique and exploratory sensitivity analyses performed by the ERG. It noted that the manufacturer used a Markov economic model to evaluate the cost effectiveness of gefitinib compared with four different double chemotherapy combinations. The clinical data used were derived from a variety of sources, and although the evaluation was primarily trial-based, the manufacturer had carried out modelling to extrapolate the health effects beyond the duration of the IPASS.\n\nThe Committee noted that the manufacturer's base-case analyses incorporated a patient access scheme. It noted that the patient access scheme involved a fixed cost being charged for each patient treated with gefitinib regardless of the length of treatment. The Committee agreed that the updated scheme submitted by the manufacturer following consultation (whereby the NHS will not be invoiced until the supply of the third monthly pack of gefitinib) was probably relatively simple to administer in the NHS and that it involved less uncertainty than the original scheme. The Committee understood that the NHS would not be charged for gefitinib if patients needed two or fewer months of treatment.\n\nThe Committee discussed the incorporation of benefits to health-related quality of life and utility in the manufacturer's economic model. The Committee noted that the values of health-related quality of life derived from gefitinib's adverse event profile were included in the economic model. The Committee accepted that measurements of quality of life specific for patients with lung cancer rather than the EQ–5D were included in IPASS, because the EQ–5D is not widely used in Asia. The Committee was aware that the manufacturer used utility estimates from a study examining second-line chemotherapy for patients with NSCLC, which had included the mode of delivery of treatment (oral versus intravenous); these estimates were also used in 'Erlotinib for the treatment of relapsed non-small cell lung cancer' (NICE technology appraisal guidance 162). Acknowledging that patients receiving second-line treatment may have had more severe disease and slightly worse utility than patients receiving gefitinib for first-line therapy, the Committee agreed that the methods used by the manufacturer were appropriate in the absence of other data. The Committee agreed that treatment with gefitinib may reduce the amount of time spent in hospital towards the end of life, which it heard from the clinical specialists and patient experts was an important benefit for patients, and noted that this may not have been fully captured in the manufacturer's economic model. The Committee concluded that these quality-of-life benefits were an important aspect of treatment with gefitinib and that taking these into account would reduce the ICERs for gefitinib.\n\nThe Committee noted that the ICERs for gefitinib estimated in the manufacturer's original base case were between £19,400 and £36,000 per QALY gained depending on the comparator chosen, and it was aware that the ICERs depended on the manufacturer having extrapolated progression-free survival and overall survival by fitting a Weibull probability distribution. The Committee considered the four alternative probability distributions presented in the manufacturer's additional analyses following its request for further clarification in the appraisal consultation document. The Committee accepted that for progression-free survival the fitted distributions for both the stratified and unstratified models appeared similar and that the manufacturer's selection of the unstratified Weibull model was appropriate because it appeared to provide the best fit to the progression-free survival data and because it met the proportional hazards assumption (that is, a constant ratio of the hazards between the two treatments across all points in time). The Committee noted that for overall survival the tails of the stratified Weibull and log-logistic models crossed after day 930. The Committee considered the final overall survival data from the NEJGSG study, submitted in confidence by the manufacturer, and accepted the manufacturer's explanation that there was no plausible clinical reason for crossing of the survival curves. The Committee was persuaded that, for both progression-free survival and overall survival, the unstratified Weibull distribution was appropriate for extrapolating the data beyond the duration of the IPASS because it appeared to fit the data better than other distributions and was consistent with long-term historical survival data in similar populations. The Committee considered the ERG's critique of the manufacturer's economic modelling. It was aware of the ERG's concern that there was an anomaly in the manufacturer's updated economic model relating to Kaplan–Meier estimates of survival in IPASS. However, the Committee accepted that the anomaly reflected a typographical error and did not affect the manufacturer's cost-effectiveness calculations.\n\nIn addition, the Committee was aware of concerns raised by the ERG that the costs of chemotherapy in the manufacturer's original model may not have been appropriate. The Committee heard from the ERG that EGFR-TK mutation-positive patients may differ from the general population with NSCLC and that the manufacturer's model did not take into account this variability. For example, a higher proportion of patients who test positive for the EGFR-TK mutation are women who, on average, have a smaller body surface area and a lower dosage of standard chemotherapy. The Committee acknowledged that this would reduce the cost of the comparator chemotherapy and increase the ICER of gefitinib. The Committee was also aware of the ERG's concerns that the maximum number of cycles of chemotherapy (six) assumed in the manufacturer's original model may not be appropriate. However, it accepted the views of the clinical specialists that, because of the availability of better anti-emetics and improved tolerability, there is an upward trend in the number of cycles given and that patients increasingly receive up to six cycles if their disease responds well, with five cycles being the average.\n\nThe Committee considered the manufacturer's additional analyses following its request for further clarification in the appraisal consultation document. These additional analyses incorporated amended costs for first-line chemotherapy and a sensitivity analysis varying the number of first-line chemotherapy cycles between four and six. The Committee accepted the ERG's view that four of the requested amendments to the modelling (a mid-cycle correction, corrected costs for first- and second-line chemotherapy, and adjusted costs to take account of patient drug exposure) had not been implemented correctly in the manufacturer's revised analysis. It further accepted that the ERG's additional analysis to adjust for this resulted in ICERs for gefitinib ranging from £30,400 per QALY gained compared with six cycles of gemcitabine and carboplatin to £40,000 per QALY gained compared with four cycles of gemcitabine and carboplatin (see section 3.39).\n\nThe Committee discussed the impact of the prevalence of the EGFR-TK mutation (10% to 15% for patients with NSCLC of adenocarcinoma histology, see section 4.7) on the cost effectiveness of gefitinib. The Committee was aware that the cost of testing was linked to the prevalence of EGFR-TK mutations and the volume of tests and heard from the clinical specialists and consultees that the cost was likely to be in the region of £150. The Committee noted that, following its request for further clarification in the appraisal consultation document, the manufacturer had provided two-way sensitivity analyses, varying both the prevalence of EGFR-TK mutations and the costs of EGFR testing. The Committee further noted that applying the ERG's corrections to the manufacturer's additional analyses (see section 3.40), and assuming a cost for EGFR-TK mutation testing of £157.50 and six cycles of chemotherapy, resulted in ICERs ranging from £31,800 per QALY gained (with a 10% prevalence of EGFR-TK mutation) to £27,500 per QALY gained (with a 17% prevalence of EGFR-TK mutation) for gefitinib compared with gemcitabine plus carboplatin. The Committee concluded that varying the prevalence of EGFR-TK mutations between 10% and 15% did not dramatically alter the ICERs for gefitinib.\n\nThe Committee discussed additional analyses performed by the ERG which expanded the manufacturer's economic model to include docetaxel plus cisplatin, and pemetrexed plus cisplatin. The Committee noted that pemetrexed and cisplatin treatment was dominated by gefitinib (that is, pemetrexed and cisplatin treatment was more expensive and less effective than gefitinib) using the manufacturer's assumptions, but not when using the spline modelling and other assumptions used by the ERG. The Committee understood that this was because of different approaches used by the manufacturer and the ERG to modelling survival for the different comparators.\n\nThe Committee noted that, following its request for further clarification in the appraisal consultation document, the manufacturer had provided additional analyses comparing gefitinib with pemetrexed plus cisplatin using either paclitaxel plus carboplatin or gefitinib as the baseline (that is, the baseline rates of survival to which the hazard ratios were applied). The Committee noted that taking into account the ERG's corrections to the manufacturer's additional analyses (see section 3.41) and using paclitaxel plus carboplatin as the baseline resulted in ICERs of £23,600 per QALY gained for a maximum of six cycles (mean 5.4\xa0cycles) and £64,500 per QALY gained for a maximum of five cycles (mean 4.6 cycles). When using gefitinib as the baseline, gefitinib dominated pemetrexed plus cisplatin (that is, pemetrexed plus cisplatin was both more expensive and less effective than gefitinib) regardless of whether the model assumed a maximum or five or six cycles. The Committee considered that it was not possible to make a judgement about the most appropriate method for applying the hazard ratios and noted the differences in the ICERs depending on the method used. Taking into account this uncertainty, together with advice received on the variation in the number of chemotherapy cycles received by patients (see section 4.14), and the probable underestimation in the modelling of quality-of-life benefits associated with gefitinib (see section 4.12) the Committee agreed that the results of the ERG's additional analyses comparing gefitinib with pemetrexed plus cisplatin suggested, on balance, that gefitinib would be a cost-effective use of NHS resources. The Committee concluded that at the fixed price agreed under the patient access scheme, gefitinib should be recommended for the first-line treatment of locally advanced or metastatic NSCLC in EGFR-TK mutation-positive patients.\n\nThe Committee considered whether its recommendations were associated with any potiental issues related to equality. The Committee was aware that selecting patients with a higher probability of being positive when testing for EGFR-TK mutations (on the basis of their gender or ethnicity) could reduce the cost to the NHS, but that this could raise issues related to equality. The Committee heard from the clinical specialists that although EGFR-TK mutation-positive patients were more likely to have certain characteristics (that is, to be Asian women who have never smoked and have tumours with adenocarcinoma histology), they would not feel comfortable limiting testing to these patients. The Committee accepted the views of the clinical specialists that testing should be carried out on all eligible patients irrespective of gender, ethnicity, and smoking status to ensure that all eligible patients who could benefit would be identified.\n\nThe Committee had initially considered whether it should follow the supplementary advice from NICE that should be taken into account when appraising treatments which may extend the life of patients with a short life expectancy and which are licensed for indications that affect small numbers of people with incurable illnesses. However, the Committee agreed that, following the additional information submitted by the manufacturer, this consideration was no longer necessary given that the most plausible ICERs, as outlined in section 4.18, fell below the threshold normally considered to be a cost-effective use of NHS resources.\n\n# Summary of Appraisal Committee's key conclusions\n\nTA192 (STA)\n\n\n\nAppraisal title: Gefitinib for the first-line treatment of locally advanced or metastatic non-small-cell lung cancer\n\nFAD section\n\nKey conclusion\n\nGefitinib is recommended as an option for the first-line treatment of people with locally advanced or metastatic non-small-cell lung cancer (NSCLC) if:\n\nthey test positive for the epidermal growth factor receptor tyrosine kinase (EGFR-TK) mutation and\n\nthe manufacturer provides gefitinib at the fixed price agreed under the patient access scheme.\n\n, 4.18\n\nCurrent practice\n\nClinical need of patients\n\n\n\nThe main aim of treatment is to extend progression-free and overall survival with the fewest adverse events and with the best quality of life possible for the remaining months of life.\n\n\n\nAvailability of alternative treatments\n\n\n\nUp to the end of 2009 standard practice in England and Wales was platinum combination therapy with no particular combination chemotherapy regimen considered more effective than another. Pemetrexed plus cisplatin is increasingly used for the treatment of non-squamous NSCLC and is likely to become the standard treatment for non-squamous NSCLC in the future.\n\n\n\nThe technology\n\nProposed benefits of the technology from the manufacturer, clinician and patient perspective\n\nGefitinib is the first oral therapy for the first-line treatment of locally advanced or metastatic NSCLC. This offers an advantage for patients because it means gefitinib can be taken at home, and would allow patients to carry on with their normal daily activities.\n\n\n\nHow innovative is the technology?\n\n\n\nThe Committee agreed that gefitinib's mechanism of action allows targeting of therapy at EGFR-TK mutation-positive patients. This is an innovative approach to treatment which allows an increase in response rate over what is normally seen in lung cancer treatment.\n\nThe marketing authorisation requires the implementation of a specific test for the EGFR-TK mutation before gefitinib treatment. Although mutation testing is not routinely carried out in UK clinical practice at present, the Committee considered that the emergence of targeted therapy such as gefitinib is likely to lead to the introduction of such testing in the NHS, and that the NHS has the capacity and expertise to undertake testing.\n\n\n\nAdverse events\n\n\n\nGefitinib is associated with fewer adverse events and an improved safety profile compared with platinum-based chemotherapy. This is an important feature for patients and their carers.\n\n\n\nEvidence for clinical effectiveness\n\nQuality of the evidence\n\n\n\nThe evidence for clinical effectiveness was derived from a large, high-quality trial that used robust randomisation techniques, and was suitably powered to demonstrate the primary objectives of the trial for the overall population.\n\n\n\nAvailability and nature of evidence\n\n\n\nThe trial provided convincing evidence that, compared with standard platinum combination therapy, gefitinib improves progression-free survival and health-related quality of life in EGFR-TK mutation-positive patients.\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\nThese outcomes were worse for EGFR-TK mutation-negative patients.\n\n\n\n\n\nThe Committee agreed that although there was uncertainty around the comparison with pemetrexed plus cisplatin, it was likely that gefitinib is no less efficacious than pemetrexed plus cisplatin, and that pemetrexed plus cisplatin was the relevant comparator for gefitinib.\n\n\n\nRelevance to general clinical practice in the NHS\n\nThe evidence for clinical effectiveness was derived mainly from a trial of gefitinib in East-Asian women, who were non-smokers and had tumours with adenocarcinoma histology. However, the efficacy of gefitinib depends on the EGFR-TK mutation status of the patient, but EGFR-TK mutation-positive patients are likely to respond to gefitinib irrespective of their gender, ethnicity, smoking status or the histological subtype of their tumour.\n\n\n\n\n\nUncertainties generated by the evidence\n\nThere is uncertainty about the prevalence of EGFR-TK mutations among patients with NSCLC in England and Wales, but it would be unlikely that patients would be wrongly identified as having a mutation when they did not have one.\n\n, 4.8\n\n\n\nEvidence for cost effectiveness\n\nAvailability and nature of evidence\n\nThe manufacturer used a Markov economic model to evaluate the cost effectiveness of gefitinib compared with four different double chemotherapy combinations; using clinical data derived from a variety of sources, and including modelling to extrapolate the health effects beyond the duration of the clinical trial. The ERG undertook exploratory sensitivity analyses and included two additional comparators.\n\n\n\nUncertainties around and plausibility of assumptions and inputs in the economic model\n\nThere is considerable uncertainty around both the manufacturer's and the ERG's methods of extrapolating overall survival data. However, the Committee was persuaded that, for both progression-free survival and overall survival, the unstratified Weibull distribution used by the manufacturer was appropriate to extrapolate survival data beyond the period of the IPASS because it appeared to fit the data better than other distributions and was consistent with long-term historical survival data in similar populations. The Committee also accepted that the anomaly identified in the manufacturer's updated economic model reflects a typographical error and does not affect the manufacturer's cost-effectiveness calculations.\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\nThere was uncertainty about the costs of first-line chemotherapy and the number of cycles of first-line chemotherapy used in the model. However, the Committee accepted evidence from the clinical specialists that, because of the availability of better anti-emetics and improved tolerability, there is an upward trend in the number of cycles given and that patients increasingly receive up to six cycles if their disease responds well, with five cycles being the average.\n\n\n\n, 4.15\n\n\n\nThere was uncertainty around the sensitivity of the ICER for gefitinib to the prevalence of EGFR-TK mutations (which the manufacturer varied between 5% and 17%), the number of EGFR-TK mutation tests and the associated cost. The Committee accepted the views of the clinical specialists and consultees that the prevalence of EGFR-TK mutations was likely to be between 10% and 15% in the target population and that the cost of mutation testing was likely to be approximately £150. The Committee concluded that varying the prevalence of EGFR-TK mutations between 10% and 15% did not dramatically alter the ICERs for gefitinib.\n\n\n\nIncorporation of health-related quality of life benefits and utility values\n\n\n\nThe benefits derived from gefitinib's favourable adverse events profile were included in the economic model.\n\n\n\n\n\n\n\n\n\nTreatment with gefitinib may reduce the amount of time spent in hospital towards the end of life, which is likely to be important for patients' quality of life and for their carers. The Committee concluded that these benefits were not fully captured in the utility values used in the economic model. The Committee concluded that these quality of life benefits were an important aspect of treatment with gefitinib and that taking these into account would have reduced the ICERs for gefitinib.\n\n\n\nMost likely cost-effectiveness estimate (given as an ICER)\n\n\n\nThe Committee concluded that it was not possible to make a judgement about the most appropriate method for applying the hazard ratios and noted the differences in the ICERs depending on the method used. Taking into account this uncertainty, together with advice received on the variation in the number of chemotherapy cycles received by patients, and the probable underestimation in the modelling of quality-of-life benefits associated with gefitinib, the Committee agreed that the results of the ERG's additional analyses comparing gefitinib with pemetrexed plus cisplatin suggested, on balance, that gefitinib would be cost effective. The Committee concluded that based on the available evidence and the fixed price agreed under the patient access scheme, gefitinib is a cost-effective use of NHS resources for the first-line treatment of locally advanced or metastatic NSCLC in EGFR-TK mutation-positive patients.\n\n\n\nAdditional factors taken into account\n\nPatient access scheme\n\n\n\nThe Committee agreed that the updated patient access scheme submitted by the manufacturer after consultation was likely to be relatively simple to administer in the NHS and that it involved less uncertainty than the original scheme.\n\n\n\nEnd-of-life considerations\n\n\n\nThe Committee had initially considered whether it should follow the supplementary advice from NICE that should be taken into account when appraising treatments which may extend the life of patients with a short life expectancy and which are licensed for indications that affect small numbers of people with incurable illnesses. However, the Committee agreed that this consideration was no longer necessary because, following consultation and the revised analyses, the most plausible ICERs were considered to fall below the threshold normally considered to be a cost-effective use of NHS resources.\n\n\n\nEqualities considerations, social value judgements\n\nTesting for EGFR mutations should be carried out on all eligible patients irrespective of their gender, ethnicity, and smoking status to ensure that all patients who could benefit from gefitinib are identified.\n\n", 'Related NICE guidance': '# Published\n\nPemetrexed for the first-line treatment of locally advanced or metastatic non-small cell lung cancer. NICE technology appraisal guidance 181 (2009).\n\nBevacizumab for the treatment of non-small-cell lung cancer (terminated appraisal).NICE technology appraisal guidance 148 (2008).\n\nThe diagnosis and treatment of lung cancer. NICE clinical guideline 24 (2005). [Replaced by NICE clinical guideline 121]\n\n# Under development\n\nNICE is developing the following guidance (details available from the NICE website):\n\nCetuximab for the treatment of advanced non-small cell lung cancer. NICE technology appraisal guidance. Publication date to be confirmed.', 'Review of guidance': 'The guidance on this technology will be considered for review in April 2013. NICE welcomes comment on this proposed date. The Guidance Executive will decide whether the technology should be reviewed based on information gathered by NICE, and in consultation with consultees and commentators.\n\nAndrew DillonChief ExecutiveJuly 2010', 'Changes after publication': 'February 2014: implementation section updated to clarify that gefitinib is recommended as an option for treating locally advanced or metastatic non-small-cell lung cancer. Additional minor maintenance update also carried out.\n\nMarch 2012: minor maintenance', 'About this guidance': 'NICE technology appraisal guidance is about the use of new and existing medicines and treatments in the NHS in England and Wales.\n\nThis guidance was developed using the NICE single technology appraisal process.\n\nWe have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available.\n\nYour responsibility\n\nThis guidance represents the views of NICE and was arrived at after careful consideration of the evidence available. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. However, the guidance does not override the individual responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.\n\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.\n\nCopyright\n\n© National Institute for Health and Clinical Excellence 2010. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.'}	https://www.nice.org.uk/guidance/ta192	Evidence-based recommendations on gefitinib (Iressa) for untreated locally advanced or metastatic non-small-cell lung cancer in adults.
68f789616d2093adc346e923a568a1b6e4406b91	nice	Percutaneous mitral valve annuloplasty	Percutaneous mitral valve annuloplasty Evidence-based recommendations on percutaneous mitral valve annuloplasty. This involves inserting a catheter into a large vein in the groin or neck and passing through to the heart. A device is placed into a large vein that sits next to the mitral valve to constrict the valve, with the aim of making it close properly. # Guidance Current evidence on the safety and efficacy of percutaneous mitral valve annuloplasty is inadequate in quality and quantity. Therefore, this procedure should only be used in the context of research, which should clearly describe patient selection, concomitant medical therapies and safety outcomes. Both objective measurements and clinical outcomes should be reported. Percutaneous mitral valve annuloplasty should only be carried out by interventional cardiologists with specific training in the procedure. NICE may review the procedure on publication of further evidence.# The procedure # Indications and current treatments Mitral regurgitation is characterised by backward flow of blood from the left ventricle to the left atrium during systole. Causes include rheumatic heart disease and annular dilation as a result of cardiomyopathy. Left untreated, moderate to severe mitral regurgitation can cause progressive congestive heart failure and eventually lead to death. Its severity is usually graded by echocardiography on a scale from grade 1 (mild) to grade 4 (severe). Mitral regurgitation results from failure of apposition of the mitral valve leaflets, which may be due to abnormalities of the mitral leaflets or their subvalvar apparatus, or from dilation of the mitral annulus. Dilation of the mitral annulus is usually a consequence of left ventricular enlargement, and is often termed 'functional' mitral regurgitation. Treatment of severe mitral regurgitation may include partial leaflet resection or chordal repair. # Outline of the procedure The aim of percutaneous mitral valve annuloplasty is to place an intravascular device percutaneously into the coronary sinus (the large vein that forms at the level of the posterior mitral annulus and drains into the right atrium at its other end) to reduce its diameter when contracted and allow approximation of the mitral valve leaflets. The procedure is carried out with the patient under general or local anaesthesia. Under fluoroscopic and often under transoesophageal echocardiographic guidance, the device is advanced on a catheter, normally via the femoral or jugular vein, towards the coronary sinus. It is deployed and usually anchored in the coronary sinus. Residual mitral regurgitation is assessed and further percutaneous manipulation of the device may be used to reduce mitral regurgitation by changing the shape and size of the mitral valve annulus. A range of different devices can be used for this procedure. # Efficacy Sections 2.3 and 2.4 describe efficacy and safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview. A case series of 48 patients, of whom 18 were not suitable for the procedure and 30 were successfully treated with a mitral annuloplasty device, reported a significant increase in Kansas City Cardiomyopathy Questionnaire score (assesses physical function, symptoms, social function and knowledge, and quality of life on a scale from 0 to 100; higher scores better) from 47 at baseline to 69 at 6-month follow up (p<0.001). The 30 treated patients also had significantly improved physical function as measured using the New York Heart Association (NYHA) classification, from an average of 2.9 at baseline to 1.8 at 6‑month follow up (p<0.001). Six-minute walk test results also improved, from an average of 307 m at baseline to 403 m at 6‑month follow up (p<0.001). The Specialist Advisers considered key efficacy outcomes to include mitral valve competence in the short (1 year), medium (5 years) and long term (10 years) for patients with degenerative disease, reduction in mitral regurgitation and mitral annular area, improved left ventricular function, improved NYHA classification, increase in 6‑minute walk distance, increased quality-of-life scores and survival, and reduced hospital admissions for patients with advanced heart failure. # Safety 22 days after the procedure, in the case series of 48 patients. Progressive heart failure resulting in death 148 days after the procedure was reported in 1 patient who was not eligible for surgical treatment because of morbid obesity and other comorbidities, in a case series of 5 patients (the device was shown to be well-positioned on postmortem examination). Myocardial infarction not requiring hospital admission was reported in 7% (3/46) of patients within 24 hours after the procedure in the case series of 48 patients. Coronary sinus dissection in 1 patient (resolved without treatment) and coronary sinus perforation in 2 patients (1 treated conservatively and the other required pericardial drainage) were reported in the case series of 48 patients. A case series of 5 patients reported anterior interventricular vein perforation and pericardial effusion in 1 patient, and transient atrial fibrillation during cannulation of the coronary sinus in another. Atrioventricular block was reported in 1 patient after device implantation in a case report. This was successfully treated with a cardiac resynchronisation device. The Specialist Advisers highlighted an anecdotal adverse event of cardiac tamponade. They considered theoretical adverse events to include compression of the coronary artery, rupture, erosion or thrombosis of the coronary sinus or its tributaries, cardiac perforation, progressive stenosis and deformation of the mitral valve orifice or its chordal apparatus, inability to remove the device, and device migration, embolisation or fracture.# Further information For related NICE guidance, see our website. # Information for patients NICE has produced information on this procedure for patients and carers ('Understanding NICE guidance'). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.	{'Guidance': 'Current evidence on the safety and efficacy of percutaneous mitral valve annuloplasty is inadequate in quality and quantity. Therefore, this procedure should only be used in the context of research, which should clearly describe patient selection, concomitant medical therapies and safety outcomes. Both objective measurements and clinical outcomes should be reported.\n\nPercutaneous mitral valve annuloplasty should only be carried out by interventional cardiologists with specific training in the procedure.\n\nNICE may review the procedure on publication of further evidence.', 'The procedure': "# Indications and current treatments\n\nMitral regurgitation is characterised by backward flow of blood from the left ventricle to the left atrium during systole. Causes include rheumatic heart disease and annular dilation as a result of cardiomyopathy. Left untreated, moderate to severe mitral regurgitation can cause progressive congestive heart failure and eventually lead to death. Its severity is usually graded by echocardiography on a scale from grade\xa01 (mild) to grade\xa04 (severe).\n\nMitral regurgitation results from failure of apposition of the mitral valve leaflets, which may be due to abnormalities of the mitral leaflets or their subvalvar apparatus, or from dilation of the mitral annulus. Dilation of the mitral annulus is usually a consequence of left ventricular enlargement, and is often termed 'functional' mitral regurgitation.\n\nTreatment of severe mitral regurgitation may include partial leaflet resection or chordal repair.\n\n# Outline of the procedure\n\nThe aim of percutaneous mitral valve annuloplasty is to place an intravascular device percutaneously into the coronary sinus (the large vein that forms at the level of the posterior mitral annulus and drains into the right atrium at its other end) to reduce its diameter when contracted and allow approximation of the mitral valve leaflets.\n\nThe procedure is carried out with the patient under general or local anaesthesia. Under fluoroscopic and often under transoesophageal echocardiographic guidance, the device is advanced on a catheter, normally via the femoral or jugular vein, towards the coronary sinus. It is deployed and usually anchored in the coronary sinus. Residual mitral regurgitation is assessed and further percutaneous manipulation of the device may be used to reduce mitral regurgitation by changing the shape and size of the mitral valve annulus.\n\nA range of different devices can be used for this procedure.\n\n# Efficacy\n\nSections 2.3 and 2.4 describe efficacy and safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview.\n\nA case series of 48\xa0patients, of whom 18\xa0were not suitable for the procedure and 30\xa0were successfully treated with a mitral annuloplasty device, reported a significant increase in Kansas City Cardiomyopathy Questionnaire score (assesses physical function, symptoms, social function and knowledge, and quality of life on a scale from 0\xa0to\xa0100; higher scores better) from 47 at baseline to 69 at 6-month follow up (p<0.001). The 30\xa0treated patients also had significantly improved physical function as measured using the New York Heart Association (NYHA) classification, from an average of 2.9 at baseline to 1.8 at 6‑month follow up (p<0.001). Six-minute walk test results also improved, from an average of 307\xa0m at baseline to 403\xa0m at 6‑month follow up (p<0.001).\n\nThe Specialist Advisers considered key efficacy outcomes to include mitral valve competence in the short (1\xa0year), medium (5\xa0years) and long term (10\xa0years) for patients with degenerative disease, reduction in mitral regurgitation and mitral annular area, improved left ventricular function, improved NYHA classification, increase in 6‑minute walk distance, increased quality-of-life scores and survival, and reduced hospital admissions for patients with advanced heart failure.\n\n# Safety\n\n22 days after the procedure, in the case series of 48\xa0patients. Progressive heart failure resulting in death 148\xa0days after the procedure was reported in 1\xa0patient who was not eligible for surgical treatment because of morbid obesity and other comorbidities, in a case series of 5\xa0patients (the device was shown to be well-positioned on postmortem examination).\n\nMyocardial infarction not requiring hospital admission was reported in 7% (3/46) of patients within 24\xa0hours after the procedure in the case series of 48\xa0patients.\n\nCoronary sinus dissection in 1\xa0patient (resolved without treatment) and coronary sinus perforation in 2\xa0patients (1\xa0treated conservatively and the other required pericardial drainage) were reported in the case series of 48\xa0patients. A case series of 5\xa0patients reported anterior interventricular vein perforation and pericardial effusion in 1\xa0patient, and transient atrial fibrillation during cannulation of the coronary sinus in another.\n\nAtrioventricular block was reported in 1\xa0patient after device implantation in a case report. This was successfully treated with a cardiac resynchronisation device.\n\nThe Specialist Advisers highlighted an anecdotal adverse event of cardiac tamponade. They considered theoretical adverse events to include compression of the coronary artery, rupture, erosion or thrombosis of the coronary sinus or its tributaries, cardiac perforation, progressive stenosis and deformation of the mitral valve orifice or its chordal apparatus, inability to remove the device, and device migration, embolisation or fracture.", 'Further information': "For related NICE guidance, see our website.\n\n# Information for patients\n\nNICE has produced information on this procedure for patients and carers ('Understanding NICE guidance'). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind."}	https://www.nice.org.uk/guidance/ipg352	Evidence-based recommendations on percutaneous mitral valve annuloplasty. This involves inserting a catheter into a large vein in the groin or neck and passing through to the heart. A device is placed into a large vein that sits next to the mitral valve to constrict the valve, with the aim of making it close properly.
73aada7cab1a3d0a88d9424a095103dd5cfdb8ff	nice	Percutaneous radiofrequency ablation for renal cancer	Percutaneous radiofrequency ablation for renal cancer The National Institute for Health and Clinical Excellence (NICE) has issued full guidance to the NHS in England, Wales, Scotland and Northern Ireland on Percutaneous radiofrequency ablation of renal cancer. # Guidance This guidance replaces previous guidance on percutaneous radiofrequency ablation of renal cancer (interventional procedure guidance 91). Current evidence on the safety and efficacy of percutaneous radiofrequency ablation (RFA) for renal cancer in the short and medium term appears adequate to support the use of this procedure provided that normal arrangements are in place for clinical governance, consent and audit, and provided that patients are followed up in the long term. Patient selection for percutaneous RFA for renal cancer should be carried out by a urological cancer multidisciplinary team. NICE encourages data collection to provide information about the outcomes of this procedure in the long term. Further research should compare the long-term outcomes of RFA with those of other treatments for renal cancer.# The procedure # Indications and current treatments There are few symptoms in the early stages of renal cancer. Typically, symptoms develop as the disease progresses. The first symptom is often blood in the urine; pain and flank mass are other classic symptoms. Renal cancer may be diagnosed incidentally on imaging studies or patients may present with symptoms. Conventional treatment for renal cancer is total or partial nephrectomy (open or laparoscopic). One of a range of non-resectional ablative procedures such as cryoablation and RFA may be selected for some smaller tumours. # Outline of the procedure Percutaneous RFA for renal cancer is carried out with the patient under either local anaesthesia and sedation or general anaesthesia. Hydrodisplacement may be used to displace the bowel away from the tumour. One or more radiofrequency electrodes are inserted percutaneously into the tumour under imaging guidance. Radiofrequency energy is delivered via the electrode(s) to coagulate and destroy the tumour tissue in the target area. The procedure can be repeated if necessary. Sections 2.3 and 2.4 describe efficacy and safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview. # Efficacy A meta-analysis of 47 studies (non-randomised comparative studies and case series) including a total of 1375 tumours treated by RFA (n = 775) or cryoablation (n = 600) reported local tumour progression (defined as radiographic or pathological evidence of residual disease after initial treatment, regardless of time to recurrence) in 13% (100/775) and 5% (31/600) of tumours respectively at a mean 19-month follow-up (p < 0.001). The meta-analysis reported progression to metastatic disease in 2% (19/775) of tumours treated by RFA and 1% (6/600) of tumours treated by cryoablation (p = not significant). In a non-randomised comparative study of 233 patients (260 tumours), residual or recurrent tumour on follow-up magnetic resonance imaging (MRI) was reported in 11% (9/81) of tumours treated by percutaneous RFA and 2% (3/179) of tumours treated by laparoscopic cryotherapy (1-year and 3-year median follow-up respectively). A non-randomised comparative study of 264 patients (301 tumours) reported radiographic success (defined as no evidence of central or nodular enhancement after treatment) in 85% (62/73) of patients treated by percutaneous RFA and 90% (125/139) of patients treated by laparoscopic cryoablation at 6-month follow-up. The case series of 151 patients reported a 3-year recurrence-free survival probability of 92% for all patients and 87% for the 84 patients with confirmed renal cell carcinoma. The case series of 31 patients reported disease-specific survival of 100%, recurrence-free survival of 89% and overall survival of 63% (all at 80 months). The Specialist Advisers listed key efficacy outcomes as radiological confirmation of tumour devascularisation, imaging follow-up to confirm tumour involution at 2 and 5 years, and overall and disease-free survival. They indicated that there is uncertainty about the procedure's efficacy in tumours 4 cm or greater in diameter. # Safety Haemorrhage was reported in 6% (5/85) of patients in a case series of 85 patients. Life-threatening haematuria approximately 42 hours after RFA treatment which required transcatheter embolisation was described in a case report. Haematoma requiring blood transfusion was reported in 1% (1/104) of patients in a case series and 1% (1/82) of RFA procedures in the non-randomised comparative study of 233 patients. Haematoma not requiring blood transfusion was reported in 5% (4/82) (3 perirenal requiring no treatment; 1 retroperitoneal) of RFA procedures in the non-randomised comparative study of 233 patients. Asymptomatic perirenal haematoma development was reported in 12% (4/34) (managed conservatively with no sequelae) of RFA procedures in the case series of 31 patients. Ureteric stricture development was reported after 1% (1/120) of treatments and in 1% (1/85) and 2% (2/104) of patients in case series of 97, 85 and 104 patients respectively. Urinoma (a collection of fluid resulting from a urine leak) was reported in 1 patient each in the case series of 97 and 85 patients. Ureteropelvic junction obstruction requiring nephrectomy was described in a case report. Thermal injury to the duodenum requiring laparotomy was reported in 1 patient in the case series of 97 patients. Renoduodenal fistula was diagnosed 5 days after the procedure in 1 patient in a case report. A computed tomography (CT) scan at 6 months showed that the tumour (a clear cell carcinoma) was growing again and an open nephrectomy was performed. Neuromuscular complications after RFA treatment were reported in 3 of 48 patients in one series. One patient developed persistent laxity of flank muscles. The other 2 developed sensory loss and paraesthesia of the lateral abdominal wall (resolved after 3 months). The Specialist Advisers stated that theoretical adverse events include bowel perforation, perirenal haematoma, pelvicalyceal injury, and pain due to intercostal nerve damage.# Further information For related NICE guidance see our website. # Information for patients NICE has produced information on this procedure for patients and carers ('Understanding NICE guidance'). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.# About this guidance NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland. This guidance was developed using the NICE interventional procedure guidance process. It updates and replaces NICE interventional procedure guidance 91. We have produced a summary of this guidance for patients and carers. Information about the evidence it is based on is also available. Changes since publication January 2012: minor maintenance. Your responsibility This guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer. Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties. Copyright © National Institute for Health and Clinical Excellence 2010. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE. Contact NICE National Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT www.nice.org.uk nice@nice.org.uk	{'Guidance': 'This guidance replaces previous guidance on percutaneous radiofrequency ablation of renal cancer (interventional procedure guidance 91).\n\nCurrent evidence on the safety and efficacy of percutaneous radiofrequency ablation (RFA) for renal cancer in the short and medium term appears adequate to support the use of this procedure provided that normal arrangements are in place for clinical governance, consent and audit, and provided that patients are followed up in the long term.\n\nPatient selection for percutaneous RFA for renal cancer should be carried out by a urological cancer multidisciplinary team.\n\nNICE encourages data collection to provide information about the outcomes of this procedure in the long term. Further research should compare the long-term outcomes of RFA with those of other treatments for renal cancer.', 'The procedure': "# Indications and current treatments\n\nThere are few symptoms in the early stages of renal cancer. Typically, symptoms develop as the disease progresses. The first symptom is often blood in the urine; pain and flank mass are other classic symptoms.\n\nRenal cancer may be diagnosed incidentally on imaging studies or patients may present with symptoms. Conventional treatment for renal cancer is total or partial nephrectomy (open or laparoscopic). One of a range of non-resectional ablative procedures such as cryoablation and RFA may be selected for some smaller tumours.\n\n# Outline of the procedure\n\nPercutaneous RFA for renal cancer is carried out with the patient under either local anaesthesia and sedation or general anaesthesia. Hydrodisplacement may be used to displace the bowel away from the tumour. One or more radiofrequency electrodes are inserted percutaneously into the tumour under imaging guidance. Radiofrequency energy is delivered via the electrode(s) to coagulate and destroy the tumour tissue in the target area. The procedure can be repeated if necessary.\n\nSections 2.3 and 2.4 describe efficacy and safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview.\n\n# Efficacy\n\nA meta-analysis of 47 studies (non-randomised comparative studies and case series) including a total of 1375 tumours treated by RFA (n = 775) or cryoablation (n = 600) reported local tumour progression (defined as radiographic or pathological evidence of residual disease after initial treatment, regardless of time to recurrence) in 13% (100/775) and 5% (31/600) of tumours respectively at a mean 19-month follow-up (p < 0.001). The meta-analysis reported progression to metastatic disease in 2% (19/775) of tumours treated by RFA and 1% (6/600) of tumours treated by cryoablation (p = not significant).\n\nIn a non-randomised comparative study of 233 patients (260 tumours), residual or recurrent tumour on follow-up magnetic resonance imaging (MRI) was reported in 11% (9/81) of tumours treated by percutaneous RFA and 2% (3/179) of tumours treated by laparoscopic cryotherapy (1-year and 3-year median follow-up respectively).\n\nA non-randomised comparative study of 264 patients (301 tumours) reported radiographic success (defined as no evidence of central or nodular enhancement after treatment) in 85% (62/73) of patients treated by percutaneous RFA and 90% (125/139) of patients treated by laparoscopic cryoablation at 6-month follow-up.\n\nThe case series of 151 patients reported a 3-year recurrence-free survival probability of 92% for all patients and 87% for the 84 patients with confirmed renal cell carcinoma. The case series of 31 patients reported disease-specific survival of 100%, recurrence-free survival of 89% and overall survival of 63% (all at 80 months).\n\nThe Specialist Advisers listed key efficacy outcomes as radiological confirmation of tumour devascularisation, imaging follow-up to confirm tumour involution at 2 and 5 years, and overall and disease-free survival. They indicated that there is uncertainty about the procedure's efficacy in tumours 4 cm or greater in diameter.\n\n# Safety\n\nHaemorrhage was reported in 6% (5/85) of patients in a case series of 85 patients. Life-threatening haematuria approximately 42 hours after RFA treatment which required transcatheter embolisation was described in a case report.\n\nHaematoma requiring blood transfusion was reported in 1% (1/104) of patients in a case series and 1% (1/82) of RFA procedures in the non-randomised comparative study of 233 patients. Haematoma not requiring blood transfusion was reported in 5% (4/82) (3 perirenal requiring no treatment; 1 retroperitoneal) of RFA procedures in the non-randomised comparative study of 233 patients. Asymptomatic perirenal haematoma development was reported in 12% (4/34) (managed conservatively with no sequelae) of RFA procedures in the case series of 31 patients.\n\nUreteric stricture development was reported after 1% (1/120) of treatments and in 1% (1/85) and 2% (2/104) of patients in case series of 97, 85 and 104 patients respectively.\n\nUrinoma (a collection of fluid resulting from a urine leak) was reported in 1 patient each in the case series of 97 and 85 patients. Ureteropelvic junction obstruction requiring nephrectomy was described in a case report.\n\nThermal injury to the duodenum requiring laparotomy was reported in 1 patient in the case series of 97 patients.\n\nRenoduodenal fistula was diagnosed 5 days after the procedure in 1 patient in a case report. A computed tomography (CT) scan at 6 months showed that the tumour (a clear cell carcinoma) was growing again and an open nephrectomy was performed.\n\nNeuromuscular complications after RFA treatment were reported in 3 of 48 patients in one series. One patient developed persistent laxity of flank muscles. The other 2 developed sensory loss and paraesthesia of the lateral abdominal wall (resolved after 3 months).\n\nThe Specialist Advisers stated that theoretical adverse events include bowel perforation, perirenal haematoma, pelvicalyceal injury, and pain due to intercostal nerve damage.", 'Further information': "For related NICE guidance see our website.\n\n# Information for patients\n\nNICE has produced information on this procedure for patients and carers ('Understanding NICE guidance'). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.", 'About this guidance': 'NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland.\n\nThis guidance was developed using the NICE interventional procedure guidance process.\n\nIt updates and replaces NICE interventional procedure guidance 91.\n\nWe have produced a summary of this guidance for patients and carers. Information about the evidence it is based on is also available.\n\nChanges since publication\n\nJanuary 2012: minor maintenance.\n\nYour responsibility\n\nThis guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.\n\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.\n\nCopyright\n\n© National Institute for Health and Clinical Excellence 2010. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.\n\nContact NICE\n\nNational Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT\n\nwww.nice.org.uk\n \n nice@nice.org.uk\n 0845 033 7780'}	https://www.nice.org.uk/guidance/ipg353	The National Institute for Health and Clinical Excellence (NICE) has issued full guidance to the NHS in England, Wales, Scotland and Northern Ireland on Percutaneous radiofrequency ablation of renal cancer.
148afd0e9b4b913adab815bddbcfdf1894b3e3f5	nice	Shoulder resurfacing arthroplasty	Shoulder resurfacing arthroplasty # Guidance Current evidence on the safety and efficacy of shoulder resurfacing arthroplasty is adequate to support the use of this procedure provided that normal arrangements are in place for clinical governance, consent and audit.# The procedure # Indications and current treatments Patients with shoulder joint disease may have shoulder pain accompanied by functional limitation and a reduced quality of life. The humeral head may degenerate as a result of a range of conditions, most commonly osteoarthritis, rheumatoid arthritis or avascular necrosis. The whole or only part of the articular surface of the humeral head may be affected. Depending on the underlying condition, conservative treatment may include physical therapy, pharmacological treatments (including pain relief and topical or oral non-steroidal anti-inflammatory drugs) and corticosteroid injections. Patients refractory to these treatments may need surgery: either shoulder arthroplasty using a stemmed humeral head prosthesis, or fusion of the joint. # Outline of the procedure The aim of shoulder resurfacing arthroplasty is to replace only the damaged joint surfaces, with minimal bone resection. The procedure is carried out with the patient in a semi-upright position and may be done using either general anaesthesia (sometimes accompanied by local anaesthesia), or local anaesthesia with or without sedation. Either a deltopectoral or anterosuperior approach may be used. The deltoid muscle is split to expose the surface of the humeral head, which is reamed to restore its shape. A hole is drilled for the central anchoring peg of the resurfacing prosthesis. The peg of the prosthesis is inserted into the drilled hole and morcellised bone or cement is used to aid fixation of the articular prosthesis, which may cover the whole or part of the humeral head. A prosthesis may be used to cover the glenoid surface of the scapula if necessary. The shoulder joint is reduced and the wound is closed. Various devices can be used for this procedure. Sections 2.3 and 2.4 describe efficacy and safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview. # Efficacy A case series of 69 patients (79 shoulders: 37 treated by resurfacing, 42 treated by resurfacing plus glenoid component) reported that mean shoulder function (measured using the Constant–Murley shoulder scale ) improved from 40% of predicted at baseline to 91% at 4.4-year follow-up in patients treated by articular resurfacing only, and from 34% at baseline to 94% at 7.6-year follow-up in patients treated by resurfacing plus a glenoid component. A non-randomised controlled trial of 44 patients reported no difference in the mean change in shoulder function (using the Constant–Murley shoulder scale) from baseline to 12-month follow-up in patients treated by shoulder resurfacing arthroplasty compared with patients treated by total shoulder arthroplasty (8.1 points vs. 8.5 points; p = 0.356). A case series of 94 patients (103 shoulders) reported that mean shoulder function (using the Constant–Murley shoulder scale) improved from 24% of predicted at baseline to 75% of predicted at 6.8-year follow-up (p < 0.001). Revision surgery for stemmed humeral prosthesis was reported in 6% (6/98) of shoulders at 6.8-year follow-up in the case series of 94 patients (103 shoulders). Revision because of persistent pain was reported in 1 of 75 shoulders at a mean follow-up of 6.5 years in the case series of 62 patients (75 shoulders). Case series of 70 patients (84 shoulders) and 69 patients (79 shoulders) reported that no patient treated by shoulder resurfacing arthroplasty needed a revision procedure at follow-up of 4.2 and 4.4 years respectively. The case series of 69 patients (79 shoulders) reported that mean shoulder pain improved from 3.9 points at baseline to 12 points at 4.4-year follow-up in patients treated by shoulder resurfacing arthroplasty, and from 2.1 points to 14 points at 7.6-year follow-up in patients treated by resurfacing plus glenoid component. A case series of 70 patients (84 shoulders) reported that, of 62 patients followed up, the percentage with severe pain reduced from 93% at baseline to 6% at a mean follow-up of 4.2 years. A non-randomised controlled trial of 44 patients reported that, of the 22 patients treated by shoulder resurfacing arthroplasty, 2 needed conversion to total shoulder arthroplasty, 1 because of glenoidal erosion and 1 because of persistent pain, at 7 and 9 months respectively. The case series of 62 patients (75 shoulders) reported that 96% of shoulders were rated as 'much better' or 'better' (not otherwise described; absolute figures not stated) at 6.5-year follow-up. The Specialist Advisers listed key efficacy outcomes as relief of pain, range of motion, quality of life, and the rate of revision procedures. # Safety Infection requiring removal of the prosthesis and fusion was reported in 1 patient at 6.8-year follow-up in the case series of 94 patients (103 shoulders). Prosthesis instability requiring removal and fusion was reported in 1 patient at 6.8-year follow-up in the case series of 94 patients (103 shoulders). Myositis ossificans causing almost complete ankylosis was reported in 1 patient in a case series of 94 patients (103 shoulders) at 6.8-year follow-up. The patient had an initial diagnosis of septic arthritis and extensive previous surgery. The Specialist Advisers listed adverse events seen or reported in the literature to include loosening of the prosthesis, impingement and overstuffing during implant if the prosthesis had been incorrectly sized. They considered theoretical adverse events to include infection, nerve injury, deep vein thrombosis, fracture, failure needing revision, and stiffness.# Further information For related NICE guidance see our website. # Information for patients NICE has produced information on this procedure for patients and carers ('Understanding NICE guidance'). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.# About this guidance NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland. This guidance was developed using the NICE interventional procedure guidance process. We have produced a summary of this guidance for patients and carers. Information about the evidence it is based on is also available. Changes since publication January 2012: minor maintenance. Your responsibility This guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer. Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties. Copyright © National Institute for Health and Clinical Excellence 2010. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE. Contact NICE National Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT www.nice.org.uk nice@nice.org.uk	{'Guidance': 'Current evidence on the safety and efficacy of shoulder resurfacing arthroplasty is adequate to support the use of this procedure provided that normal arrangements are in place for clinical governance, consent and audit.', 'The procedure': "# Indications and current treatments\n\nPatients with shoulder joint disease may have shoulder pain accompanied by functional limitation and a reduced quality of life. The humeral head may degenerate as a result of a range of conditions, most commonly osteoarthritis, rheumatoid arthritis or avascular necrosis. The whole or only part of the articular surface of the humeral head may be affected.\n\nDepending on the underlying condition, conservative treatment may include physical therapy, pharmacological treatments (including pain relief and topical or oral non-steroidal anti-inflammatory drugs) and corticosteroid injections. Patients refractory to these treatments may need surgery: either shoulder arthroplasty using a stemmed humeral head prosthesis, or fusion of the joint.\n\n# Outline of the procedure\n\nThe aim of shoulder resurfacing arthroplasty is to replace only the damaged joint surfaces, with minimal bone resection.\n\nThe procedure is carried out with the patient in a semi-upright position and may be done using either general anaesthesia (sometimes accompanied by local anaesthesia), or local anaesthesia with or without sedation. Either a deltopectoral or anterosuperior approach may be used. The deltoid muscle is split to expose the surface of the humeral head, which is reamed to restore its shape. A hole is drilled for the central anchoring peg of the resurfacing prosthesis.\n\nThe peg of the prosthesis is inserted into the drilled hole and morcellised bone or cement is used to aid fixation of the articular prosthesis, which may cover the whole or part of the humeral head. A prosthesis may be used to cover the glenoid surface of the scapula if necessary. The shoulder joint is reduced and the wound is closed.\n\nVarious devices can be used for this procedure.\n\nSections 2.3 and 2.4 describe efficacy and safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview.\n\n# Efficacy\n\nA case series of 69 patients (79 shoulders: 37 treated by resurfacing, 42 treated by resurfacing plus glenoid component) reported that mean shoulder function (measured using the Constant–Murley shoulder scale [100-point scale; higher scores better]) improved from 40% of predicted at baseline to 91% at 4.4-year follow-up in patients treated by articular resurfacing only, and from 34% at baseline to 94% at 7.6-year follow-up in patients treated by resurfacing plus a glenoid component.\n\nA non-randomised controlled trial of 44 patients reported no difference in the mean change in shoulder function (using the Constant–Murley shoulder scale) from baseline to 12-month follow-up in patients treated by shoulder resurfacing arthroplasty compared with patients treated by total shoulder arthroplasty (8.1 points vs. 8.5 points; p = 0.356). A case series of 94 patients (103 shoulders) reported that mean shoulder function (using the Constant–Murley shoulder scale) improved from 24% of predicted at baseline to 75% of predicted at 6.8-year follow-up (p < 0.001).\n\nRevision surgery for stemmed humeral prosthesis was reported in 6% (6/98) of shoulders at 6.8-year follow-up in the case series of 94 patients (103 shoulders). Revision because of persistent pain was reported in 1 of 75 shoulders at a mean follow-up of 6.5 years in the case series of 62 patients (75 shoulders). Case series of 70 patients (84 shoulders) and 69 patients (79 shoulders) reported that no patient treated by shoulder resurfacing arthroplasty needed a revision procedure at follow-up of 4.2 and 4.4 years respectively.\n\nThe case series of 69 patients (79 shoulders) reported that mean shoulder pain improved from 3.9 points at baseline to 12 points at 4.4-year follow-up in patients treated by shoulder resurfacing arthroplasty, and from 2.1 points to 14 points at 7.6-year follow-up in patients treated by resurfacing plus glenoid component. A case series of 70 patients (84 shoulders) reported that, of 62 patients followed up, the percentage with severe pain reduced from 93% at baseline to 6% at a mean follow-up of 4.2 years.\n\nA non-randomised controlled trial of 44 patients reported that, of the 22 patients treated by shoulder resurfacing arthroplasty, 2 needed conversion to total shoulder arthroplasty, 1 because of glenoidal erosion and 1 because of persistent pain, at 7 and 9 months respectively.\n\nThe case series of 62 patients (75 shoulders) reported that 96% of shoulders were rated as 'much better' or 'better' (not otherwise described; absolute figures not stated) at 6.5-year follow-up.\n\nThe Specialist Advisers listed key efficacy outcomes as relief of pain, range of motion, quality of life, and the rate of revision procedures.\n\n# Safety\n\nInfection requiring removal of the prosthesis and fusion was reported in 1 patient at 6.8-year follow-up in the case series of 94 patients (103 shoulders).\n\nProsthesis instability requiring removal and fusion was reported in 1 patient at 6.8-year follow-up in the case series of 94 patients (103 shoulders).\n\nMyositis ossificans causing almost complete ankylosis was reported in 1 patient in a case series of 94 patients (103 shoulders) at 6.8-year follow-up. The patient had an initial diagnosis of septic arthritis and extensive previous surgery.\n\nThe Specialist Advisers listed adverse events seen or reported in the literature to include loosening of the prosthesis, impingement and overstuffing during implant if the prosthesis had been incorrectly sized. They considered theoretical adverse events to include infection, nerve injury, deep vein thrombosis, fracture, failure needing revision, and stiffness.", 'Further information': "For related NICE guidance see our website.\n\n# Information for patients\n\nNICE has produced information on this procedure for patients and carers ('Understanding NICE guidance'). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.", 'About this guidance': 'NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland.\n\nThis guidance was developed using the NICE interventional procedure guidance process.\n\nWe have produced a summary of this guidance for patients and carers. Information about the evidence it is based on is also available.\n\nChanges since publication\n\nJanuary 2012: minor maintenance.\n\nYour responsibility\n\nThis guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.\n\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.\n\nCopyright\n\n© National Institute for Health and Clinical Excellence 2010. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.\n\nContact NICE\n\nNational Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT\n\nwww.nice.org.uk\n \n nice@nice.org.uk\n 0845 033 7780'}	https://www.nice.org.uk/guidance/ipg354
ffb2cb5c5124e3234b2517be36fd7b939aac0e10	nice	Percutaneous occlusion of the left atrial appendage in non-valvular atrial fibrillation for the prevention of thromboembolism	Percutaneous occlusion of the left atrial appendage in non-valvular atrial fibrillation for the prevention of thromboembolism # Guidance This guidance replaces previous guidance on percutaneous occlusion of the left atrial appendage for atrial fibrillation (interventional procedure guidance 181). Current evidence suggests that percutaneous occlusion of the left atrial appendage (LAA) is efficacious in reducing the risk of thromboembolic complications associated with non-valvular atrial fibrillation (AF). With regard to safety, there is a risk of life-threatening complications from the procedure, but the incidence of these is low. Therefore, this procedure may be used provided that normal arrangements are in place for clinical governance, consent and audit. Patient selection should be carried out by a multidisciplinary team including a cardiologist and other appropriate clinicians experienced in the management of patients with AF at risk of stroke. Patients should be considered for alternative treatments to reduce the risk of thromboembolism associated with AF, and should be informed about these alternatives. Percutaneous occlusion of the LAA is a technically challenging procedure which should only be carried out by clinicians with specific training and appropriate experience in the procedure. This procedure should be carried out only in units with on-site cardiac surgery. Any device-related adverse events resulting from the procedure should be reported to the Medicines and Healthcare products Regulatory Agency (MHRA).# The procedure # Indications and current treatments AF is the irregular and rapid beating of the atria. Patients with AF may be asymptomatic or may have symptoms such as fatigue, palpitations, chest pain, shortness of breath and fainting. They also have an increased risk of thromboembolic stroke. In non-rheumatic AF, thrombi largely develop in the LAA. Patients with AF who are considered to be at high risk of thromboembolic stroke are often treated with warfarin anticoagulation therapy. Surgical intervention may involve obliteration of the LAA through an open or thoracoscopic approach. # Outline of the procedure Percutaneous occlusion of the LAA is usually carried out with the patient under general anaesthesia. Using fluoroscopic guidance, a catheter is advanced through the femoral vein into the right atrium and then into the left atrium via a transseptal puncture. The location of the LAA is confirmed and the size of the LAA orifice is established by transoesophageal echocardiography (TOE). An appropriately sized device is selected and deployed in the mouth of the LAA where it is expanded to fit the space. The position and patency of the occlusion device may be confirmed postoperatively using echocardiographic imaging. Sections 2.3 and 2.4 describe efficacy and safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview. # Efficacy A randomised controlled trial (RCT) of 707 patients treated by percutaneous closure of the LAA (n = 463) or warfarin (n = 244) reported 2.3 and 3.2 all-cause strokes respectively per 100 patient-years (rate ratio 0.71, credible interval 0.35 to 1.64). A case series of 111 patients reported stroke in 2 patients at 173- and 215-day follow-up. TOE at 1 and 6 months revealed a stable device in both patients and no thrombogenic layer on the surface of the device. Transient ischaemic attack was reported in 2 patients in the case series of 111 patients (not otherwise described). The RCT of 707 patients treated by the procedure or warfarin reported successful closure in 88% (408/463) of patients randomised to the procedure. The Specialist Advisers listed key efficacy outcomes as freedom from stroke, and other neurological and cardiac events. # Safety Cardiac tamponade requiring median sternotomy, pericardiocentesis and ligation of the LAA occurred 4 hours after the procedure in 1 patient in the case series of 111 patients. The patient later developed deep vein thrombosis and died 27 days after the procedure (attributed to cerebral haemorrhage associated with anticoagulation therapy). Cardiac arrest 30 minutes after the procedure because of device embolisation was reported in 1 patient, who subsequently died, in a case series of 73 patients. Device embolisation was reported in less than 1% (3/463) of patients in the RCT of 707 patients: 1 detected during the procedure, and 2 detected on TOE at 45-day follow-up (1 was removedpercutaneously and 2 underwent surgery; not otherwise described). The case series of 73 patients reported that 1 implant required open heart surgery because the device was unstable. Delivery wire fracture requiring surgical removal was reported in 1 patient in the case series of 75 patients. The RCT of 707 patients reported pericardial effusion successfully treated surgically or with pericardiocentesis in 5% (22/463), pericardial effusion not requiring drainage in 2% (8/463), oesophageal tear in less than 1% (1/463) and procedure-related arrhythmia in less than 1% (1/463) of patients treated by percutaneous occlusion. Perforation of the right femoral artery when accessing the right femoral vein and left atrial thrombus at the time of the procedure preventing the implantation of the device was reported in 1 patient each in the case series of 111 patients. The Specialist Advisers considered theoretical adverse events to include the inability to recover an incorrectly positioned device by endovascular means, so requiring emergency surgery; and persistent atrial septal defect. # Other comments The Committee noted that the published evidence included different occlusion devices and were mindful that clinical outcomes may not necessarily be the same with all devices. The Committee noted that new pharmacological products are in development for use in reducing the risk of thromboembolism associated with AF.# Further information For related NICE guidance see our website. # Information for patients NICE has produced information on this procedure for patients and carers ('Understanding NICE guidance'). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.# About this guidance NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland. This guidance was developed using the NICE interventional procedure guidance process. It updates and replaces NICE interventional procedure guidance 181. It has been incorporated into the NICE pathway on stroke, along with other related guidance and products We have produced a summary of this guidance for patients and carers. Information about the evidence it is based on is also available. Changes since publication January 2012: minor maintenance. Your responsibility This guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer. Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties. Copyright © National Institute for Health and Clinical Excellence 2010. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE. Contact NICE National Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT www.nice.org.uk nice@nice.org.uk	{'Guidance': 'This guidance replaces previous guidance on percutaneous occlusion of the left atrial appendage for atrial fibrillation (interventional procedure guidance 181).\n\nCurrent evidence suggests that percutaneous occlusion of the left atrial appendage (LAA) is efficacious in reducing the risk of thromboembolic complications associated with non-valvular atrial fibrillation (AF). With regard to safety, there is a risk of life-threatening complications from the procedure, but the incidence of these is low. Therefore, this procedure may be used provided that normal arrangements are in place for clinical governance, consent and audit.\n\nPatient selection should be carried out by a multidisciplinary team including a cardiologist and other appropriate clinicians experienced in the management of patients with AF at risk of stroke. Patients should be considered for alternative treatments to reduce the risk of thromboembolism associated with AF, and should be informed about these alternatives.\n\nPercutaneous occlusion of the LAA is a technically challenging procedure which should only be carried out by clinicians with specific training and appropriate experience in the procedure.\n\nThis procedure should be carried out only in units with on-site cardiac surgery.\n\nAny device-related adverse events resulting from the procedure should be reported to the Medicines and Healthcare products Regulatory Agency (MHRA).', 'The procedure': '# Indications and current treatments\n\nAF is the irregular and rapid beating of the atria. Patients with AF may be asymptomatic or may have symptoms such as fatigue, palpitations, chest pain, shortness of breath and fainting. They also have an increased risk of thromboembolic stroke. In non-rheumatic AF, thrombi largely develop in the LAA.\n\nPatients with AF who are considered to be at high risk of thromboembolic stroke are often treated with warfarin anticoagulation therapy. Surgical intervention may involve obliteration of the LAA through an open or thoracoscopic approach.\n\n# Outline of the procedure\n\nPercutaneous occlusion of the LAA is usually carried out with the patient under general anaesthesia. Using fluoroscopic guidance, a catheter is advanced through the femoral vein into the right atrium and then into the left atrium via a transseptal puncture. The location of the LAA is confirmed and the size of the LAA orifice is established by transoesophageal echocardiography (TOE). An appropriately sized device is selected and deployed in the mouth of the LAA where it is expanded to fit the space.\n\nThe position and patency of the occlusion device may be confirmed postoperatively using echocardiographic imaging.\n\nSections 2.3 and 2.4 describe efficacy and safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview.\n\n# Efficacy\n\nA randomised controlled trial (RCT) of 707 patients treated by percutaneous closure of the LAA (n = 463) or warfarin (n = 244) reported 2.3 and 3.2 all-cause strokes respectively per 100 patient-years (rate ratio 0.71, credible interval [CrI] 0.35 to 1.64).\n\nA case series of 111 patients reported stroke in 2 patients at 173- and 215-day follow-up. TOE at 1 and 6 months revealed a stable device in both patients and no thrombogenic layer on the surface of the device.\n\nTransient ischaemic attack was reported in 2 patients in the case series of 111 patients (not otherwise described).\n\nThe RCT of 707 patients treated by the procedure or warfarin reported successful closure in 88% (408/463) of patients randomised to the procedure.\n\nThe Specialist Advisers listed key efficacy outcomes as freedom from stroke, and other neurological and cardiac events.\n\n# Safety\n\nCardiac tamponade requiring median sternotomy, pericardiocentesis and ligation of the LAA occurred 4 hours after the procedure in 1 patient in the case series of 111 patients. The patient later developed deep vein thrombosis and died 27 days after the procedure (attributed to cerebral haemorrhage associated with anticoagulation therapy).\n\nCardiac arrest 30 minutes after the procedure because of device embolisation was reported in 1 patient, who subsequently died, in a case series of 73 patients.\n\nDevice embolisation was reported in less than 1% (3/463) of patients in the RCT of 707 patients: 1 detected during the procedure, and 2 detected on TOE at 45-day follow-up (1 was removedpercutaneously and 2 underwent surgery; not otherwise described).\n\nThe case series of 73 patients reported that 1 implant required open heart surgery because the device was unstable.\n\nDelivery wire fracture requiring surgical removal was reported in 1 patient in the case series of 75 patients.\n\nThe RCT of 707 patients reported pericardial effusion successfully treated surgically or with pericardiocentesis in 5% (22/463), pericardial effusion not requiring drainage in 2% (8/463), oesophageal tear in less than 1% (1/463) and procedure-related arrhythmia in less than 1% (1/463) of patients treated by percutaneous occlusion.\n\nPerforation of the right femoral artery when accessing the right femoral vein and left atrial thrombus at the time of the procedure preventing the implantation of the device was reported in 1 patient each in the case series of 111 patients.\n\nThe Specialist Advisers considered theoretical adverse events to include the inability to recover an incorrectly positioned device by endovascular means, so requiring emergency surgery; and persistent atrial septal defect.\n\n# Other comments\n\nThe Committee noted that the published evidence included different occlusion devices and were mindful that clinical outcomes may not necessarily be the same with all devices.\n\nThe Committee noted that new pharmacological products are in development for use in reducing the risk of thromboembolism associated with AF.', 'Further information': "For related NICE guidance see our website.\n\n# Information for patients\n\nNICE has produced information on this procedure for patients and carers ('Understanding NICE guidance'). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.", 'About this guidance': 'NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland.\n\nThis guidance was developed using the NICE interventional procedure guidance process.\n\nIt updates and replaces NICE interventional procedure guidance 181.\n\nIt has been incorporated into the NICE pathway on stroke, along with other related guidance and products\n\nWe have produced a summary of this guidance for patients and carers. Information about the evidence it is based on is also available.\n\nChanges since publication\n\nJanuary 2012: minor maintenance.\n\nYour responsibility\n\nThis guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.\n\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.\n\nCopyright\n\n© National Institute for Health and Clinical Excellence 2010. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.\n\nContact NICE\n\nNational Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT\n\nwww.nice.org.uk\n \n nice@nice.org.uk\n 0845 033 7780'}	https://www.nice.org.uk/guidance/ipg349
d0261bb02acfae74ac838422392ac34a348dac79	nice	Photodynamic therapy for Barrett's oesophagus	Photodynamic therapy for Barrett's oesophagus # Guidance This guidance replaces the previous guidance on Photodynamic therapy for Barrett's oesophagus, 82, August 2004. Current evidence on the efficacy of photodynamic therapy (PDT) for patients with Barrett's oesophagus with high-grade dysplasia (HGD) is adequate, provided that patients are followed up in the long term. There are no major safety concerns, although there is a risk of oesophageal stricture, and photosensitivity reactions are common. This procedure may be used in patients with Barrett's oesophagus with HGD provided that normal arrangements are in place for clinical governance, consent and audit. Current evidence on the efficacy and safety of PDT in patients with Barrett's oesophagus with either low-grade dysplasia (LGD) or no dysplasia is inadequate in quality and quantity, and the balance of risks and benefits is not clear. Therefore, for these patients, the procedure should be used only with special arrangements for clinical governance, consent and audit or research. Clinicians wishing to undertake PDT in patients with Barrett's oesophagus with either LGD or no dysplasia should take the following actions. Inform the clinical governance leads in their Trusts. Ensure that patients and their carers understand the uncertainty about the procedure's safety and efficacy and provide them with clear written information. In addition, the use of NICE's information for patients ('Understanding NICE guidance') is recommended. Audit and review clinical outcomes of patients with Barrett's oesophagus other than HGD having PDT (see section 3.1). Patient selection should be carried out by a multidisciplinary team experienced in the management of the condition. PDT for Barrett's oesophagus should only be carried out by endoscopists with specific training in this procedure.# The procedure # Indications and current treatments Barrett's oesophagus is characterised by abnormal epithelium of the oesophagus. In some patients metaplasia and dysplasia could progress to oesophageal adenocarcinoma. Cancer risk is higher for patients who have Barrett's oesophagus with HGD (some of whom may already have developed early-stage cancer) than for those with LGD or no dysplasia. Patients with HGD are usually offered oesophagectomy, or frequent endoscopic surveillance and re-biopsy (to detect neoplastic changes early) followed by oesophagectomy. Endoscopic treatments aiming to remove or ablate abnormal epithelium include endoscopic mucosal resection and different ablative treatments. Patients with LGD or no dysplasia are usually offered regular endoscopic surveillance and re-biopsy (with the aim of detecting potential progression to HGD or cancer). # Outline of the procedure PDT is carried out as an inpatient procedure, with the patient under intravenous sedation. A photosensitising agent is injected intravenously and is activated by illuminating the selected area with a laser inserted into the oesophagus. The photosensitising agent absorbs the light and forms high-energy oxygen molecules that cause necrosis of the Barrett's epithelium through a photochemical effect. For extensive Barrett's oesophagus, more than 1 treatment session may be required. Patients are advised to avoid exposure to bright light and direct sunlight for several weeks after the procedure to minimise risk of photosensitivity reactions. Sections 2.3 and 2.4 describe efficacy and safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview. # Efficacy A randomised controlled trial (RCT) of 208 patients with HGD treated by PDT and omeprazole or omeprazole alone reported absence of HGD in 75% (104/138) and 36% (25/70) of patients respectively at 18-month follow-up (p < 0.0001) and in 48% and 4% of patients at 5-year follow-up (p < 0.0001). An RCT of 72 patients without dysplasia treated by PDT or argon plasma coagulation (APC) reported complete response (reversal of columnar to squamous epithelium) in 50% (17/34) and 97% (33/34) of patients respectively at 12-month follow-up (p < 0.0001). The RCT of 208 patients treated by PDT and omeprazole or omeprazole alone reported adenocarcinoma development in 15% (21/138) and 29% (20/70) of patients respectively during 5-year follow-up. The Specialist Advisers listed key efficacy outcomes as reversal of dysplasia and metaplasia, and prevention of progression to adenocarcinoma. # Safety One patient died 3 days after PDT treatment, with transmural oesophageal necrosis without perforation, in an RCT of 40 patients (13 with single-dose PDT vs 13 with two-dose PDT vs 14 with APC). Oesophageal stricture was reported in 36% (49/138), 3% (1/34), 33% (20/60), 15% (2/13), and 27% (35/131) of patients treated by PDT in RCTs of 208, 72, 60, 26 and a non-randomised controlled trial of 199 patients respectively. Most were treated successfully with dilatation but 2 patients had perforation requiring oesophagectomy, as a result of dilatation. Dysphagia was reported in 19% (absolute figures not stated) of patients treated by PDT in the RCT of 208 patients (symptom timing not stated). Photosensitivity reactions within 90 days occurred in 69% of patients in the PDT arm of the RCT of 208 patients (absolute figures not stated). Photosensitivity reactions occurred in 15% (5/34) and 15% (2/13) of patients in RCTs of 72 and 26 patients respectively, and in 60% (77/129) of patients in the non-randomised controlled trial of 199 patients. In the RCT of 72 patients treated by PDT or APC, buried glands were reported in 24% (4/17) and 21% (7/33) of patients respectively (difference reported as 'not-significant'). Specialist Advisers listed anecdotal adverse events as pain and inflammation, ulceration and severe hypotension after PDT with 5-aminolevulinic acid. They considered theoretical adverse events to include decompensation in patients with cirrhosis of the liver, and skin and retinal damage due to photosensitisation.# Further information This guidance requires that clinicians undertaking the procedure for LGD or no dysplasia make special arrangements for audit. NICE has identified relevant audit criteria and has developed an audit tool (which is for use at local discretion). For related NICE guidance see our website. # Information for patients NICE has produced information on this procedure for patients and carers ('Understanding NICE guidance'). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.# Other NICE recommendations on photodynamic therapy Further recommendations have been made as part of the clinical guideline on Barrett's oesophagus - ablative therapy published in August 2010, as follows: Consider using radiofrequency ablation alone or photodynamic therapy alone for flat high-grade dysplasia, taking into account the evidence of their long-term efficacy, cost and complication rates. Clinical and cost-effectiveness evidence was reviewed in the development of this guideline which has led to this more specific recommendation. More information is available. The IP guidance on photodynamic therapy for Barrett's oesophagus remains current, and should be read in conjunction with the clinical guideline.# About this guidance NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland. This guidance was developed using the NICE interventional procedure guidance process. It updates and replaces NICE interventional procedure guidance 82. We have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available. Changes since publication January 2012: minor maintenance. Your responsibility This guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer. Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties. Copyright © National Institute for Health and Clinical Excellence 2010. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE. Contact NICE National Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT www.nice.org.uk nice@nice.org.uk	{'Guidance': "This guidance replaces the previous guidance on Photodynamic therapy for Barrett's oesophagus, 82, August 2004.\n\nCurrent evidence on the efficacy of photodynamic therapy (PDT) for patients with Barrett's oesophagus with high-grade dysplasia (HGD) is adequate, provided that patients are followed up in the long term. There are no major safety concerns, although there is a risk of oesophageal stricture, and photosensitivity reactions are common. This procedure may be used in patients with Barrett's oesophagus with HGD provided that normal arrangements are in place for clinical governance, consent and audit.\n\nCurrent evidence on the efficacy and safety of PDT in patients with Barrett's oesophagus with either low-grade dysplasia (LGD) or no dysplasia is inadequate in quality and quantity, and the balance of risks and benefits is not clear. Therefore, for these patients, the procedure should be used only with special arrangements for clinical governance, consent and audit or research.\n\nClinicians wishing to undertake PDT in patients with Barrett's oesophagus with either LGD or no dysplasia should take the following actions.\n\nInform the clinical governance leads in their Trusts.\n\nEnsure that patients and their carers understand the uncertainty about the procedure's safety and efficacy and provide them with clear written information. In addition, the use of NICE's information for patients ('Understanding NICE guidance') is recommended.\n\nAudit and review clinical outcomes of patients with Barrett's oesophagus other than HGD having PDT (see section 3.1).\n\nPatient selection should be carried out by a multidisciplinary team experienced in the management of the condition.\n\nPDT for Barrett's oesophagus should only be carried out by endoscopists with specific training in this procedure.", 'The procedure': "# Indications and current treatments\n\nBarrett's oesophagus is characterised by abnormal epithelium of the oesophagus. In some patients metaplasia and dysplasia could progress to oesophageal adenocarcinoma.\n\nCancer risk is higher for patients who have Barrett's oesophagus with HGD (some of whom may already have developed early-stage cancer) than for those with LGD or no dysplasia. Patients with HGD are usually offered oesophagectomy, or frequent endoscopic surveillance and re-biopsy (to detect neoplastic changes early) followed by oesophagectomy. Endoscopic treatments aiming to remove or ablate abnormal epithelium include endoscopic mucosal resection and different ablative treatments.\n\nPatients with LGD or no dysplasia are usually offered regular endoscopic surveillance and re-biopsy (with the aim of detecting potential progression to HGD or cancer).\n\n# Outline of the procedure\n\nPDT is carried out as an inpatient procedure, with the patient under intravenous sedation. A photosensitising agent is injected intravenously and is activated by illuminating the selected area with a laser inserted into the oesophagus. The photosensitising agent absorbs the light and forms high-energy oxygen molecules that cause necrosis of the Barrett's epithelium through a photochemical effect. For extensive Barrett's oesophagus, more than 1 treatment session may be required.\n\nPatients are advised to avoid exposure to bright light and direct sunlight for several weeks after the procedure to minimise risk of photosensitivity reactions.\n\nSections 2.3 and 2.4 describe efficacy and safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview.\n\n# Efficacy\n\nA randomised controlled trial (RCT) of 208 patients with HGD treated by PDT and omeprazole or omeprazole alone reported absence of HGD in 75% (104/138) and 36% (25/70) of patients respectively at 18-month follow-up (p < 0.0001) and in 48% and 4% of patients at 5-year follow-up (p < 0.0001).\n\nAn RCT of 72 patients without dysplasia treated by PDT or argon plasma coagulation (APC) reported complete response (reversal of columnar to squamous epithelium) in 50% (17/34) and 97% (33/34) of patients respectively at 12-month follow-up (p < 0.0001).\n\nThe RCT of 208 patients treated by PDT and omeprazole or omeprazole alone reported adenocarcinoma development in 15% (21/138) and 29% (20/70) of patients respectively during 5-year follow-up.\n\nThe Specialist Advisers listed key efficacy outcomes as reversal of dysplasia and metaplasia, and prevention of progression to adenocarcinoma.\n\n# Safety\n\nOne patient died 3 days after PDT treatment, with transmural oesophageal necrosis without perforation, in an RCT of 40 patients (13 with single-dose PDT vs 13 with two-dose PDT vs 14 with APC).\n\nOesophageal stricture was reported in 36% (49/138), 3% (1/34), 33% (20/60), 15% (2/13), and 27% (35/131) of patients treated by PDT in RCTs of 208, 72, 60, 26 and a non-randomised controlled trial of 199 patients respectively. Most were treated successfully with dilatation but 2 patients had perforation requiring oesophagectomy, as a result of dilatation.\n\nDysphagia was reported in 19% (absolute figures not stated) of patients treated by PDT in the RCT of 208 patients (symptom timing not stated).\n\nPhotosensitivity reactions within 90 days occurred in 69% of patients in the PDT arm of the RCT of 208 patients (absolute figures not stated). Photosensitivity reactions occurred in 15% (5/34) and 15% (2/13) of patients in RCTs of 72 and 26 patients respectively, and in 60% (77/129) of patients in the non-randomised controlled trial of 199 patients.\n\nIn the RCT of 72 patients treated by PDT or APC, buried glands were reported in 24% (4/17) and 21% (7/33) of patients respectively (difference reported as 'not-significant').\n\nSpecialist Advisers listed anecdotal adverse events as pain and inflammation, ulceration and severe hypotension after PDT with 5-aminolevulinic acid. They considered theoretical adverse events to include decompensation in patients with cirrhosis of the liver, and skin and retinal damage due to photosensitisation.", 'Further information': "This guidance requires that clinicians undertaking the procedure for LGD or no dysplasia make special arrangements for audit. NICE has identified relevant audit criteria and has developed an audit tool (which is for use at local discretion).\n\nFor related NICE guidance see our website.\n\n# Information for patients\n\nNICE has produced information on this procedure for patients and carers ('Understanding NICE guidance'). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.", 'Other NICE recommendations on photodynamic therapy': "Further recommendations have been made as part of the clinical guideline on Barrett's oesophagus - ablative therapy published in August 2010, as follows:\n\nConsider using radiofrequency ablation alone or photodynamic therapy alone for flat high-grade dysplasia, taking into account the evidence of their long-term efficacy, cost and complication rates.\n\nClinical and cost-effectiveness evidence was reviewed in the development of this guideline which has led to this more specific recommendation. More information is available.\n\nThe IP guidance on photodynamic therapy for Barrett's oesophagus remains current, and should be read in conjunction with the clinical guideline.", 'About this guidance': 'NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland.\n\nThis guidance was developed using the NICE interventional procedure guidance process.\n\nIt updates and replaces NICE interventional procedure guidance 82.\n\nWe have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available.\n\nChanges since publication\n\nJanuary 2012: minor maintenance.\n\nYour responsibility\n\nThis guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.\n\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.\n\nCopyright\n\n© National Institute for Health and Clinical Excellence 2010. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.\n\nContact NICE\n\nNational Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT\n\nwww.nice.org.uk\n \n nice@nice.org.uk\n 0845 033 7780'}	https://www.nice.org.uk/guidance/ipg350
e6c171e0beca03a79f7e5344b1809a618edb6fd4	nice	Stapled transanal rectal resection for obstructed defaecation syndrome	Stapled transanal rectal resection for obstructed defaecation syndrome # Guidance This document replaces previous guidance on stapled transanal rectal resection for obstructed defaecation syndrome (interventional procedure guidance 169). Current evidence on the safety and efficacy of stapled transanal rectal resection (STARR) for obstructed defaecation syndrome (ODS) is adequate in the context of this condition, which can significantly affect quality of life. The procedure may therefore be used with normal arrangements for clinical governance, consent and audit. Stapled transanal rectal resection for ODS should be carried out only in units specialising in the investigation and management of pelvic floor disorders. Patient selection and management should involve a multidisciplinary team including a urogynaecologist or urologist and a colorectal surgeon experienced in this procedure.# The procedure # Indications and current treatments ODS is a complex and multifactorial condition, characterised by an urge to defaecate but an impaired ability to expel the faecal bolus. Symptoms include unsuccessful faecal evacuation attempts, excessive straining, pain, bleeding after defaecation and a sense of incomplete faecal evacuation. ODS is often associated with structural defects in the rectum such as rectocele, internal rectal prolapse and perineal descent. Women, particularly multiparous women, are more likely to present with symptoms of ODS than men. Conservative treatments include diet, biofeedback, laxatives and pelvic floor retraining. In patients refractory to conservative treatment, and/or if a structural abnormality is present, surgery may be considered including stapled transanal prolapsectomy and perineal levatorplasty (STAPL) and laparoscopic ventral mesh sacrocolporectopexy. # Outline of the procedure Patients having STARR usually receive bowel preparation and prophylactic antibiotics before surgery. With the patient under spinal or general anaesthesia, a circular anal dilator is introduced into the anal canal and secured with skin sutures. Resection of the redundant parts of the anterior and posterior rectal walls is done sequentially. Traction sutures are inserted (with an anoscope to aid visualisation) above the anorectal junction to prolapse the redundant rectal wall into the anvil of a stapler, which is then fired to produce a full thickness resection. The opposite posterior or anterior wall is protected with a spatula. Any bleeding at the circumferential staple line is controlled with interrupted sutures. Sections 2.3 and 2.4 describe efficacy and safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview. # Efficacy A randomised controlled trial (RCT) of 50 patients treated by STARR or STAPL reported a good or excellent clinical outcome (1–2 episodes per month or symptom free) in 88% (22/25) and 76% (19/25) of patients respectively at 20-month follow-up. An RCT of 119 patients treated by STARR or biofeedback reported treatment success (defined as a decrease in ODS score of at least 50% at 1 year) in 82% (44/54) and 33% (13/39) of patients respectively (p < 0.0001). A non-randomised comparative study of 73 patients reported a failure in 17% (6/36) for women treated by STARR and 22% (8/37) for women treated by transvaginal repair at mean follow-ups of 8 months and 14 months respectively (p = 0.80). Register data on 2838 patients reported a mean baseline ODS score (higher score indicates more severe symptoms) of 17.8 (95% confidence interval 15.5 to 16.0). This reduced to 5.8 (95% CI 5.3 to 6.4) at 12-month follow-up among 2224 patients treated by STARR (p < 0.001). The Specialist Advisers listed an additional key efficacy outcome as improvement in quality of life. # Safety Septic events (not otherwise described) were reported in 4% (124/2838) of patients in a register. In a case series of 38 patients, 1 patient developed septic shock and died as a result of necrotising pelvic fasciitis. The register of 2838 patients reported 1 case of rectal necrosis requiring a diverting stoma (timing of event not stated). The register of 2838 patients reported 1 case of rectal necrosis requiring a diverting stoma (timing of event not stated). Early stenosis was reported in 1 patient in each treatment group in the RCT of STARR (25 patients) versus STAPL (25 patients), and in 2% (2/90), 2% (2/85) and 1% (1/104) in case series of 90, 85 and 104 patients respectively. A 3% incidence of stenosis was reported after 1 month in the case series of 90 patients. Rectovaginal fistula (timing of event not stated) was reported in the register of 2838 patients and case series of 230 patients in 1 patient each. Postoperative faecal incontinence was reported in 8% (3/36) of patients treated by STARR and 3% (1/37) of patients treated by transvaginal repair (follow-up not stated) in the non-randomised comparative study of 73 patients; and in 9% (9/104) of patients at 12-month follow-up in the case series of 104 patients. Dyspareunia was reported in less than 1% (3/2838) of patients from the register of 2838. Defaecatory urgency was reported in 16% (4/25) and 4% (1/25) of patients treated by STARR or STAPL respectively (within 7 days after surgery). Defecatory urgency continued to occur in 6% (6/104) of patients in the case series of 104 patients at 12-month follow-up. Instances of bleeding were reported in 10 studies with rates of 2% (1/54), 3% (3/104), 3% (2/68), 4% (1/25), 4% (4/90), 4% (10/230), 5% (143/2838), 7% (2/29), 12% (10/85) and 19% (7/36). In 6 of these studies, at least 1 patient required further hospital intervention. The Specialist Advisers considered theoretical adverse events to include pain, staple line complications, rectal wall perforation or haematoma. # Other comments The Committee noted that the procedure may sometimes be followed by defaecation urgency and incontinence. However, it remains unclear whether these sequelae are caused by the procedure or whether they are the results of pre-existing abnormalities. NICE received 9 completed questionnaires from patients treated by the procedure. Five of the patient commentators reported substantial improvements in quality of life after the procedure.# Further information For related NICE guidance see www.nice.org.uk Information for patients NICE has produced information on this procedure for patients and carers ('Understanding NICE guidance'). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.	{'Guidance': 'This document replaces previous guidance on stapled transanal rectal resection for obstructed defaecation syndrome (interventional procedure guidance 169).\n\nCurrent evidence on the safety and efficacy of stapled transanal rectal resection (STARR) for obstructed defaecation syndrome (ODS) is adequate in the context of this condition, which can significantly affect quality of life. The procedure may therefore be used with normal arrangements for clinical governance, consent and audit.\n\nStapled transanal rectal resection for ODS should be carried out only in units specialising in the investigation and management of pelvic floor disorders. Patient selection and management should involve a multidisciplinary team including a urogynaecologist or urologist and a colorectal surgeon experienced in this procedure.', 'The procedure': '# Indications and current treatments\n\nODS is a complex and multifactorial condition, characterised by an urge to defaecate but an impaired ability to expel the faecal bolus. Symptoms include unsuccessful faecal evacuation attempts, excessive straining, pain, bleeding after defaecation and a sense of incomplete faecal evacuation. ODS is often associated with structural defects in the rectum such as rectocele, internal rectal prolapse and perineal descent. Women, particularly multiparous women, are more likely to present with symptoms of ODS than men.\n\nConservative treatments include diet, biofeedback, laxatives and pelvic floor retraining. In patients refractory to conservative treatment, and/or if a structural abnormality is present, surgery may be considered including stapled transanal prolapsectomy and perineal levatorplasty (STAPL) and laparoscopic ventral mesh sacrocolporectopexy.\n\n# Outline of the procedure\n\nPatients having STARR usually receive bowel preparation and prophylactic antibiotics before surgery. With the patient under spinal or general anaesthesia, a circular anal dilator is introduced into the anal canal and secured with skin sutures. Resection of the redundant parts of the anterior and posterior rectal walls is done sequentially. Traction sutures are inserted (with an anoscope to aid visualisation) above the anorectal junction to prolapse the redundant rectal wall into the anvil of a stapler, which is then fired to produce a full thickness resection. The opposite posterior or anterior wall is protected with a spatula. Any bleeding at the circumferential staple line is controlled with interrupted sutures.\n\nSections 2.3 and 2.4 describe efficacy and safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview.\n\n# Efficacy\n\nA randomised controlled trial (RCT) of 50 patients treated by STARR or STAPL reported a good or excellent clinical outcome (1–2 episodes per month or symptom free) in 88% (22/25) and 76% (19/25) of patients respectively at 20-month follow-up. An RCT of 119 patients treated by STARR or biofeedback reported treatment success (defined as a decrease in ODS score of at least 50% at 1 year) in 82% (44/54) and 33% (13/39) of patients respectively (p < 0.0001).\n\nA non-randomised comparative study of 73 patients reported a failure in 17% (6/36) for women treated by STARR and 22% (8/37) for women treated by transvaginal repair at mean follow-ups of 8 months and 14 months respectively (p = 0.80).\n\nRegister data on 2838 patients reported a mean baseline ODS score (higher score indicates more severe symptoms) of 17.8 (95% confidence interval [CI] 15.5 to 16.0). This reduced to 5.8 (95% CI 5.3 to 6.4) at 12-month follow-up among 2224 patients treated by STARR (p < 0.001).\n\nThe Specialist Advisers listed an additional key efficacy outcome as improvement in quality of life.\n\n# Safety\n\nSeptic events (not otherwise described) were reported in 4% (124/2838) of patients in a register. In a case series of 38 patients, 1 patient developed septic shock and died as a result of necrotising pelvic fasciitis.\n\nThe register of 2838 patients reported 1 case of rectal necrosis requiring a diverting stoma (timing of event not stated).\n\nThe register of 2838 patients reported 1 case of rectal necrosis requiring a diverting stoma (timing of event not stated).\n\nEarly stenosis was reported in 1 patient in each treatment group in the RCT of STARR (25 patients) versus STAPL (25 patients), and in 2% (2/90), 2% (2/85) and 1% (1/104) in case series of 90, 85 and 104 patients respectively. A 3% incidence of stenosis was reported after 1 month in the case series of 90 patients.\n\nRectovaginal fistula (timing of event not stated) was reported in the register of 2838 patients and case series of 230 patients in 1 patient each.\n\nPostoperative faecal incontinence was reported in 8% (3/36) of patients treated by STARR and 3% (1/37) of patients treated by transvaginal repair (follow-up not stated) in the non-randomised comparative study of 73 patients; and in 9% (9/104) of patients at 12-month follow-up in the case series of 104 patients. Dyspareunia was reported in less than 1% (3/2838) of patients from the register of 2838.\n\nDefaecatory urgency was reported in 16% (4/25) and 4% (1/25) of patients treated by STARR or STAPL respectively (within 7 days after surgery). Defecatory urgency continued to occur in 6% (6/104) of patients in the case series of 104 patients at 12-month follow-up. Instances of bleeding were reported in 10 studies with rates of 2% (1/54), 3% (3/104), 3% (2/68), 4% (1/25), 4% (4/90), 4% (10/230), 5% (143/2838), 7% (2/29), 12% (10/85) and 19% (7/36). In 6 of these studies, at least 1 patient required further hospital intervention.\n\nThe Specialist Advisers considered theoretical adverse events to include pain, staple line complications, rectal wall perforation or haematoma.\n\n# Other comments\n\nThe Committee noted that the procedure may sometimes be followed by defaecation urgency and incontinence. However, it remains unclear whether these sequelae are caused by the procedure or whether they are the results of pre-existing abnormalities.\n\nNICE received 9 completed questionnaires from patients treated by the procedure. Five of the patient commentators reported substantial improvements in quality of life after the procedure.', 'Further information': "For related NICE guidance see www.nice.org.uk\n\nInformation for patients\n\nNICE has produced information on this procedure for patients and carers ('Understanding NICE guidance'). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind."}	https://www.nice.org.uk/guidance/ipg351
2414f2585d8c147c6401fa01f10178a6e98925e8	nice	Cardiovascular disease prevention	Cardiovascular disease prevention This guideline covers the main risk factors linked with cardiovascular disease: poor diet, physical inactivity, smoking and excessive alcohol consumption. It aims to reduce the high incidence of cardiovascular disease. This, in turn, will help prevent other major causes of death and illness, such as type 2 diabetes and many cancers. # Introduction The Department of Health (DH) asked the National Institute for Health and Clinical Excellence (NICE) to produce public health guidance on the prevention of cardiovascular disease (CVD) at population level. CVD includes coronary heart disease (CHD), stroke and peripheral arterial disease. These conditions are frequently brought about by the development of atheroma and thrombosis (blockages in the arteries). They are also linked to conditions such as heart failure, chronic kidney disease and dementia. The guidance is for government, the NHS, local authorities, industry and all those whose actions influence the population's cardiovascular health. This includes commissioners, managers and practitioners working in local authorities and the wider public, private, voluntary and community sectors. It may also be of interest to members of the public. The guidance complements, but does not replace, NICE guidance on: smoking cessation and prevention and tobacco control, physical activity, obesity, hypertension and maternal and child nutrition (for further details, see section 7). It will also complement NICE guidance on alcohol misuse. The Programme Development Group (PDG) developed the recommendations on the basis of reviews of the evidence, economic modelling, expert advice, stakeholder comments and fieldwork. Members of the PDG are listed in appendix A. The methods used to develop the guidance are summarised in appendix B. Supporting documents used to prepare this document are listed in appendix E. Full details of the evidence collated, including fieldwork data and activities and stakeholder comments, are available on the NICE website, along with a list of the stakeholders involved and NICE's supporting process and methods manuals.# Recommendations This is NICE's formal guidance on preventing cardiovascular disease (CVD) at population level. When writing the recommendations, the Programme Development Group (PDG) (see appendix A) considered the evidence of effectiveness (including cost effectiveness), fieldwork data and comments from stakeholders and experts. Full details are available online. The evidence statements underpinning the recommendations are listed in appendix C. The evidence reviews, supporting evidence statements and economic modelling report are available online. # Recommendations for policy: a national framework for action Changes in cardiovascular disease (CVD) risk factors can be brought about by intervening at the population and individual level. Government has addressed – and continues to address – the risk factors at both levels. Interventions focused on changing an individual's behaviour are important and are supported by a range of existing NICE guidance (see section 7, 'Related NICE guidance'). Changes at the population-level could lead to further substantial benefits and this guidance breaks new ground for NICE, by focusing on action to bring about such changes. They may be achieved in a number of ways but national or regional policy and legislation are particularly powerful levers. (For more on the importance of interventions aimed at the whole population, see considerations 3.12, 3.13, 3.14 and 3.15.) This guidance makes the case that CVD is a major public health problem. Recommendations 1 to 12 are based on extensive and consistent evidence. This suggests that the policy goals identified provide the outline for a sound, evidence-based national framework for action which is likely to be the most effective and cost-effective way of reducing CVD at population level. It would require a range of legislative, regulatory and voluntary changes including the further development of existing policies. The framework would be established through policy, led by the Department of Health. It would involve government, government agencies, industry and key, non-governmental organisations working together. The final decision on whether these policy options are adopted – and how they are prioritised – will be determined by government through normal political processes. The recommendations for practice (recommendations 13 to 24) support and complement – and are supported by – these policy options. ## Who should take action? As well as the Department of Health, the following should be involved: Chief Medical Officer National Clinical Director for Coronary Heart Disease Government Chief Scientific Adviser Department of Health Chief Scientist Advertising Standards Authority Department for Business, Innovation and Skills Department for Culture, Media and Sport Department for Education Department for Environment, Food and Rural Affairs Department for Transport Department of Communities and Local Government Food Standards Agency HM Treasury National Institute for Health Research Ofcom Other research organisations (for example, the Medical Research Council and the Economic and Social Research Council). Other key players include: caterers food and drink producers food and drink retailers marketing and media industries national, non-governmental organisations including, for example, the British Heart Foundation, Cancer Research UK, Diabetes UK, National Heart Forum, the Stroke Association and other chronic disease charities the farming sector. ## Recommendation 1 Salt High levels of salt in the diet are linked with high blood pressure which, in turn, can lead to stroke and coronary heart disease. High levels of salt in processed food have a major impact on the total amount consumed by the population. Over recent years the food industry, working with the Food Standards Agency, has made considerable progress in reducing salt in everyday foods. As a result, products with no added salt are now increasingly available. However, it is taking too long to reduce average salt intake among the population. Furthermore, average intake among children is above the recommended level – and some children consume as much salt as adults. Progress towards a low-salt diet needs to be accelerated as a matter of urgency. Reduce population-level consumption of salt. To achieve this, the evidence suggests that the following are among the measures that should be considered. Accelerate the reduction in salt intake among the population. Aim for a maximum intake of 6 g per day per adult by 2015 and 3 g by 2025. Ensure children's salt intake does not exceed age-appropriate guidelines (these guidelines should be based on up-to-date assessments of the available scientific evidence). Promote the benefits of a reduction in the population's salt intake to the European Union (EU). Introduce national legislation if necessary. Ensure national policy on salt in England is not weakened by less effective action in other parts of the EU. Ensure food producers and caterers continue to reduce the salt content of commonly consumed foods (including bread, meat products, cheese, soups and breakfast cereals). This can be achieved by progressively changing recipes, products and manufacturing and production methods. Establish the principle that children under 11 should consume substantially less salt than adults. (This is based on advice from the Scientific Advisory Committee on Nutrition.) Support the Food Standards Agency so that it can continue to promote – and take the lead on – the development of EU-wide salt targets for processed foods. Establish an independent system for monitoring national salt levels in commonly consumed foods. Ensure low-salt products are sold more cheaply than their higher salt equivalents. Clearly label products which are naturally high in salt and cannot meaningfully be reformulated. Use the Food Standards Agency-approved traffic light system. The labels should also state that these products should only be consumed occasionally. Discourage the use of potassium and other substitutes to replace salt. The aim of avoiding potassium substitution is twofold: to help consumers' readjust their perception of 'saltiness' and to avoid additives which may have other effects on health. Promote best practice in relation to the reduction of salt consumption, as exemplified in these recommendations, to the wider EU. ## Recommendation 2 Saturated fats Reducing general consumption of saturated fat is crucial to preventing CVD. Over recent years, much has been done (by the Food Standards Agency, consumers and industry) to reduce the population's intake. Consumption levels are gradually moving towards the goal set by the Food Standards Agency: to reduce population intake of saturated fat from 13.3% to below 11% of food energy. However, a further substantial reduction would greatly reduce CVD and deaths from CVD. Taking the example of Japan (where consumption of saturated fat is much lower than in the UK), halving the average intake (from 14% to 6–7% of total energy) might prevent approximately 30,000 CVD deaths annually. It would also prevent a corresponding number of new cases of CVD annually. (Note that low-fat products are not recommended for children under 2 years, but are fine thereafter.) Reduce population-level consumption of saturated fat. To achieve this, the evidence suggests that the following are among the measures that should be considered. Encourage manufacturers, caterers and producers to reduce substantially the amount of saturated fat in all food products. If necessary, consider supportive legislation. Ensure no manufacturer, caterer or producer is at an unfair advantage as a result. Create the conditions whereby products containing lower levels of saturated fat are sold more cheaply than high saturated fat products. Consider legislation and fiscal levers if necessary. Create favourable conditions for industry and agriculture to produce dairy products for human consumption that are low in saturated fat. Continue to promote semi-skimmed milk for children aged over 2 years. This is in line with the American Heart Association's pediatric dietary strategy. ## Recommendation 3 Trans fats Industrially-produced trans fatty acids (IPTFAs) constitute a significant health hazard. In recent years many manufacturers and caterers, with the encouragement of the Food Standards Agency and other organisations, have considerably reduced the amount of IPTFAs in their products. However, certain sections of the population may be consuming a substantially higher amount of IPTFAs than average (for instance, those who regularly eat fried fast-food). It is important to protect all social groups from the adverse effects of IPTFAs. In some countries and regions (for instance, Denmark, Austria and New York), IPTFAs have been successfully banned. A study for the European Parliament recently recommended that it, too, should consider an EU-wide ban. In the meantime, some large UK caterers, retailers and producers have removed IPTFAs from their products. Ensure all groups in the population are protected from the harmful effects of IPTFAs. To achieve this, the evidence suggests that the following are among the measures that should be considered. Eliminate the use of IPTFAs for human consumption. In line with other EU countries (specifically, Denmark and Austria), introduce legislation to ensure that IPTFA levels do not exceed 2% in the fats and oils used in food manufacturing and cooking. Direct the bodies responsible for national surveys to measure and report on consumption of IPTFAs by different population subgroups – rather than only by mean consumption across the population as a whole. Establish guidelines for local authorities to monitor independently IPTFA levels in the restaurant, fast-food and home food trades using existing statutory powers (in relation to trading standards or environmental health). Create and sustain local and national conditions which support a reduction in the amount of IPTFAs in foods, while ensuring levels of saturated fat are not increased. Encourage the use of vegetable oils high in polyunsaturated and monounsaturated fatty acids to replace oils containing IPTFAs. Saturated fats should not be used as an IPTFA substitute. Develop UK-validated guidelines and information for the food service sector and local government on removing IPTFAs from the food preparation process. This will support UK-wide implementation of any legislation produced on IPTFAs. ## Recommendation 4 Marketing and promotions aimed at children and young people Eating and drinking patterns get established at an early age so measures to protect children from the dangers of a poor diet should be given serious consideration. Current advertising restrictions have reduced the number of advertisments for foods high in fat, salt or sugar during television programmes made for children and young people. However, advertisements, promotions, product placements and sponsorship shown between programmes for older audiences also have a powerful influence on children and young people. Marketing bans have been successfully introduced in several other countries; evidence shows that a 9pm watershed for such TV advertisements would reduce children and young people's exposure to this type of advertising by 82%. Ensure children and young people under 16 are protected from all forms of marketing, advertising and promotions (including product placements) which encourage an unhealthy diet. To achieve this, the evidence suggests that the following are among the measures that should be considered. Develop a comprehensive, agreed set of principles for food and beverage marketing aimed at children and young people. This could be similar to the 'Sydney principles'. They should be based on a child's right to a healthy diet. Extend TV advertising scheduling restrictions on food and drink high in fat, salt or sugar (as determined by the Food Standards Agency's nutrient profile) up to 9pm. Develop equivalent standards, supported by legislation, to restrict the marketing, advertising and promotion of food and drink high in fat, salt or sugar via all non-broadcast media. This includes manufacturers' websites, use of the Internet generally, mobile phones and other new technologies. Ensure restrictions for non-broadcast media on advertising, marketing and promotion of food and drink high in fat, salt or sugar are underpinned by the Food Standards Agency nutrient profiling system. ## Recommendation 5 Commercial interests If deaths and illnesses associated with CVD are to be reduced, it is important that food and drink manufacturers, retailers, caterers, producers and growers, along with associated organisations, deliver goods that underpin this goal. Many commercial organisations are already taking positive action. Ensure dealings between government, government agencies and the commercial sector are conducted in a transparent manner that supports public health objectives and is in line with best practice. (This includes full disclosure of interests.) To achieve this, the following are among the measures that should be considered. Encourage best practice for all meetings, including lobbying, between the food and drink industry and government (and government agencies). This includes full disclosure of interests by all parties. It also involves a requirement that information provided by the food and drink, catering and agriculture industries is available for the general public and is auditable. ## Recommendation 6 Product labelling Clear labelling which describes the content of food and drink products is important because it helps consumers to make informed choices. It may also be an important means of encouraging manufacturers and retailers to reformulate processed foods high in saturated fats, salt and added sugars. Evidence shows that simple traffic light labelling consistently works better than more complex schemes. Ensure the Food Standards Agency's integrated front-of-pack labelling system is rapidly implemented. Ensure labelling regulations in England are not adversely influenced by EU regulation.To achieve this, the evidence suggests that the following are among the measures that should be considered. Establish the Food Standards Agency's single, integrated, front-of-pack traffic light colour-coded system as the national standard for food and drink products sold in England. This includes the simple, traffic light, colour-coding visual icon and text which indicates whether food or drink contains a 'high', 'medium' or 'low' level of salt, fat or sugar. It also includes text to indicate the product's percentage contribution to the guideline daily amount (GDA) from each category. Consider using legislation to ensure universal implementation of the Food Standards Agency's front-of-pack traffic light labelling system. Develop and implement nutritional labelling for use on shelves or packaging for bread, cakes, meat and dairy products displayed in a loose or unwrapped state or packed on the premises. The labelling should be consistent with the Food Standards Agency's traffic light labelling system. Ensure food and drink labelling is consistent in format and content. In particular, it should refer to salt (as opposed to sodium), the content per 100 g and use kcals as the measure of energy. Continue to support the Food Standards Agency in providing clear information about healthy eating. Ensure the UK continues to set the standard of best practice by pursuing exemption from potentially less effective EU food labelling regulations when appropriate. ## Recommendation 7 Health impact assessment (see also recommendation 22) Policies in a wide variety of areas can have a positive or negative impact on CVD risk factors – and frequently the consequences are unintended. The Cabinet Office has indicated that, where relevant, government departments should assess the impact of policies on the health of the population. Well-developed tools and techniques exist for achieving this. Ensure government policy is assessed for its impact on CVD. Ensure any such assessments are adequately incorporated into the policy making process. To achieve this, the following are among the measures that should be considered. Assess (in line with the Cabinet Office requirement) all public policy and programmes for the potential impact (positive and negative) on CVD and other related chronic diseases. In addition, assess the potential impact on health inequalities. Assessments should be carried out using health and policy impact assessment and other similar, existing tools. Monitor the outcomes of policy and programmes after the assessment and use them to follow up and amend future plans. Make health impact assessment mandatory in specific scenarios. (Note that strategic environmental assessment, environmental impact assessment and regulatory impact assessment are already mandatory in certain contexts.) ## Recommendation 8 Common agricultural policy The common agricultural policy (CAP) is the overarching framework used by EU member countries to form their own agricultural policies. The burden of diet-related disease has grown considerably since CAP was first implemented. CAP reform offers a significant opportunity to address the burden of CVD. However, there are still a number of significant 'distortions' in relation to certain food prices and production processes which potentially increase the burden of disease. Further reform should aim to remove these distortions to promote health and wellbeing and to provide a basis for UK government action to prevent CVD. The CAP has two main 'pillars': market measures (first pillar) and rural development policy (second pillar). Recent CAP reform has shifted money from the first to the second pillar which now focuses more on 'public goods'. However, health has not been formally recognised as a 'public good'. CAP reforms have begun to address this issue, but a clearer focus on CVD and its antecedents (that is, the production of foods high in fat, sugar or salt) is needed. Ensure promoting health and reducing disease is made an explicit part of the CAP's 'public goods' so that European money promotes the wellbeing of EU citizens. Ensure CAP spending takes adequate account of its potential impact on CVD risk factors and is used in a way that optimises the public health outcomes. To achieve this, the following are among the measures that should be considered. Negotiate at EU and national level to ensure the CAP takes account of public health issues. Health benefits should be an explicit, legitimate outcome of CAP spending. This can be achieved through formal recognition of health as a 'public good'. Progressively phase out payments under 'pillar one' so that all payments fall under 'pillar two'. This will allow for better protection of health, climate and the environment. It will also improve and stimulate economic growth. Encourage the principle that future 'pillar two' funds should reward or encourage the production of highly nutritious foods such as fruit, vegetables, whole grains and leaner meats. Negotiate to ensure the European Commission's impact assessment procedure takes cardiovascular health and other health issues into account. (Impact assessment is part of the European Commission's strategic planning and programming cycle.) ## Recommendation 9 Physically active travel (see also recommendation 21) Travel offers an important opportunity to help people become more physically active. However, inactive modes of transport have increasingly dominated in recent years. In England, schemes to encourage people to opt for more physically active forms of travel (such as walking and cycling) are 'patchy'. Ensure government funding supports physically active modes of travel.To achieve this, the evidence suggests that the following are among the measures that should be considered. Ensure guidance for local transport plans supports physically active travel. This can be achieved by allocating a percentage of the integrated block allocation fund to schemes which support walking and cycling as modes of transport. Create an environment and incentives which promote physical activity, including physically active travel to and at work. Consider and address factors which discourage physical activity, including physically active travel to and at work. An example of the latter is subsidised parking. ## Recommendation 10 Public sector catering guidelines (see also recommendations 19 and 20) Public sector organisations are important providers of food and drink to large sections of the population. It is estimated that they provide around one in three meals eaten outside the home. Hence, an effective way to reduce the risk of CVD would be to improve the nutritional quality of the food and drink they provide. Ensure publicly funded food and drink provision contributes to a healthy, balanced diet and the prevention of CVD. Ensure public sector catering practice offers a good example of what can be done to promote a healthy, balanced diet. To achieve this, the evidence suggests that the following are among the measures that should be considered. Ensure all publicly funded catering departments meet Food Standards Agency-approved dietary guidelines. This includes catering in schools, hospitals and public sector work canteens. Assess the effectiveness of the 'Healthier food mark' pilot. If successful, develop a timetable to implement it on a permanent basis. ## Recommendation 11 Take-aways and other food outlets (see also recommendations 23 and 24) Food from take-aways and other outlets (the 'informal eating out sector') comprises a significant part of many people's diet. Local planning authorities have powers to control fast-food outlets. Empower local authorities to influence planning permission for food retail outlets in relation to preventing and reducing CVD. To achieve this, the following are among the measures that should be considered. Encourage local planning authorities to restrict planning permission for take-aways and other food retail outlets in specific areas (for example, within walking distance of schools). Help them implement existing planning policy guidance in line with public health objectives. (See also recommendation 12.) Review and amend 'classes of use' orders for England to address disease prevention via the concentration of outlets in a given area. These orders are set out in the Town and Country Planning (Use Classes) Order 1987 and subsequent amendments. ## Recommendation 12 Monitoring CVD is responsible for around 33% of the observed gap in life expectancy among people living in areas with the worst health and deprivation indicators compared with those living elsewhere in England. Independent monitoring, using a full range of available data, is vital when assessing the need for additional measures to address such health inequalities, including those related to CVD. Ensure all appropriate data are available for monitoring and analysis to inform CVD prevention policy. To achieve this, the evidence suggests that the following are among the measures that should be considered. Ensure data on CVD prevention is available for scrutiny by the public health community as a whole. Ensure new econometric data (including pooled consumer purchasing data) are rapidly made available by industry for monitoring and analysis by independent agencies. Use population surveys (including the 'National diet and nutrition survey' and the 'Low income diet and nutrition survey' ) and data from all relevant sources to monitor intake of nutrients for all population groups. (Sources include: the Food Standards Agency, Department of Health, Department for Environment, Food and Rural Affairs, Office for National Statistics, the Public Health Observatories, academic and other researchers.) Monitor the intake of salt, trans fatty acids, saturated fatty acids and mono and polyunsaturated fatty acids among different population groups and report the findings for those groups. Support the 'National diet and nutrition survey' and the 'Low income diet and nutrition survey'. Ensure the CVD module (including lipid profile measures) routinely appears in the 'Health surveys for England'. Develop an international public health information system (resembling GLOBALink) for CVD prevention and use it to ensure widespread dissemination of these data. # Recommendations for practice ## Recommendations 13–18 Regional CVD prevention programmes Recommendations13–18 provide for a comprehensive regional and local CVD prevention programme. They should all be implemented, following the order set out below and in conjunction with recommendations 1–12, which they support. The aim is to plan, develop and maintain effective programmes. The target population for recommendations 13–18 and the list of who should take action is outlined below. This is followed by the specific actions to be taken in relation to each element of the programme. The population that falls within a local authority, primary care trust (PCT) area or across combined PCT and local authority areas or within a particular region of the country. Commissioners and providers of public health intervention programmes within: city region partnerships government regional offices local authorities local strategic partnerships non-governmental organisations, including charities and community groups PCTs strategic health authorities. ## Recommendation 13 Regional CVD prevention programmes – good practice principles Ensure a CVD prevention programme comprises intense, multi-component interventions. Ensure it takes into account issues identified in recommendations 1 to 12. Ensure it includes initiatives aimed at the whole population (such as local policy and regulatory initiatives) which complement existing programmes aimed at individuals at high risk of CVD. Ensure it is sustainable for a minimum of 5 years. Ensure appropriate time and resources are allocated for all stages, including planning and evaluation. ## Recommendation 14 Regional CVD prevention programmes – preparation Gain a good understanding of the prevalence and incidence of CVD in the community. Find out about any previous CVD prevention initiatives that have been run (including any positive or negative experiences). Consider how existing policies relating to food, tobacco control and physical activity, including those developed by the local authority, may impact on the prevalence of CVD locally. Gauge the community's level of knowledge of, and beliefs about, CVD risk factors. This includes beliefs that smoking is the only solace in life for people with little money, or that only people who have a lot of money eat salad. Gauge how confident people in the community are that they can change their behaviour to reduce the risks of CVD. (See 'Behaviour change' .) Identify groups of the population who are disproportionately affected by CVD and develop strategies with them to address their needs. Take into account the community's exposure to risk factors (factors currently facing adults and those emerging for children and younger people). ## Recommendation 15 Regional CVD prevention programmes – programme development Develop a population-based approach. Ensure a 'programme theory' is developed and used to underpin the programme. This should cover the reasons why particular actions are expected to have particular outcomes. Ensure the programme helps address local area agreement targets and acts as a local incentive for world class commissioning in the NHS. Also ensure it tackles health inequalities. Link the programme with existing strategies for targeting people at particularly high risk of CVD and take account of ongoing, accredited screening activities by GPs and other healthcare professionals. This includes the NHS Health Checks programme. Work closely with regional and local authorities and other organisations to promote policies which are likely to encourage healthier eating, tobacco control and increased physical activity. Policies may cover spatial planning, transport, food retailing and procurement. Organisations that may get involved could include statutory, public sector and civil society groups (examples of the latter are charities, clubs, self-help and community groups).When developing CVD programmes, take account of relevant recommendations made within the following NICE guidance: 'Brief interventions and referrals for smoking cessation' (NICE public health guidance 1) 'Four commonly used methods to increase physical activity' (NICE public health guidance 2) 'Workplace interventions to promote smoking cessation' (NICE public health guidance 5) 'Behaviour change' (NICE public health guidance 6) 'Physical activity and the environment' (NICE public health guidance 8) 'Community engagement' (NICE public health guidance 9) 'Smoking cessation services' (NICE public health guidance 10) 'Maternal and child nutrition' (NICE public health guidance 11) 'Promoting physical activity in the workplace' (NICE public health guidance 13) 'Identifying and supporting people most at risk of dying prematurely' (NICE public health guidance 15) 'Physical activity and children' (NICE public health guidance 17) 'Obesity' (NICE clinical guideline 43). Only develop, plan and implement a strategic, integrated media campaign as part of a wider package of interventions to address CVD risk factors. Media campaigns should be based on an acknowledged theoretical framework. ## Recommendation 16 Regional CVD prevention programmes – resources Ensure the programme lasts a minimum of 5 years (while subject to annual evaluation reports) to maximise its potential impact. Produce a long-term plan – and gain political commitment – for funding to ensure the programme has adequate resources and is sustainable beyond the end of the research or evaluation period. Ensure the programme is adequately staffed. Avoid adding CVD prevention to the workload of existing staff without relieving them of other tasks. Ensure volunteers are an additional (rather than a core) resource and that their training and support is adequately resourced. Ensure steps are taken to retain staff. Where staff are recruited from the local community ensure, as far as possible, that they reflect the local culture and ethnic mix. Ensure there are effective links with other existing and relevant community initiatives. ## Recommendation 17 Regional CVD prevention programmes – leadership Act as leader and governor of CVD prevention. Identify and articulate local community needs and aspirations and how these may impact on the community's risk of CVD. Reconcile these needs and aspirations or arbitrate on them to help prevent CVD. Identify senior figures within PCTs and local authorities as champions for CVD prevention. Identify people to lead the CVD programme, including members of the local community. Identify in advance – and provide for – the training and other needs of these potential leaders. Develop systems within local strategic partnerships and other subregional or regional partnerships for agreeing shared priorities with other organisations involved in CVD prevention. Ensure senior staff are involved, as appropriate. ## Recommendation 18 Regional CVD prevention programmes – evaluation Establish baseline measures before the CVD programme begins. These should include lifestyle and other factors that influence cardiovascular risk, as well as figures on CVD prevalence and mortality. The establishment of such measures should be budgeted for as part of the programme. Ensure evaluation is built in (in line with 'Behaviour change' .). It should include the policies and activities of partner organisations which are likely to influence CVD prevalence. Ensure appropriate methods (using multiple approaches and measures) are used to evaluate the programme's processes, outcomes and measures or indicators. Evaluation should include determining how acceptable the programme is to the local community or the groups targeted. Ensure the results of evaluation are freely available and shared with partner organisations. Use the findings to inform future activities. ## Recommendation 19 Children and young people Children and young people aged under 16 years. Parents and carers of children and young people under the age of 16. Local authorities (providers of cultural and leisure services). Schools (governors and teachers). Catering staff. Nursery nurses and workers in pre-school day care settings such as nurseries. Managers of children's centres. Help children and young people to have a healthy diet and lifestyle. This includes helping them to develop positive, life-long habits in relation to food. This can be achieved by ensuring the messages conveyed about food, the food and drink available – and where it is consumed – is conducive to a healthy diet. (For more details see 'Maternal and child nutrition' and 'Physical activity and children' .) When public money is used to procure food and drink in venues outside the direct control of the public sector, ensure those venues provide a range of affordable healthier options (including from vending machines). Ideally, the healthier options should be cheaper than the less healthy alternatives. For instance, carbonated or sweetened drinks should not be the only options and fruit and water should be available at an affordable price. (Examples of when public money is used in this way include school visits to museums, sports centres, cinemas and fun parks.) Encourage venues frequented by children and young people and supported by public money to resist sponsorship or product placement from companies associated with foods high in fat, sugar or salt. (This includes fun parks and museums.) Organisations in the public sector should avoid sponsorship from companies associated with foods high in fat, sugar or salt. ## Recommendation 20 Public sector food provision Anyone who eats food provided by public sector organisations. Education authorities. Government departments and agencies. Local authorities. NHS organisations. Prison services. The armed forces. The emergency services. Ensure all food procured by, and provided for, people working in the public sector and all food provided for people who use public services: is low in salt and saturated fats is nutritionally balanced and varied, in line with recommendations made in the 'eatwell plate' does not contain industrially produced trans fatty acids (IPTFAs). ## Recommendation 21 Physical activity Everyone. Local authorities. PCTs. Ensure the physical environment encourages people to be physically active (see 'Physical activity and the environment' ). Implement changes where necessary. This includes prioritising the needs of pedestrians and cyclists over motorists when developing or redeveloping highways. It also includes developing and implementing public sector workplace travel plans that incorporate physical activity (see 'Promoting physical activity in the workplace' ). Encourage and support employers in other sectors to do the same. Ensure the need for children and young people to be physically active is addressed (see 'Promoting physical activity for children and young people' ). This includes providing adequate play spaces and opportunities for formal and informal physical activity. Audit bye-laws and amend those that prohibit physical activity in public spaces (such as those that prohibit ball games). Consider offering free swimming to parents and carers who accompany children aged under 5 years to swimming facilities. Apportion part of the local transport plan (LTP) block allocation to promote walking, cycling and other forms of travel that involve physical activity. The proportion allocated should be in line with growth targets for the use of these modes of transport. Ensure cycle tracks created under the Cycle Tracks Act 1984 are part of the definitive map (the legal record of public rights of way). Align all 'planning gain' agreements with the promotion of heart health to ensure there is funding to support physically active travel. (For example, Section 106 agreements are sometimes used to bring development in line with sustainable development objectives.) ## Recommendation 22 Health impact assessments of regional and local plans and policies Everyone. Local policy makers. PCTs. Regional and local government. Use a variety of methods to assess the potential impact (positive and negative) that all local and regional policies and plans may have on rates of CVD and related chronic diseases. Take account of any potential impact on health inequalities. Identify those policies and plans that are likely to have a significant impact on CVD rates. This can be achieved by using screening questions that cover the social, economic and environmental determinants of CVD. Monitor the outcomes following an assessment and use this to follow up and amend plans. Identify where expertise is required to carry out assessments and where this is available locally. Identify the training and support needs of staff involved in carrying out assessments and provide the necessary resources. ## Recommendation 23 Take-aways and other food outlets Everyone but particularly those who frequently use these food outlets. ## Who should take action? Environmental health officers. Local government planning departments. Public health nutritionists. Trading standards officers. Use bye-laws to regulate the opening hours of take-aways and other food outlets, particularly those near schools that specialise in foods high in fat, salt or sugar. Use existing powers to set limits for the number of take-aways and other food outlets in a given area. Directives should specify the distance from schools and the maximum number that can be located in certain areas. Help owners and managers of take-aways and other food outlets to improve the nutritional quality of the food they provide. This could include monitoring the type of food for sale and advice on content and preparation techniques. ## Recommendation 24 Nutrition training People eating snacks and meals provided by public sector services. Caterers. Chartered Institute of Environmental Health (CIEH). Local authorities. Providers of hygiene training. The food and farming network (Feast). Ensure the links between nutrition and health are an integral part of training for catering managers. In particular, they should be made aware of the adverse effect that frying practices and the use of salt, industrial trans fats and saturated fats can have on health. Ensure they are aware of the healthy alternatives to frying and to using salt and sugar excessively, based on the 'eatwell plate'. The PDG considers that all the recommended measures are cost effective. For the research recommendations and gaps in research, see section 5 and appendix D respectively. Blas E, Gilson L, Kelly MP et al. (2008) Addressing social determinants of health inequities: what can the state and civil society do? The Lancet 372: 1684–9. Kelly MP, Stewart E, Morgan A et al. (2009a) A conceptual framework for public health: NICE's emerging approach. Public Health 123: e14–20. Marmot M (2010) Fair society, healthy lives: strategic review of health inequalities in England post 2010. Rose G (2008) Rose's strategy of preventive medicine. Commentary by Khaw KT, Marmot M. Oxford: Oxford University Press. American Heart Association (2005) Dietary recommendations for children and adolescents. A guide for practitioners: consensus statement from the American Heart Association. Circulation 112: 2061–75. Office of Communications (2006) Annex 7 – impact assessment. Annex to consultation on television advertising of food and drink to children. Swinburn B, Sacks G, Lobstein T et al. (2007) The 'Sydney principles' for reducing the commercial promotion of foods and beverages to children. Public Health Nutrition 11 (9): 881–6. Kelly B, Hughes C, Chapman K et al. (2009b) Consumer testing of the acceptability and effectiveness of front-of-pack food labelling systems for the Australian grocery market. Health Promotion International 24 (2): 120–9. Lloyd Williams F, Mwatsama M, Birt C et al. (2008) Estimating the cardiovascular mortality burden attributable to the European Common Agricultural Policy on dietary saturated fats. Geneva: World Health Organization. Lock K, Pomerleau J (2005) Fruit and vegetable policy in the European Union: its effect on cardiovascular disease. Brussels: European Health Network. The scope of what are regarded as 'European public goods' in the EU is broader than the strict definition of a 'public good' used by some economists. Pawson R (2001) Evidence based policy: 2. The promise of 'realist synthesis'. HM Government; Communities and Local Government (2008) Creating strong, safe and prosperous communities. Statutory guidance. London: Community and Local Government Publications.# Public health need and practice Cardiovascular disease (CVD) is generally due to reduced blood flow to the heart, brain or body caused by atheroma or thrombosis. It is increasingly common after the age of 60, but rare below the age of 30. Plaques (plates) of fatty atheroma build up in different arteries during adult life. These can eventually cause narrowing of the arteries, or trigger a local thrombosis (blood clot) which completely blocks the blood flow. The main types of CVD are: coronary heart disease (CHD), stroke and peripheral arterial disease (PVD) (British Heart Foundation 2009a). Globally, CVD is the leading cause of death (World Health Organization 2007). It is also associated with a large burden of preventable illnesses. # CVD in England and the UK In England in 2007, CVD led to nearly 159,000 deaths (accounting for nearly 34% of all deaths in England). This includes 74,185 deaths from coronary heart disease (CHD) and 43,539 from stroke (British Heart Foundation 2009b). Most premature deaths from CVD – that is, among people aged less than 75 – are preventable. In 2006, CVD accounted for around 30% of premature deaths among men and 21% among women, accounting for just over 40,000 premature deaths in that year. The purpose of preventing premature death from CVD is to enable high quality life for as long as possible. An estimated 2.8 million men and 2.8 million women in the UK are living with CVD. The British Heart Foundation estimates that around 111,000 people have a stroke for the first time every year. (Its report notes that national stroke audit data is more conservative, putting the estimated 'first time' strokes a year at approximately 72,000 (British Heart Foundation 2009c). In addition, there are an estimated 96,000 new cases of angina in the UK each year (52,000 among men and about 43,000 among women) and around 113,000 heart attacks per year (67,000 among men and 46,000 among women) (British Heart Foundation 2009c). New cases of heart failure total around 68,000 a year (about 38,000 among men and 30,000 among women). Overall, CVD costs the UK approximately £30 billion annually (Luengo-Fernandez et al. 2006). Despite recent improvements, death rates in the UK from CVD are relatively high compared with other developed countries (only Ireland and Finland have higher rates). There is also considerable variation within the UK itself – geographically, ethnically and socially. For instance, premature death rates from CVD are up to six times higher among lower socioeconomic groups than among more affluent groups (O'Flaherty et al. 2009). In addition, death rates from CVD are approximately 50% higher than average among South Asian groups (Allender et al. 2007). The reduction in CVD-related risks among younger men (and perhaps women) over previous years seems to have stalled in England from around 2003. This is also the case in a number of other countries including Scotland (O'Flaherty et al. 2009), Australia (Wilson and Siskind 1995) and the United States (Ford and Capewell 2007). The higher incidence of CVD is a major reason why people living in areas with the worst health and deprivation indicators have a lower life expectancy compared with those living elsewhere in England. For males, it accounts for 35% of this gap in life expectancy (of that, approximately 25% is due to CHD and 10% due to other forms of CVD). Among females, it accounts for 30% of the gap (DH 2008a). # Risk factors for CVD Lifetime risk of CVD is strongly influenced by diet and physical activity levels since childhood (National Heart Forum 2003). The risk among adults is determined by a variety of 'upstream' factors (such as food production and availability, access to a safe environment that encourages physical activity and access to education). It is also influenced by 'downstream' behavioural issues (such as diet and smoking). In more than 90% of cases, the risk of a first heart attack is related to nine potentially modifiable risk factors (Yusuf et al. 2004): smoking/tobacco use poor diet high blood cholesterol high blood pressure insufficient physical activity -verweight/obesity diabetes psychosocial stress (linked to people's ability to influence the potentially stressful environments in which they live) excess alcohol consumption. Other factors, such as maternal nutrition and air pollution may also be linked to the disease (Allender et al. 2007). # How these risk factors cause many other illnesses Addressing diet, physical inactivity, smoking and excessive alcohol consumption to reduce CVD will also help reduce a wide range of other chronic conditions. This includes many of the other main causes of death and illness in England such as type 2 diabetes and many common cancers (see also 3.73). Type 2 diabetes, which affects over two million people in the UK, is associated with being overweight and sedentary. (It also accounts for an estimated 5% of UK healthcare expenditure.) Between 8% and 42% of certain cancers (endometrial, breast, and colon) are attributable to excess body fat. The report 'Food matters' (Cabinet Office 2008) estimates that a total of around 70,000 lives would be saved each year in the UK if people's diet matched the nutritional guidelines on fruit and vegetable consumption and saturated fat, added sugar and salt intake. # Tackling the risk factors Reducing the risks, for example, by quitting tobacco or improving the diet (so reducing cholesterol or blood pressure levels) can rapidly reduce the likelihood of developing CVD. Actions which impact on the whole population most effectively reduce these risk factors (Kelly et al. 2009a). Some population-based prevention programmes have been accompanied by a substantial reduction in the rate of CVD deaths. However, the degree to which these are attributable to the programme is contested. This is due to a number of reasons including: It is difficult to design studies which evaluate entire cities, regions or countries or are of sufficient duration. Control sites can become 'contaminated' (that is, if the intervention affects people living in the control area). There may be unreasonable expectations about the speed of change. Behaviour change is often erratic or slow. Failure to address 'upstream' influences such as policy or manufacturing and commercial practices. The crucial importance of using policy to modify population-wide CVD risk factors has been recognised on an international, European and national level. For example, the World Health Organization's (WHO) first global treaty on health, the 'Framework convention on tobacco control' (2003) undertook to enact key tobacco control measures, such as tobacco tax increases, smokefree public places and tobacco advertising controls. Parties to the treaty included the UK. In 2004, WHO member states also agreed to a non-binding global strategy on diet, physical activity and health. In addition, since 1993 the European Union (EU) has legislated on issues such as advertising and the labelling of consumer products like food and tobacco. In 2009, the Cardio and Vascular Coalition published 'Destination 2020', the voluntary sector's plan for cardiac and vascular health in England (Cardio and Vascular Coalition 2009). # Government policy Government policy in many areas influences CVD. The 'Choosing health' white paper (DH 2004) set priorities for action on nutrition, physical activity, obesity and tobacco control. It was supported by delivery plans on food, physical activity and tobacco control, including the provision of NHS Stop Smoking Services. Since that time, a wide variety of policy documents have been published including: 'Active travel strategy' (Department for Transport 2010) 'A smokefree future: a comprehensive tobacco control strategy for England' (DH 2010) 'Be active be healthy. A plan for getting the nation moving' (DH 2009a) 'Commissioning framework for health and well-being' (DH 2007a) 'Delivering choosing health: making healthier choices easier' (DH 2005a) 'Food 2030' (Department for Environment, Food and Rural Affairs 2010) 'Health challenge England – next steps for choosing health' (DH 2006a) 'Health inequalities: progress and next steps' (DH 2008b) 'Healthy weight, healthy lives: a cross-government strategy for England' (DH 2008c) 'National stroke strategy' (DH 2007b) 'NHS 2010 – 2015: from good to great. Preventative, people-centred, productive' (DH 2009b) 'Our health, our care, our say' (DH 2006b) 'Putting prevention first – vascular checks: risk assessment and management' (DH 2008d) 'Tackling health inequalities – a programme for action' (DH 2003) 'Tackling health inequalities: what works' (DH 2005b) 'Tackling health inequalities: 2007 status report on the programme for action' (DH 2008a) 'The NHS in England: the operating framework for 2006/7' (DH 2006c) 'The NHS in England: the operating framework for 2008/9' (DH 2007c) 'Wanless report: securing good health for the whole population' (Wanless 2004).# Considerations The Programme Development Group (PDG) took account of a number of factors and issues when developing the recommendations. # Introduction Evidence was presented on how to prevent or reduce the combination of modifiable risk factors that can cause cardiovascular disease (CVD). The PDG also considered evidence and expert testimony on separate key risk factors. The reviews, together with the expert testimonies, are listed in appendix A. Relevant existing NICE guidance was also summarised. The key CVD risk factors that can be modified are: smoking, a poor diet, obesity, lack of physical activity and high alcohol consumption (Emberson et al. 2004; Yusuf et al. 2004). CVD risk factors tend to 'cluster together'. Thus people who smoke are more likely to have a poor diet and exercise less. This 'clustering' also tends to have a disproportionate effect on people who are disadvantaged, further accentuating health inequalities. The PDG noted that approximately 100,000 people die from smoking-related diseases in the UK every year. Tobacco accounts for approximately 29% of deaths from cancer, 13% of cardiovascular deaths and 30% of deaths from respiratory disease (Action on Smoking and Health 2008). It also acknowledged that smoking accounts for over half the disproportionate burden of illnesses experienced by disadvantaged groups. The PDG strongly endorsed the national tobacco control measures set out in 'Beyond smoking kills' (Action on Smoking and Health 2008). Approaches to helping people quit smoking, or to stop using other forms of tobacco, are covered by recommendations made in other NICE guidance. This includes: 'Smoking cessation services' (NICE public health guidance 10); 'Workplace interventions to promote smoking cessation' (NICE public health guidance 5) and 'Brief interventions and referral for smoking cessation' (NICE public health guidance 1). As a result, tobacco issues are not covered in this guidance. The PDG noted that nicotine replacement therapy (NRT) can help to reduce CVD among people who are addicted to nicotine. It fully endorses the Tobacco Advisory Group's recommendations on the regulation and marketing of NRT (Royal College of Physicians 2007). (The report advocates making NRT more acceptable and accessible to people who smoke and who find it impossible to quit.) Taking a population-based approach, the PDG focused on the major contributors to CVD risk found in the typical UK diet. These include: a high intake of saturated and industrially-produced trans fatty acids and salt. It acknowledged and supports the work of the Food Standards Agency and other organisations (such as the Advertising Standards Authority) in helping to reduce general consumption of these products. However, it believes further action is essential to achieve greater reductions in premature death and disease and to reduce health inequalities. A consistent message on lifestyle risk factors related to CVD is important. The recommendations made in this guidance are not intended to replace existing advice to the public on diet. Rather, they will support the next stage of policy development to tackle the substantial burden of ill health from CVD and other chronic diseases (see also section 2). This includes the development of effective local and regional, population-level programmes to prevent CVD, diabetes, obesity, kidney disease and some common cancers. In response to stakeholder feedback, the PDG considered the evidence on interventions targeting specific CVD risk factors. For example, in relation to salt, saturated fats and trans fatty acids. Policies to promote physical activity were considered. However, physical activity, smoking and obesity have all been covered by other NICE guidance. In addition, as policies to increase the consumption of fresh fruit and vegetables are already agreed and widely implemented, the PDG did not consider them in detail. (See section 7.) # Population versus individual approach CVD risk factors can be reduced in a number of ways. Two different (and frequently, complementary) approaches are often described as 'individual-' and 'population-based'. The former involves interventions which tend to give people direct encouragement to change their behaviour. It may involve providing information about the health risks of their current behaviour, advice (such as to be more active) or prescribing a treatment. Alternatively, it may involve altering the way the NHS and other organisations deliver prevention or healthcare services. Population-based interventions, on the other hand, aim to change the risks from the social, economic, material and environmental factors that affect an entire population. This can be achieved through regulation, legislation, subsidy and taxation or rearranging the physical layout of communities. The PDG focused on population-based approaches. The NHS Health Check programme, which was being rolled out as this guidance was published, is aimed at all those aged 40–74. It will ensure everyone in this age range is assessed to determine their risk of heart disease, stroke, kidney disease and diabetes. It will also help them to reduce or manage that risk by providing individually tailored advice. This guidance complements the NHS Health Check programme by focusing on the CVD risk factors for an entire population. It will benefit the NHS, local authorities and industry, as well as individuals, by substantially reducing the number of people who need statin or anti-hypertensive medication. It will also enable services to focus more on those who still need treatment. The PDG recognised that smoking cessation and other services that focus on helping individuals to change their behaviour have an important role to play in preventing CVD. Many of these services or approaches have been the focus of earlier NICE guidance (see section 7). Previously in the UK, interventions focused on individuals have tended to dominate CVD prevention activities and it is important to identify and treat those who are at higher risk. However, a much larger overall benefit could be achieved by making changes (albeit small ones) among any given population as a whole. As indicated by the Rose hypothesis, a small reduction in risk among a large number of people may prevent many more cases, rather than treating a small number at higher risk. A whole-population approach explicitly focuses on changing everyone's exposure to risk (Rose 2008). There is growing evidence in support of the Rose hypothesis (see point above). For instance, data were recently pooled from six general population cohort studies involving 109,954 European participants. These data were analysed to compare different CVD strategies. The analysis found that a 10%, population-wide reduction in blood cholesterol, blood pressure and smoking prevalence would save approximately 9120 lives per million population over 10 years. In contrast, treating 40% of high-risk individuals with a 'polypill' (containing a statin, three half-dose anti-hypertensives and aspirin) would save about 3720 lives per million, even assuming complete, long-term adherence (Cooney et al. 2009). It should be noted that, as indicated above, population- and individual-based approaches are both important and can be complementary. They do not have to be considered as alternatives for CVD prevention. # Population-based approaches: health inequalities Both population- and individual-based approaches can influence health inequalities. However, population-based approaches may be more likely to reduce health inequalities. That is because there are many reasons why people who are disadvantaged might find it more difficult to change their behaviour than those who are affluent (Swann et al. 2009). As a result, some activities aimed at individuals may inadvertently increase health inequalities. 'Upstream', population-level interventions include: fiscal measures (such as taxation), national or regional policy and legislation (such as legislation on smokefree public places or the way food is produced); and environmental changes. They are not reliant on an individual's knowledge or ability to choose healthier options. Social and economic action can also change people's risk of CVD (in such cases, the health outcomes are side effects – albeit desirable). The recommendations in this guidance do not, in the main, rely on individual choice. Rather, they aim to improve social environments and thus ensure the healthy choice is the easy choice. The emphasis is on changing policies, systems, regulations, the physical environment and other 'upstream' factors. This approach is likely to reduce, rather than increase, health inequalities and is congruent with NICE's guidance on behaviour change (see section 7). # Population-level approaches: cost effectiveness The financial modelling for this guidance shows that considerable cost savings could be made. Using a number of conservative assumptions, it found that halving CVD events across England and Wales (a population of 50 million) would result in discounted savings in healthcare costs of approximately £14 billion per year. Reducing mean population cholesterol or blood pressure levels by 5% would result in discounted annual savings of approximately £0.7 billion and £0.9 billion respectively. Reducing population cardiovascular risk by even 1% would generate discounted savings of approximately £260 million per year. A 3 g reduction in mean daily salt intake by adults (to achieve a target of 6 g daily) would lead to around 14–20,000 fewer deaths from CVD annually (Strazzullo et al. 2009). Using conservative assumptions, this means approximately £350 million in healthcare costs would be saved. In addition, approximately 130,000 quality-adjusted life years (QALYs) would be gained. A mean reduction of 6 g per day would double the benefits: an annual saving of £700 million in healthcare costs and a gain of around 260,000 QALYs. A 3 g reduction in daily salt intake (a reasonably conservative estimate of what could be achieved) would reduce systolic blood pressure by approximately 2 mmHg. This would equate to a 2% decrease in the risk reduction model. Similarly, a reduction of IPTFA intake to approximately 0.7% of total fat energy might save approximately 571,000 life years – and some £2 billion. # Epidemiology The PDG noted that CVD death rates are no longer falling among young and middle aged people in the UK (for instance, they are no longer falling among those aged 35–54 in the most socially disadvantaged groups in Scotland), the USA and Australia. This reflects a combination of adverse risk factors including smoking, a poor diet and disadvantage (O'Flaherty et al. 2009). The prevalence of obesity and over weight continues to rise (National Heart Forum 2010). This, in turn, will lead to a rise in Type 2 diabetes which can increase the risk of CVD. The risk of CHD is particularly high among women with diabetes (Barrett-Connor et al. 1991). Epidemiological studies indicate that approximately 45–75% of the recent fall in CVD deaths in Westernised industrialised countries was the result of a reduction in the major risk factors. This includes a reduction in smoking prevalence and salt and saturated fat consumption. The decline in CVD deaths noted above began long before effective treatments were introduced. In Finland and Iceland, coronary heart disease mortality rates declined by 63% between 1982 and 1997. Seventy five per cent of this was attributed to a reduction in smoking, blood pressure and cholesterol levels (Aspelund et al. 2009; Laatikainen et al. 2005). Sweden also observed a large reduction in CVD-related mortality. This was attributed to dietary reductions in cholesterol and blood pressure. In contrast, blood pressure and cholesterol levels in the UK have, thus far, only fallen a modest amount (Unal et al. 2005). The fall in blood pressure and cholesterol levels seen in many Western populations are mainly attributable to lifestyle changes and changes in the wider determinants of health – rather than to medication. Changes to the wider determinants of health have often been as a consequence of public health policy. Preventive services are unlikely to tackle these wider determinants unless supported by national policies and systems (Capewell and O'Flaherty 2008). Data from 'natural experiments' in a whole population (where there were no randomised controlled trials to assess the results) provide compelling evidence of the links between CVD and diet. Rapid and large falls in CVD deaths have been observed in diverse populations including those living in Poland, Mauritius, Finland, Iceland and Norway. In Poland, a 26% decrease in coronary deaths followed a substantial reduction in the consumption of animal fats and increased consumption of vegetable oils and fruit after the break-up of the Soviet Union (Zatonski and Willett 2005). In Mauritius, CVD deaths fell following the introduction of legislation to make it mandatory to use polyunsaturated oils as a substitute for highly saturated cooking oils (Dowse et al. 1995). A substantial fall in CVD deaths also followed a reduction in saturated fat intake in Finland, Iceland, Norway and elsewhere (Zatonski and Willet 2005, Laatikainen et al. 2005.) Conversely, rapid rises in CVD mortality have been seen in China and elsewhere, principally due to the adoption of a Western diet rich in saturated fats (Critchley et al. 2004). The PDG discussed the nature and quality of evidence relevant to CVD prevention in whole populations. As indicated in consideration 3.71, this evidence is not drawn from randomised trials alone. The PDG felt it important to consider natural experiments and observational studies as well. The studies had to include a known cause–effect mechanism and an association which was both strong and consistent. # Primordial prevention The PDG noted the importance of taking action to prevent the elevation of CVD risk factors among children, by ensuring they have a healthy, balanced diet and are physically active. This supports the principle of 'primordial prevention'. In this context, this means ensuring the low cholesterol and blood pressure levels seen in normal childhood are maintained throughout life (Labarthe 1999). This is crucial to prevent risk factor 'tracking' whereby, for instance, children with obesity, elevated blood pressure or raised cholesterol are very likely to become adults with above-average risk-factor levels. There is also a strong association between early abuse and neglect and subsequent depression, drug abuse and ischemic heart disease. In addition, some evidence suggests that childhood maltreatment, including both abuse and neglect, influences depression and heart disease in ways that are gender-dependent. Maternal and fetal nutrition may have an important influence on whether or not people develop CVD later in life. Some evidence suggests that breastfeeding may protect against the development of risk factors for CVD. For example, it is associated with small reductions in blood pressure (Martin et al. 2005) and serum cholesterol. It is also associated with a reduced risk of being overweight (Harder et al. 2005) or having type 2 diabetes. However, the evidence on breastfeeding per se as a means of preventing CVD is weak (Owen et al. 2006; 2008). The PDG recognised the many benefits of breastfeeding (including the benefits of continuing to breastfeed beyond the recommended first 6 months after birth). However, it concluded that there was insufficient evidence to make a recommendation related to CVD prevention. Note: NICE's guidance on maternal and child nutrition (NICE public health guidance 11) is referred to in the recommendations. # Single risk factors The Strategy Unit report 'Food matters' (2008) concluded that some 70,000 premature UK deaths could be avoided with a healthier diet. More recently, the Food Standards Agency suggested that poor dietary health in the UK could contribute to up to 150,000 CVD deaths – and a further 155,000 cancer deaths – per year (Food Standards Agency 2009). Much of the observational evidence that links diet to CVD is based on individual nutrients. However, the PDG recognised that their impact should also be considered in the context of the whole diet. It recognised that a 'healthier' diet is likely to comprise a favourable balance of food and nutrients and a reduction in the intake of harmful elements. In a typical Western diet, the latter include substantial amounts of salt, saturated fat and trans fats (Hu 2008). A 'healthier' diet based on fruit, legumes, pulses, other vegetables, wholegrain foods, fish and poultry is consistently associated with lower levels of CVD risk factors (Fung et al. 2001; Lopez-Garcia et al. 2004) and lower CVD mortality (Heidemann et al. 2008; Osler et al. 2001). Vegetarian and 'Mediterranean' diets are also consistently associated with lower CVD mortality (Hu 2008; Mann et al. 2009). Interventions promoting these types of 'healthier' diet have been shown to be highly effective in reducing blood pressure, cholesterol and subsequently CVD (Appel et al. 1997; de Lorgeril et al. 1999). The PDG emphasised its support for a healthy diet, as advocated in the 'eatwell' plate (Food Standards Agency 2007). The PDG discussed whether it would be feasible for food labels to present calorie content in terms of the hours of physical activity required to use them up. There was no evidence to support this approach. However, there is evidence that presenting the total calorific content on food labels might help reduce intake (Ludwig and Brownell 2009). Salt intake is a major determinant of CVD in the UK, mainly due to its effect on blood pressure. On average, 70%–90% of people's intake comes from salt added during the manufacturing process; only 10–30% comes from adding it during cooking or at the table. Reducing the population's salt intake will, therefore, involve encouraging the food industry to reduce the salt used in processed foods – as well as encouraging people to reduce the salt they add themselves. The PDG believes the former will best be achieved by using a combination of voluntary and regulatory action. The UK population's per capita daily salt intake has fallen by 0.9 g in the last 5 years (a reduction of around 2% per year). This means people are consuming an average 8.6 g of salt per day. The reduction has mainly come about as a result of public awareness campaigns and a voluntary code of practice for industry, led by the Food Standards Agency. The voluntary agreement came into force in 2004 and was followed by progressive targets (in 2006 and 2009). The campaigns, which cost just £15 million, led to approximately 6000 fewer CVD deaths per year, saving the UK economy approximately £1.5 billion per annum. The PDG noted the new targets for 2010 and 2012. Recent evidence shows that it is feasible to reduce the salt content of foods even further and that this would lead to substantial health benefits (Appel and Anderson 2010). For example, a 10% reduction in the salt content of items like bread and soup is not detected by consumers and does not, therefore, affect consumer choice. This would reduce both strokes and cardiovascular events. A reduction in mean salt intake of 3 g per day for adults (to achieve a target of 6 g daily) would lead to around 14–20,000 fewer deaths from CVD annually (Strazzullo et al. 2009). Using conservative assumptions, this means approximately 130,000 quality-adjusted life years (QALYs) would be gained and around £350 million would be saved in healthcare costs. A reduction of 6 g per day would lead to twice the gain: some 260,000 QALYs and an annual saving of £700 million in healthcare costs. Many children in the UK may be consuming as much salt as adults (He et al. 2008). Indeed, single helpings of soup or 'meal deals' may contain as much as 3 g of salt. Currently, it is recommended that: children aged from 1 to 3 years should consume no more than 2 g salt a day (0.8 g sodium); from 4 to 6 years they should consume no more than 3 g salt a day (1.2 g sodium); and from 7 to 10 years a maximum of 5 g salt a day (2 g sodium) (Scientific Advisory Committee on Nutrition 2003). The PDG discussed the benefits of substituting mono-unsaturated or polyunsaturated fats for saturated fats (Hu 2008) and of reducing total fat consumption. Evidence suggests that reducing saturated fat intake from 14% to 7% of energy intake (to reach the levels seen in Japan) might prevent around 30,000 CVD deaths annually. Changes in CVD deaths are also addressed in consideration 3.27. The PDG discussed whether to recommend 'low' rather than 'full-fat' products as there is a risk that if saturated fat is removed to create a 'low-fat' product, it could still be used in another product, with no overall reduction in the population's fat consumption. In addition, the Group felt that there was a risk that some fat content would be replaced with high levels of sugar – so losing some of the benefit of reducing calorie intake. The PDG discussed the potential problems that might arise if low-fat milk was made cheaper than full-fat milk. In general, most of the population should aim for a low-fat diet. However, full-fat products are the 'healthier' choice for some groups. Children aged under 2, for instance, may need the additional calories and fat-soluble vitamins found in full-fat milk and the PDG noted that full-fat milk is recommended for this group when cow's milk is being used. The Group was concerned that increasing the relative price of full-fat milk (to make lower-fat milk a more attractive option) could place an added financial burden on disadvantaged groups. However, it also believed that this added burden could be addressed by the tax and benefits system. The PDG agreed with the 2009 World Health Organization (WHO) review of industrially-produced trans fatty acids (IPTFAs) – also known as partially hydrogenated vegetable oils (PHVOs). In line with the WHO review, the PDG concluded that IPTFAs are unnecessary and 'toxic' and should be eliminated from foodstuffs. The WHO review states that because IPTFAs are produced by partial hydrogenation they are not normally present naturally in foods and have no known health benefits. The review defined them as 'industrial additives'. It recommended that food services, restaurants, and food and cooking fat manufacturers should avoid their use (Uauy et al. 2009). A recent study commissioned by the European Parliament advocated that an EU-wide ban on IPTFAs should be considered. The PDG noted that IPTFAs have been successfully banned in Denmark and New York City. The WHO review of industrially-produced trans fatty acids noted that people who use partially hydrogenated vegetable oils (PHVOs) for cooking would have mean trans fatty acids intakes considerably higher than the national average. The same would be true for those who eat a high proportion of industrially processed or 'fast food'. The review noted that '…replacing TFAs with vegetable oils high in polyunsaturated fatty acids (PUFA) and monounsaturated fatty acids (MUFA) is the preferred option for health benefits… Eliminating use of TFA-containing PHVO should be considered as hazard removal, in line with risk management models used to address many other food safety issues.' The PDG concurred. Assuming a linear dose response, if less than 1% of food energy came from IPTFAs, between 4500 and nearly 7000 lives might be saved in England. The PDG commended the substantial efforts made by much of the UK-based food industry and the Food Standards Agency to remove IPTFAs from the UK food chain. It also noted the review of trans fats by the Scientific Advisory Committee on Nutrition (SACN). New concerns have now emerged, particularly in relation to imported products and fried food prepared in some settings. People from disadvantaged groups are likely consume more of these products which, in turn, could be an important contributory factor to health inequalities. Some products (this includes fried food from take-away venues) may contain substantial levels of IPTFAs. The PDG noted that some people may be consuming this sort of meal on a frequent basis. Hence, it considered that IPTFA consumption across different population groups is relevant – and that simply looking at average intake will not suffice. The Group discussed the links between sedentary behaviour and CVD – and the need to encourage people to be more physically active. However, evidence on how to address sedentary behaviour is not well developed and remains an area for further study. The PDG noted the importance of ensuring physical activity is enjoyable and can be incorporated into daily life. Effective interventions to encourage physical activity are possible both nationally and locally. For example, NICE has made recommendations on how to help people to be physically active in: 'Four commonly used methods to promote physical activity' (NICE public health guidance 2); 'Physical activity and the environment' (NICE public health guidance 8); 'Promoting physical activity in the workplace' (NICE public health guidance 13); and 'Promoting physical activity for children and young people' (NICE public health guidance 17). # Achieving change: national level Public, private, voluntary and community sector organisations all have a role to play in preventing CVD at national level. For example, measures to encourage commercial markets to be health promoting could be highly cost saving (Abelson 2003; Catford 2009; Trust for America's Health 2008; Wanless 2004). Such measures might include: improving the content of products (re-formulation); controls on the marketing of energy-dense, nutrient-poor foods, foods high in fat, salt or sugar and processed foods; and package labelling. Those preparing, producing and selling food have a particularly important role in improving the diet of the nation. Although such organisations must consider their commercial interests, the PDG considers it also reasonable to expect them to work with others to help prevent CVD. It takes this view in light of the diseases and deaths caused by CVD (and the consequent costs to the exchequer and society). The PDG recognised that many responsible commercial organisations are already taking positive action. Many organisations, for instance, have taken praiseworthy action to reduce the salt or saturated fat content of food, or to remove industrially-produced trans fats from their processes (Brownell and Warner 2009).. The PDG believes that more could be done to assist those sectors which have, for a variety of reasons, been unable or unwilling to take positive action. Such action would not only benefit the population, but would also help provide a 'level playing field', where all businesses work to the same standard. Brownell and Warner (2009) state: 'there is an opportunity if the industry chooses to seize it – an opportunity to talk about the moral high ground and to occupy it'. Advertising and other marketing activities have an important influence on consumption patterns. They encourage people to change brands and they also encourage overall increases in consumption of related brands. The PDG noted the work of the Advertising Standards Authority and others to develop the existing overarching regulatory system that controls food advertising aimed at children. Furthermore, the Group noted and praised the important work involved in developing the current UK advertising regulations. The Ofcom/Food Standards Agency restrictions on TV advertisements for foods high in salt, fat or sugar aimed at children are a good example of these regulations being put into practice. However, the PDG felt that children are particularly vulnerable and need further protection from commercial pressures. The 'Sydney principles' (developed by the International Obesity Taskforce Working Group in Sydney, Australia ) provide for the type of protection that it believes is still needed in the UK. The principles state that any action to reduce marketing to children should: support their rights; afford them substantial protection; be statutory in nature; take a wide definition of commercial promotion; guarantee commercial-free childhood settings; include cross-border media; and be evaluated, monitored and enforced. In other words, the PDG considers that a comprehensive model which includes marketing, advertising, promotion and product placement would provide the necessary protection. Advertising restrictions are gaining support. In 2007, WHO called for recommendations to restrict food marketing to children. Examples of jurisdictions that have successfully introduced such restrictions now include Norway, Sweden, Belgium, Greece, Romania and Quebec. National policy has an important role in changing the risk factors faced by a population (both direct, indirect and unintentional). However, the PDG recognised that developing and implementing such policy is a highly complex process: it is not linear and rarely moves simply from design to implementation. In addition, the Group acknowledged that evidence alone is rarely sufficient to bring about policy change. The way research evidence influences the policy process and gets translated into action can be explained by a model such as Kingdon's (1995) 'policy windows'. This suggests that 'windows' open (and close) by the coupling (or de-coupling) of three 'streams': problems, policies and politics. It can be applied nationally and locally (Exworthy et al. 2002). Other policy models also provide a potentially valuable insight into this complex, non-linear process. Whichever model is applied, however, all parties concerned need to acknowledge that the problem is important. In addition, it has to be possible to devise policies to remedy it – and there has to be a political willingness to act. Examples from other countries of where policy has been successfully used to reduce CVD are particularly valuable in showing what could be achieved in the UK. This guidance has made the case unequivocally that CVD is a major and, most significantly, a preventable problem. It has also identified policy options which would be effective at the population level. Nationally, the campaigning activities of charities such as the British Heart Foundation, the National Heart Forum and others focused on chronic diseases are particularly influential. Voluntary action may be effective. However, if the pace of change is insufficient mandatory measures may be needed. The success of legislation banning tobacco advertising and smoking in public places followed unsuccessful voluntary agreements with industry. This also demonstrates the effectiveness of national government action to improve the public's health. # Achieving change: the regional, community and private sectors Regional government offices and strategic health authorities could make an important contribution to CVD prevention. For example, they could negotiate to maximise the number of local area agreements (LAAs) that include 'stretch' targets related to CVD. They could also ensure all PCT 'world class commissioning' strategies for healthcare adequately address CVD prevention at a population and individual level. This involves having long-term strategies for sustainable change that avoid an over-dependence on medical solutions. There is also scope for effective action by public sector bodies at a sub-regional level. This was the case in Merseyside where, prior to the national ban on smoking in public places, a private members bill supporting local smoking restrictions had been developed in case national legislation was delayed. Local authorities and PCTs, working with the private and 'the third sector' in local strategic partnerships (LSPs), have demonstrated their commitment to CVD prevention. (The third sector includes voluntary and community groups, social enterprises, charities, cooperatives and mutual organisations.) For example, many have established health and wellbeing partnerships. In addition, 5 of the 15 most popular improvement targets in LSP local area agreements relate directly or indirectly to CVD prevention. Fifty-one LSPs have also selected national indicator (NI) 121 (mortality rate from all circulatory diseases for those aged under 75) as an indicator for the current round of local area agreements, which runs to 2011. Only 5 (6.7%) of the 74 green flags awarded to the 152 LSPs in England as part of their first comprehensive area assessment related to public health (green flags represent exceptional performance or outstanding improvement); 19 (30.6%) of the 62 red flags awarded related to public health. Of these, 15 (24.2%) related directly or indirectly to CVD prevention. (Red flags indicate the need to improve outcomes.) The first comprehensive area assessment reports were published in December 2009. Local advocacy by 'third sector' groups and organisations, including the voluntary sector, is an important part of CVD prevention activities. For example, it could have an impact on planning applications for fast-food outlets. Addressing the needs of disadvantaged groups involves working beyond geographical boundaries with different communities. The leaders of some communities may be able to deliver CVD prevention programmes effectively. However, it should not be assumed that all community leaders will be able or willing to participate – or that it would be appropriate. # Evidence Many studies considered in the reviews of effectiveness for this guidance were carried out some years ago (that is, studies reporting on regional, population-level programmes).The majority were published before 2000, with a substantial number published before 1990. This reflects, in part, the decision to include studies such as the North Karelia and HeartBeat Wales CVD population programmes which took place in the 1970s and 1980s. The age of the studies means a number of factors have to be taken into account when considering effectiveness. In particular: The risk factor levels for CVD are likely to have changed. For instance, intake of salt and saturated fat and the prevalence of smoking may have fallen, while a sedentary lifestyle and rates of obesity may have increased. The political and cultural environments which potentially influence the effectiveness of interventions may have changed substantially. A number of issues have to be taken into account when considering evidence of the effectiveness of population-level interventions: Changes may have come about inadvertently, for instance, as a result of a change in agriculture practice following economic developments. Any evaluation of such changes is likely to have been carried out after the event, using proxy data. It is often difficult to find a suitable control population where conditions are relatively similar to those in the intervention group. Where a control group is used, there is often contamination between the two groups which can lead to an underestimation of any beneficial effects. It is ethically wrong – and practically impossible – to randomly allocate country-wide populations to controlled trials. The best evidence available has to be gleaned from other research designs – in particular, natural experiments, epidemiological models and cost effectiveness and cost–benefit analyses. The potential effect of any intervention may change according to the initial level of risk. For instance, it may be easier to reduce salt consumption among a population with a high intake than among a population where intakes of salt are lower. However, epidemiological modelling suggests that substantial reductions in CVD rates can be achieved by reducing the major risk factors as much as possible. This is the case even in countries where CVD mortality rates are already relatively low, such as Italy (Palmieri et al. 2009). The economic modelling used for this guidance was based on conservative assumptions. Nevertheless, it suggested that the recommended population-based approaches are likely to be consistently cost saving (see considerations 3.33 and 3.45 and appendix C). # Interpreting the evidence The PDG recognised that empirical data alone, even from the best conducted investigation, seldom provides a sufficient or complete basis for making recommendations. Rather, it requires interpretation and analysis. Therefore, the PDG developed its recommendations using the best available empirical data and inductive and deductive reasoning, using prior knowledge and understanding and existing models and theories. The development of policy to reduce mortality and morbidity from CVD flow from these inductive and deductive interpretations. The PDG acknowledged that the traditional hierarchy of evidence does not resolve all the problems associated with empirical data. For example, while it explicates the degree of bias attributable to poor internal validity, it does not answer it completely. Nor does it deal with external validity, that is, the degree to which findings are transferable to other experimental settings or to practice. The PDG therefore, took a broad approach to the evidence available to it. (For further details, see chapters 3 and 7 of 'Methods for development of NICE public health guidance '.) # Other issues Many of the risk factors that the PDG considered are also associated with other health-related conditions including some common cancers, chronic respiratory disease, obesity, diabetes, kidney disease and mental wellbeing. The strategies discussed in this guidance are likely to help prevent some of these other health conditions. (Certainly, they are not likely to increase the risk of any common chronic diseases.) However, it was not possible to consider each of these other health conditions in detail. Daily consumption of products containing plant sterols and stanols may reduce blood cholesterol by about 10% – and so may reduce CVD mortality substantially. However, it was not clear how a recommendation on their use might impact on inequalities in health. The PDG believes this issue deserves further attention. Agricultural and transport policy and practice (and associated issues) has a powerful impact on people's diet and physical activity levels. It also has an impact on climate change and sustainable development (which, in turn, can affect health). An analysis of transport patterns in London and how they could be changed indicates the extent of this synergy (Woodcock et al. 2009). One scenario described a 'sustainable transport future' featuring more physically active travel and low-emission vehicles to cut CO2 emissions by three-fifths. The report points out that physically active travel could bring substantial benefits: the incidence of heart disease and stroke could fall by 10–20%, with reductions in breast cancer (12–13%), dementia (8%) and depression (5%). Reductions in air pollution would bring additional health benefits. Agriculture and food production account for 10–12% of greenhouse gas emissions (Friel et al. 2009). Livestock farming is responsible for four-fifths of these emissions (including methane). A 30% fall in adult consumption of saturated fat from animal sources (and an associated fall in livestock-related greenhouse gas emissions) would reduce heart disease by around 15% in the UK. If additional, positive effects are taken into account (such as a reduction in the prevalence of obesity and diet-related cancers) the health gains might been even more substantial. Monitoring is crucial. The PDG commended the regular Food Standards Agency/Department of Health-sponsored surveys. These include the 'National diet and nutrition survey' (NDNS) and the 'Low income diet and nutrition survey' (LIDNS).# Recommendations for research The Programme Development Group (PDG) recommends that the following research questions should be addressed. It notes that 'effectiveness' in this context relates not only to the size of the effect, but also to cost effectiveness rapidity and duration of effect. It also takes into account any harmful/negative side effects. What has been the impact of marketing bans on foods high in fat, sugar or salt in Norway, Sweden, Romania and Quebec? What lessons can the UK learn? How do inequalities contribute to: the consumption of trans fats, poly-unsaturated and mono-unsaturated fats, fresh fruit and vegetables and stanols? variations in physical activity levels among different population groups? CVD prevention aimed at individuals tends to widen health inequalities. Is there any effective way to ameliorate this? Conversely, is there any further empirical evidence that population-wide policy interventions or CVD preventive strategies narrow the inequalities gap? What impact would food taxes and subsidies, particularly in relation to salt, saturated fats and fruit and vegetable consumption, have on CVD risk and health inequalities? Could 'natural' experiments aid understanding of the impact that 'upstream' factors such as the social, economic and physical environment have on the incidence and rates of cardiovascular disease (CVD)? How could CVD modelling be developed in the UK, particularly to examine health inequalities? What effect would a regular daily intake of 2.5 g of stanols or sterols have on the incidence of cardiac and stroke events? How can we best evaluate stanols in terms of their acceptability, affordability, effectiveness, cost-effectiveness and impact on health inequalities? More detail on the gaps in the evidence identified during development of this guidance is provided in appendix D.# Updating the recommendations This guidance will be reviewed at 3 and 5 years after publication to determine whether all or part of it should be updated. Information on the progress of any update will be posted on our website.# Related NICE guidance Alcohol-use disorders: preventing harmful drinking. NICE public health guidance 24 (2010). Promoting physical activity for children and young people. NICE public health guidance 17 (2009). Cardiovascular risk assessment and the modification of blood lipids for the primary and secondary prevention of cardiovascular disease. NICE clinical guideline 67 (2008). Identifying and supporting people most at risk of dying prematurely. NICE public health guidance 15 (2008). Preventing the uptake of smoking by children and young people. NICE public health guidance 14 (2008). Promoting physical activity in the workplace. NICE public health guidance 13 (2008). Maternal and child nutrition. NICE public health guidance 11 (2008). Smoking cessation services. NICE public health guidance 10 (2008). Community engagement. NICE public health guidance 9 (2008). Physical activity and the environment. NICE public health guidance 8 (2008). Behaviour change. NICE public health guidance 6 (2007). Workplace interventions to promote smoking cessation. NICE public health guidance 5 (2007). Four commonly used methods to increase physical activity. NICE public health guidance 2 (2006). Brief interventions and referral for smoking cessation in primary care and other settings. NICE public health guidance 1 (2006). Obesity: the prevention, identification, assessment and management of overweight and obesity in adults and children. NICE clinical guideline 43 (2006). Hypertension: management of hypertension in adults in primary care. 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(2004) Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the INTERHEART study): case-control study. The Lancet 364: 937–52 Zatonski WA, Willett W (2005) Changes in dietary fat and declining coronary heart disease in Poland: population based study. BMJ 331: 187–9# Appendix B: Summary of the methods used to develop this guidance # Introduction The reviews, expert reports and economic analysis include full details of the methods used to select the evidence (including search strategies), assess its quality and summarise it. The minutes of the PDG meetings provide further detail about the Group's interpretation of the evidence and development of the recommendations. All supporting documents are listed in appendix E and are available online. # Guidance development The stages involved in developing public health programme guidance are outlined in the box below. . Draft scope released for consultation . Stakeholder meeting about the draft scope . Stakeholder comments used to revise the scope . Final scope and responses to comments published on website . Evidence reviews, economic modelling and expert testimony undertaken and submitted to PDG . PDG produces draft recommendations . Draft guidance (and evidence) released for consultation and for field testing . PDG amends recommendations . Final guidance published on website . Responses to comments published on website # Key questions The key questions were established as part of the scope. They formed the starting point for the reviews of evidence and were used by the PDG to help develop the recommendations. The overarching questions were: Which multiple risk-factor interventions are effective and cost effective in preventing the onset of cardiovascular disease (CVD) within a given population (primary prevention)? How does effectiveness and cost effectiveness vary between different population groups? The subsidiary question was: What barriers and facilitators influence the effectiveness of multiple risk-factor programmes aimed at reducing CVD (or the risk factors associated with CVD) among a given population (including subgroups experiencing health inequalities, where the data allows)? These questions were made more specific for each review (see reviews for further details). Single risk factors were considered using expert testimony. See appendix C for details. # Reviewing the evidence Three reviews of effectiveness (reviews 1,2 and 3), one qualitative review (review 4), one primary study of barriers and facilitators (review 5) and one review of cost effectiveness (review 6) were conducted. ## Identifying the evidence The following databases were searched for randomised controlled trials (RCTs); controlled before-and-after trials; cohort studies; case–control studies; before-and-after studies; and interrupted time series (from 1970 onwards): ASSIA (Applied Social Science Index and Abstracts) CINAHL (Cumulative Index of Nursing and Allied Health Literature) Cochrane Database of Systematic Reviews (CDSR) Cochrane Library (Wiley) Database of Abstracts of Reviews of Effects (DARE) DH-Data EMBASE Health Management Information Service (HELMIS) Health Technology Assessment (HTA) HMIC (Health Management Information Consortium) King's Fund Database MEDLINE MEDLINE In Process PsycINFO The following websites were also searched: Centre for the Evaluation of Public Health Interventions, London School of Hygiene & Tropical Medicine Cochrane Public Health Group Health evidence The Campbell Collaboration The Evidence for Policy and Practice Information and Coordinating Centre Further details of the databases, search terms and strategies used are included in the review reports. ## Selection criteria Studies were included in the effectiveness reviews if they: Involved a population at least the size of one covered by a UK primary care trust. Were based in an Organisation for Economic Co-operation and Development (OECD) country, another developed country or within a World Health Organization region. Included primary prevention strategies to tackle at least two of the key risk factors for CVD. Studies were excluded if they were: Confined to populations clinically diagnosed as being at high risk of CVD or diagnosed with CVD. Published before 1970. Not published in English. ## Quality appraisal Included papers were assessed for methodological rigour and quality using the NICE methodology checklist, as set out in the NICE technical manual 'Methods for the development of NICE public health guidance' (see appendix E). Each study was graded (++, +, –) to reflect the risk of potential bias arising from its design and execution. ++ All or most of the checklist criteria have been fulfilled. Where they have not been fulfilled, the conclusions are very unlikely to alter. - Some of the checklist criteria have been fulfilled. Those criteria that have not been fulfilled or not adequately described are unlikely to alter the conclusions. – Few or no checklist criteria have been fulfilled. The conclusions of the study are likely or very likely to alter. # Economic analysis The economic analysis consisted of a review of economic evaluations (review 6) and a cost effectiveness analysis. ## Review of economic evaluations The same protocol was used to conduct the literature reviews for all phases of the review. In a minor departure from the protocol, the list of included study designs was extended to include cost-consequences. The following databases were searched from 1970 to August 2008: ECONLIT EMBASE MEDLINE NHS EED database (Cochrane Library, Wiley). The search was limited to articles published from 1970 onwards and in the English language. In addition to the general bibliographic database searches, specific searches were conducted for each programme found during the general searches to ensure all published evaluations, particularly economic evaluations, were identified. Study quality was assessed using an evidence form based on the 'Methods for the development of NICE public health guidance' (second edition 2009) and adapted to reflect the parameters of this review. It was supplemented with questions from the Drummond checklist (Drummond MF Guidelines for authors and peer reviewers of economic submissions to the BMJ. London: BMJ). The selection criteria were the same as for the effectiveness reviews (see pages 53–54). The following study types were included: cost–benefit, cost-effectiveness and cost–utility analyses. ## Modelling An economic model was constructed to incorporate data from the reviews of effectiveness and cost effectiveness. The results are reported in: 'Prevention of cardiovascular disease at population level: modelling strategies for primary prevention of cardiovascular disease'. # Fieldwork Fieldwork was carried out to evaluate how relevant and useful NICE's recommendations are for practitioners and how feasible it would be to put them into practice. It was conducted with practitioners and commissioners who are involved in activities relevant to cardiovascular disease. They included those working in the food industry (such as food retailers, food producers and trade associations), local planning departments, local authority catering representatives and representatives from the NHS and PCTs. The fieldwork comprised: Eight half-day workshops. Nine case studies (interviews involving practitioners, commissioners and professionals). Each reviewed recommendations made in the following specific areas: health impact assessments CVD prevention programmes (two case studies) take-away planning training caterers public sector food provision physically active travel the dairy industry reformulation of food. Telephone interviews covering the following topics: mass media, government departments, and key food industry producers. The studies were commissioned to ensure there was ample geographical coverage. The main issues arising from these studies are set out in appendix C under fieldwork findings. The full fieldwork report, 'Fieldwork on prevention of cardiovascular disease at population level' is available online. # How the PDG formulated the recommendations At its meetings between September 2008 and July 2009, the PDG considered the evidence of effectiveness, expert reports and cost effectiveness to determine: whether there was sufficient evidence (in terms of strength and applicability) to form a judgement where relevant, whether (on balance) the evidence demonstrates that the intervention or programme/activity can be effective or is inconclusive where relevant, the typical size of effect (where there is one) Whether the evidence is applicable to the target groups and context covered by the guidance. The PDG developed draft recommendations through informal consensus, based on the following criteria: Strength (type, quality quantity and consistency) of the evidence. The applicability of the evidence to the populations/settings referred to in the scope. Effect size and potential impact on the target population's health. Impact on inequalities in health between different groups of the population. Equality and diversity legislation. Ethical issues and social value judgements. Cost effectiveness (for the NHS and other public sector organisations). Balance of harms and benefits. Ease of implementation and any anticipated changes in practice. Where possible, recommendations were linked to evidence statements (see appendix C for details). Where a recommendation was inferred from the evidence, this was indicated by the reference 'IDE' (inference derived from the evidence). The draft guidance, including the recommendations, was released for consultation in October 2009. At its meeting in December 2009, the PDG amended the guidance in light of comments from stakeholders and experts and the fieldwork. The guidance was signed off by the NICE Guidance Executive in May 2010.# Appendix C: The evidence This appendix lists the evidence statements from four reviews, a cost-effectiveness review and a primary research study provided by external contractors (see appendix A) and links them to the relevant recommendations. (See appendix B for the key to quality assessments.) The evidence statements are presented here without references – these can be found in the full reviews (see appendix E for details). The appendix also sets out a brief summary of findings from the economic analysis. The four reviews (reviews 1–4), the primary research study (review 5) and the cost-effectiveness review (review 6) are: Evidence reviews: Review 1: 'Prevention of cardiovascular disease at population level (Question 1; phase 1)' Review 2: 'Prevention of cardiovascular disease at population level (Question 1; phase 2)' Review 3: 'Prevention of cardiovascular disease at population level (Question 1; phase 3)' Review 4: 'Barriers to, and facilitators for, multiple risk factor programmes aimed at reducing cardiovascular disease within a given population: a systematic review of qualitative research' Primary research: Review 5: 'Population and community programmes addressing multiple risk factors to prevent cardiovascular disease: A qualitative study into how and why some programmes are more successful than others' Cost-effectiveness review: Review 6: 'Prevention of cardiovascular disease at population level (Question 1; cost-effectiveness)' Evidence statement R3.E1a indicates that the linked statement is numbered E1a in review 3. Evidence statement R5.12 indicates that the linked statement is numbered 12 in the primary research study (review 5). Evidence statement ER1 indicates that the linked statement is from expert report 1 (see additional evidence). Evidence statement CE1 indicates that the linked statement is numbered 1 in the cost-effectiveness review (review 6). ' The reviews, economic analysis and additional evidence are available online where a recommendation is not directly taken from the evidence statements, but is inferred from the evidence, this is indicated by IDE (inference derived from the evidence). Where the PDG has considered other evidence, it is linked to the appropriate recommendation below. It is also listed in the additional evidence section of this appendix. This includes evidence used to develop other NICE guidelines and guidance. Recommendation 1: evidence statement R3.E1m; additional evidence ER3 Recommendation 2: evidence statements R3.E1b; R3E1h; R3.E1i; R3.E1j; R3.E1k; additional evidence ER10 Recommendation 3: additional evidence ER9; ER10 Recommendation 4: additional evidence ER4; ER6; CG43 (1) Recommendation 5: additional evidence ER4 Recommendation 6: additional evidence ER3; ER4; ER6; CG43 (2) Recommendation 7: additional evidence ER1; ER10; ER13 Recommendation 8: additional evidence ER10; ER13 Recommendation 9: additional evidence ER1; CG43 (3) Recommendation 10: additional evidence CG43 (4) Recommendation 11: evidence statements R4.18a; R4.18b Recommendation 12: IDE Recommendation 13: evidence statements R3.E2a–f, R4.2a–c, R4.17a–d, R4.18a–c, R4.19a, R4.20a, R4.21a–c, R4.22a, R4.23a–b, R4.24a–d, R4.25a–d, R4.26a–d, R5.2 Recommendation 14: evidence statements R3.E1a–o, R3.E2a–f, R3.E3a–c, R4.14a–b, R5.5, R5.7, R5.10, CE 1–9; additional evidence ER 7, ER 8, ER 13 Recommendation 15: evidence statements R4.3a, R4.3b, R4.10a–d, R4.11a, R4. 11b, R4.12a, R4.13a–d, R4.15a, R4.15b, R5.2, R5.4, R5.6, R5.7 Recommendation 16: evidence statements R4.1b, R4.7c, R4.10d, R5.2, R5.3 Recommendation 17: evidence statements R4.16a–c, R5.12 Recommendation 18: evidence statements R3.E1n, R3.E3c, R4.4a, R4.9f, R4.18a, R4.18c; additional evidence ER 1 Recommendation 19: evidence statements R3.E5c, R4.18a–c; additional evidence ER 4 Recommendation 20: evidence statements R3.E1a–m, R3.E3c, R4.4a, R4.9e, R4.18a, R4.18b, R4.25e; additional evidence ER 3, ER 9, ER 10 Recommendation 21: evidence statements R4.1b, R4.3a, R4.3b, R4.7a–c, R4.8a–d, R4.16a–c, R4.17a–d, R5.3, R5.7, R5.8, R5.9, R5.11, R5.12; additional evidence ER 5, ER 7, ER 8 Recommendation 22: evidence statements R4.3a, R4.18a, R4.18c, R5.10; additional evidence ER 1, ER 5, ER 7, ER 8, ER 12, IDE Recommendation 23: evidence statements R3.E3a, R3.E3c, R4.18a, R4.18b; additional evidence ER 3, ER 4, ER 9, ER 10 Recommendation 24: evidence statements R4.9e; additional evidence ER 3, ER 9, ER 10 In addition, the approach taken in recommendations 1 to 12 is supported by the following evidence statements: R4.3a, R4.3b, R4.4a, R4.18a, R418b, R418c, R5.9 and additional evidence ER10, ER11, ER12, ER13. # Evidence statements Please note that the wording of some evidence statements has been altered slightly from those in the evidence reviews to make them more consistent with each other and NICE's standard house style. ## Evidence statement R3.E1a CVD mortality and morbidity: Limited evidence from 3 out of 38 programme evaluations using different summary effect measures demonstrate a mixed effect of multiple risk factor interventions (MRFI) on CVD mortality (the majority of programmes were beneficial) with two controlled before-and-after (CBA) studies demonstrating a net decrease in CVD mortality and one randomised controlled trial (RCT) demonstrating no net change. Limited evidence from 4 out of 38 programme evaluations, using different summary effect measures, demonstrate a mixed effect of MRFI on CVD morbidity (the majority disbeneficial) with one CBA study and one RCT demonstrating a net increase in morbidity and one RCT demonstrating no net change in morbidity. The effect of one programme on morbidity and mortality is unclear. ## Evidence statement R3.E1b Blood cholesterol: A large body of evidence from 15 CBA studies and 5 RCTs demonstrates a mixed direction of effect (majority of programmes beneficial) of MRFI programmes on blood cholesterol. Fourteen studies (nine CBA and five RCTs) demonstrate a beneficial net effect. Four CBA studies demonstrate no net effect or inconclusive net effects and two CBA studies demonstrate a disbeneficial net effect. The most optimistic result was from a CBA study, reporting a 0.7mmol/l net reduction in blood cholesterol. The least optimistic result was from a CBA study, reporting a +0.5mmol/l net increase in blood cholesterol. ## Evidence statement R3.E1c Diastolic and systolic blood pressure: A large body of evidence demonstrates a mixed direction of effect (majority of programmes beneficial) in favour of MRFI programmes on diastolic and systolic blood pressure. Fourteen CBA studies and five RCTs demonstrate a mixed direction of effect (majority of programmes beneficial) on diastolic blood pressure. Twelve studies (seven CBA studies and five RCTs) demonstrate a beneficial net effect. Five CBA studies demonstrate no net effect or inconclusive net effects and two CBA studies demonstrate a disbeneficial net effect. The most optimistic result was from a CBA study, reporting a 5.5mmHg net reduction in diastolic blood pressure. The least optimistic result was from a CBA study, reporting a 6mmHg net increase in diastolic blood pressure. Fourteen CBA studies and five RCTs demonstrate a mixed effect (majority of programmes beneficial) on systolic blood pressure. Ten studies (five CBA studies and five RCTs) demonstrate a beneficial net effect. Five CBA studies demonstrate no net effect or inconclusive net effects and four CBA studies demonstrate a disbeneficial net effect. The most optimistic result was from a CBA study, reporting an 11.8 mmHg net reduction in systolic blood pressure. The least optimistic result was from a CBA study, reporting a 5mmHg net increase in systolic blood pressure. ## Evidence statement R3.E1d Smoking: A large body of evidence from twenty CBA studies and four RCTs demonstrate a mixed effect of MRFI on smoking prevalence (the majority of programmes beneficial). Twelve studies (nine CBA studies and three RCTs) demonstrate a beneficial net effect. Seven studies (six CBA studies and one RCT) demonstrate no net effect or inconclusive net effects and five CBA studies demonstrate a disbeneficial net effect. The most optimistic result was from a CBA study, reporting an 18.6% net reduction in smoking prevalence. The least optimistic result was from a CBA study, reporting a 12.8% net increase in smoking prevalence. ## Evidence statement R3.E1e BMI: A large body of evidence from fourteen CBA studies and three RCTs demonstrate a mixed effect of MRFI programmes on body mass index (BMI) (the majority of programmes beneficial). Ten studies (seven CBA studies and three RCTs) demonstrate a beneficial net effect. Four CBA studies demonstrate no net effect or inconclusive net effects and three CBA studies demonstrate a disbeneficial net effect. The most optimistic result was from a CBA study, reporting a 1.3kg/m2 net reduction in BMI. The least optimistic result was from a CBA study, reporting a 0.7kg/m2 net increase in BMI. ## Evidence statement R3.E1f Blood glucose: Limited evidence from 3 out of 38 programme evaluations, using different summary effect measures, demonstrate a mixed effect of MRFI on blood glucose. One RCT and one CBA study report mixed results: net decreases in men and net increases in women, whilst one CBA study demonstrates no net effect. ## Evidence statement R3.E1g Triglyceride levels, high-density lipoprotein/low-density lipoprotein (HDL/LDL) ratio or lipid levels: No evidence has been identified on the effects of MRFI programmes on triglyceride levels, HDL/LDL ratio or lipid levels. ## Evidence statement R3.E1h Dietary change – low versus high fat spreads: Five CBA studies and one RCT (+) demonstrate a mixed effect of MRFI programmes on consumption or low versus high fat spreads (the majority of programmes beneficial). Four studies (three CBA studies and one RCT) demonstrate a beneficial net effect. One CBA study demonstrates an inconclusive net effect and one CBA study demonstrates an unfavourable net effect. The most optimistic result was from a CBA study, reporting a 24% net reduction in the number of people with high consumption of fat spread on bread. The least optimistic result was from a CBA study, reporting a 3.3% net decrease in the use of unsaturated spreading fats. ## Evidence statement R3.E1i Dietary change – vegetable versus animal fats for cooking: Four CBA studies demonstrate a mixed effect of MRFI programmes on the use of vegetable versus animal fat for cooking (the majority of programmes beneficial). Three CBA studies demonstrate a beneficial net effect and one CBA study demonstrates an inconclusive net effect. The most optimistic result was from a CBA study, reporting a 6% net increase in the use of unsaturated fats for cooking. The least optimistic result was from a CBA study, reporting a 2% net decrease in the use of vegetable fats for cooking. ## Evidence statement R3.E1j Dietary change – low versus high fat milk: Five CBA studies and one RCT (+) demonstrate a mixed effect of MRFI programmes on the consumption of low- versus high-fat milk (the majority of programmes beneficial). Three CBA studies and one RCT demonstrate a beneficial net effect and two CBA studies demonstrate an inconclusive net effect. The most optimistic result was from a CBA study, reporting a 9% net increase in the use of low fat milk in men. The least optimistic result was from a CBA study, reporting a 1% net decrease in the use of low fat milk in women. ## Evidence statement R3.E1k Dietary change – consumption high fat foods: Six CBA studies demonstrate a mixed effect of MRFI programmes on the percentage of high-fat foods in the diet (the majority of programmes beneficial). Three CBA studies demonstrate a beneficial net effect, two CBA studies demonstrate no net effect or inconclusive net effects and one CBA study demonstrates a disbeneficial net effect. The most optimistic result was from a CBA study, reporting a 24% net decrease in saturated fat intake. The least optimistic result was from a CBA study, reporting a 3.4% net increase in high-fat/junk food consumption. ## Evidence statement R3.E1l Dietary change – consumption of fruit and vegetables and wholemeal bread: Limited evidence is available on the effects of MRFI programmes on the consumption of fruit and vegetables and wholemeal bread (the majority of programmes beneficial). Three CBA studies demonstrate a mixed effect of MRFI programmes on the consumption of fruit and vegetables. Two CBA studies demonstrate a beneficial net effect and one CBA study demonstrates an inconclusive net effect. The most optimistic result is from a CBA study, reporting a 9% net increase in the number of people consuming five portions of fruit and vegetables per day. The least optimistic result is from a CBA study, reporting a 0.2% net decrease in fruit consumption. Two CBA studies demonstrate a mixed effect on the consumption of wholemeal bread. One CBA study demonstrates a beneficial net effect and one CBA study demonstrates an inconclusive effect. The most optimistic result is from a CBA study, reporting a 3% increase in children. The least optimistic result is from the same CBA study, reporting a 0.3% net decrease in adults. ## Evidence statement R3.E1m Dietary change – salt intake: Two CBA studies (one and one ) provide mixed results for the effects of MRFI programmes on salt intake. One CBA study demonstrates a beneficial net treatment effect and one CBA demonstrates an inconclusive net treatment effect. ## Evidence statement R3.E1n Physical activity: Evidence from 11 CBA studies and one RCT (+) provide a mixed pattern for the effect of MRFI programmes on physical activity (the majority of studies are disbeneficial). Three CBA studies and two RCTs demonstrate a favourable net effect. Three CBA studies demonstrate inconclusive net effects and four CBA studies demonstrate a disbeneficial net effect. The most optimistic result is from a CBA study, reporting an 11.5% net increase in the number of people doing strenuous physical activity more than three times per week. The least optimistic result is from a CBA study, reporting a 6% net decrease in the number of people who were physically active. ## Evidence statement R3.E1o Attitudes, knowledge and intentions relating to CVD risk factors: Limited evidence is available on the effects of MRFI programmes on CVD risk factor attitudes, knowledge and intention to change. One CBA study and one uncontrolled before-and-after study suggest beneficial changes in CVD knowledge following MRFI programmes. One of these studies showed a net increase in the number of individuals intending to lose weight. No evidence has been identified on the effects of MRFI programmes on CVD risk factor attitudes. ## Evidence statement R3.E2a General: Evidence for variation in effectiveness in subgroups of the population is limited and inconsistently reported across included programmes. There is no clear pattern with respect to gender, age, ethnicity or measures of deprivation which may be the result of the limited information available, confounding and selective reporting. ## Evidence statement R3.E2b Ethnicity: Three programmes report the results of subgroup analysis of effectiveness according to ethnicity. One uncontrolled before-and-after study reports lower effectiveness in ethnic minorities in acquisition of CVD knowledge. One CBA study reports lower effectiveness in ethnic minority groups for reducing smoking prevalence, reducing BMI and increasing fruit and vegetable intake and one CBA study reports no difference in effectiveness according to ethnic group. ## Evidence statement R3.E2c Age: Six programmes report results of subgroup analysis according to age. Two uncontrolled before-and-after studies report a reduction in effectiveness in acquisition of CVD knowledge in younger participants and one uncontrolled before-and-after study reports a reduction in effectiveness in reducing salt intake in younger participants. One CBA study reports a reduction in effectiveness in promoting CVD awareness in older participants. Two CBA studies report no differences in effectiveness according to age. ## Evidence statement R3.E2d Gender: Seven programmes report results of subgroup analysis according to gender. Four programmes report a reduction in effectiveness in women compared to men. One RCT reports a reduction in effectiveness in increasing physical activity in women compared to men. One uncontrolled before-and- after study and two CBA studies report a reduction in effectiveness in reducing smoking prevalence in women compared to men. One CBA study reports a reduction in effectiveness in reducing cholesterol in women compared to men. One CBA study reports a reduction in effectiveness in drinking low-fat compared to high-fat milk in women compared to men. Two programmes report a reduction in effectiveness in men compared to women. Two CBA studies report a reduction in effectiveness in promoting CVD awareness and acquisition of CVD knowledge in men compared to women and one CBA study reports a reduction in effectiveness in reducing CVD morbidity and mortality in men compared to women. One CBA study reports no differences in effectiveness according to gender. ## Evidence statement R3.E2e Social class: Two programmes report results of subgroup analysis according to social class. One CBA study reports a reduction in effectiveness in reducing smoking in lower social classes compared to higher social classes. One CBA study reports no differences in effectiveness according to social class. ## Evidence statement R3.E2f Level of education: One programme reports results of subgroup analysis according to level of education. One CBA study reports a reduction in effectiveness in CVD awareness in those relatively more educated. ## Evidence statement R3.E3a Nature of the interventions: Thirty one programmes were concerned with the effectiveness of population programmes using education and mass media, and seven with screening programmes directed at large populations in the community or primary care. However, 16 of the education and mass-media programmes contained screening components. Counselling was a key process in many programmes, undertaken individually in 24 programmes and amongst groups in 16 programmes. The 38 programmes varied in many other ways. Programme length ranged from one to over 20 years. The size of the population addressed ranged from approximately 2500 to over 1 million. Fourteen of the programmes implemented changes to the environment. Health departments (n=23) , local health committees (n=12), voluntary organisations (n=11) and community volunteers (n=9) had roles in programme delivery. Programmes were delivered in a variety of settings including workplaces (n=12) and schools (n=18). ## Evidence statement E.3b Education and mass-media based programmes compared to screening based: As indicated this was the most marked contrast between the programmes. However comparing the effectiveness of the two groups is complicated: Many of the education and mass-media based programmes contain elements of screening. There are many CVD screening programmes, particularly focused on moderate or high-risk populations which are not included in this review. The comparison between the two groups is likely to be confounded by other factors, a very important one of which is that CBA studies are used to evaluate most of the education and mass-media based programmes, and RCTs all the screening based programmes. With these provisos (and reference to pages 127–31 in report 3), the pattern of results for the risk factors of cholesterol, blood pressure (BP), smoking and BMI in the two different groups of programmes are summarised in the table below: Programme type (n=38) Programme result, based on direction of effect Beneficial Inconclusive Disbenefical No data Net change in mean total cholesterol in mmol/L Educ & MM 9 Screening 5 Net change in systolic BP in mmHg Educ & MM 6 Screening 5 Net change in diastolic BP in mmHg Educ & MM 7 Screening 5 Net change in BMI in kg/m2 Educ & MM 8 Screening 3 Net change in smoking prevalence in % Educ & MM 9 Screening 3 Although the results are similar, there does appear to be a more consistent pattern of benefit in the programmes focusing on screening. As well as the provisos mentioned above, the following also need to be borne in mind when taking this observation at face value: Whether this difference could be accounted for by chance alone. Whether the difference would persist if the size of the effects could be taken into account. Vote counting as a method of summarising the results in a systematic review is recognised to be the weakest approach. ## Evidence statement R3.E3c Possible variations in effectiveness by other aspects of the nature of the intervention: Over the three reports, many other plausible reasons for the noted variation in effectiveness have been identified. These include: duration of programme intensity of programme use of an underlying theoretical model to inform the design of the programme pre-programme investigation of particular risk factors operating in a population community involvement in planning and/or design of programme adaptability of the programme as new challenges emerge level of integration of the separate components of the programme inclusion of environmental changes as part of the programme. Whether any of these factors account for differences in effectiveness which could not arise by chance alone has not been fully explored, and their potential importance can neither be confirmed nor refuted. Unfortunately, the extent to which the differences could ever be satisfactorily explored using the results from these evaluations is debatable given noted limitations in the reporting of the precise differences in nature of the programmes and the amount of statistical information available. ## Evidence statement R3.E5c Age: Fifteen programmes report participation in programme interventions and/or programme evaluation surveys according to age. One uncontrolled before-and-after study and 13 CBA studies report lower participation in evaluation surveys or programme interventions by those of younger age whilst one CBA study reports no difference in participation according to age. ## Evidence statement R4.1b These suggest that factors influencing success include: time limitations for projects, leadership, (including difficulties engaging community members at strategic levels), and cooperation between partner organisations. ## Evidence statement R4.2a Four study reports show conflicting evidence about the degree and methods of community engagement important for success. ## Evidence statement R4.2b For programmes that were successful, one study reports that positive community expectations about the potential of the programme to effect wider change facilitated community engagement. It is suggested that insufficient community engagement did not significantly impact on another programme's success. ## Evidence statement R4.2c For programmes that were unsuccessful, one study reports that previous negative experiences of community programmes discouraged community engagement. Conversely, another study reports engagement in the programme increased willingness for future involvement. ## Evidence statement R4.3a There is evidence from five study reports that community programmes to address heart health can be affected by the broader political context. ## Evidence statement R4.3b This can effect diverse organisational elements such as: the availability of project funding, the development of partnerships between organisations and a sense of shared purpose at different administrative levels. Individual responses may also be affected through legislation incentives to healthier behaviours. ## Evidence statement R4.4a There is evidence from four study reports that high pricing can impact on people's ability and willingness to adopt healthy eating behaviours and to participate in organised physical activity. ## Evidence statement R4.7a Six study reports discuss factors relating to organisational and strategic issues. ## Evidence statement R4.7b There is evidence from four studies that short time frames limit the ability to plan and develop the programme, engage the community, develop partnerships and communication, meet targets and leave a positive legacy. ## Evidence statement R4.7c Leadership was identified as a key organisational benefit of programmes by three studies. It is required to develop partnerships and collaborations within communities, and is important at all levels, from volunteers to with senior administrators. One study failed to see the desired shift in leadership to the community itself. ## Evidence statement R4.8a Evidence from six study reports is related to the organisational culture and partnerships of those involved in CVD programme services. ## Evidence statement R4.8b Three studies note differences in culture between partner organisations including frames of reference, terminology and programme expectations although this didn't always lead to conflict. ## Evidence statement R4.8c Four studies suggest that CVD programmes are enhanced where partner organisations have aligned values, priorities, focus and goals between organisations. ## Evidence statement R4.8d Partnerships may have positive effects through interagency learning, increasing the visibility of smaller organisations and enhanced funding opportunities. ## Evidence statement R4.9e Two studies note that to sustain the provision of healthier food options, communities need to take them up and so they need to be made attractive and clear. ## Evidence statement R4.9f One study found that community projects were largely unwilling address smoking, preferring to promote physical activity. ## Evidence statement R4.10a Five studies reported on staffing successful programmes. ## Evidence statement R4.10b Three studies report difficulties in recruitment and retention. ## Evidence statement R4.10c Positive staff contributions were defined in three studies where successful networking allowed staff to use their time effectively because they were not duplicating activities; where they were assisted by structures that focus on heart health issues and where flexibility allowed them to spend significant periods of time with participants. ## Evidence statement R4.10d Positive staff characteristics included knowledge and interest in heart health and being upbeat and friendly. A range of specialist staff should be involved. ## Evidence statement R4.11a Six study reports make specific comments about funding and resource requirements. ## Evidence statement R4 11.b Five study reports note the need for those with existing roles and responsibilities to be given resources to take on additional CVD programme work, or for dedicated positions to be created. Limited time for school-based staff may be a particular problem. ## Evidence statement R4.12a Two studies identify effective communication between organisations, staff and the community, to be important, but use different mechanisms to achieve this: lay health advisers or having a full time project coordinator. ## Evidence statement R4.13a Four study reports discuss recruiting and retaining programme volunteers. ## Evidence statement R4.13b Volunteers need adequate resourcing and leadership, and may be motivated by witnessing positive changes in the community. ## Evidence statement R4.13c One study suggests that volunteers find health promotion less satisfying than traditional patient service roles. ## Evidence statement R4.13d Two study reports about the same programme note that lay health advisers, recruited from the target community, were key. ## Evidence statement R4.14a Two study reports mention the role of GPs in community CVD projects. ## Evidence statement R4.14b GP uptake was slow and it is suggested that GPs may be less comfortable in health promotion roles than their traditional role of secondary prevention. ## Evidence statement R4.15a Evidence relating to staff training were identified by six study reports. ## Evidence statement R4.15b While skills training is needed, involvement in the programme itself increases skills and knowledge through sharing information and implementing theoretical knowledge. ## Evidence statement R4.16a Five study reports relate to the evaluation of CVD prevention programmes. ## Evidence statement R4.16b Two study reports found that process evaluation and action research raised self-awareness among staff and promoted programme improvement. While a third reports that time limited projects limit the possibility of such learning. ## Evidence statement R4.16c Data management was a challenge in long-term projects and those with multiple strands across a number of organisations. ## Evidence statement R4.17a There is evidence from eight study reports about community engagement in CVD prevention programmes. ## Evidence statement R4.17b Two study reports suggest that successful community engagement requires multiple approaches across populations. ## Evidence statement R4.17c Two study reports suggest that successful programmes need to be sensitive to communities' habits and cultural patterns, while a further three describe the important of matching programme staff to the social and/or ethnic characteristics of the target communities. ## Evidence statement R4.17d Challenges to community engagement include engaging community representatives at strategic levels; building confidence in community leaders; difficulties breaking into existing networks; competing with other community events; reaching young people; reluctance due to the legacy of negative experiences with previous initiatives; lack of enthusiasm in the community. ## Evidence statement R4.18a Seven studies report that the local physical environment had important effects on the ability of community CVD risk-reduction projects to be successful. ## Evidence statement R4.18b Five studies reported that access to healthy food options was limited, while unhealthy food was more visible, both in the community and in school-based programmes. ## Evidence statement R4.18c Local barriers to physical activity including no sidewalks, unmetalled roads or loose dogs; lack of school provision to secure bikes or store kit which discourages extra-curricular exercise; and local availability of gyms or other facilities. ## Evidence statement R4.19a Community and familial norms: There is evidence from one study report among British Asians that stress from a variety of sources was a noted problem among both men and women and this might lead to inability to access essential services or to communicate with professionals. ## Evidence statement R4.20a Attitudes to food and cooking: There is evidence from three study reports that specific foods and eating patterns may be regarded as important expressions of cultural identity. Cultural norms about food types and their preparation may not be the most healthy from a CVD prevention perspective. ## Evidence statement R4.21a There is evidence from three study reports about cultural attitudes to weight and exercise. ## Evidence statement R4.21b These suggest that, among some groups, understandings of greater weight as a sign of wealth and health may persist which may challenge successful adoption of CVD prevention activities. ## Evidence statement R4.21c Further, specific connotations of language used to describe weight and physical activities may exist, so shared understandings between clinical and community meanings should not be assumed. ## Evidence statement R4.22a Fatalism and health: There is evidence from three study reports, among three different ethnic groups, of fatalistic attitudes where one's state of health is the will of God. ## Evidence statement R4.23a There is evidence from six study reports to suggest that a benefit of community CVD programmes is in providing leadership that encourages local attitudes to change for the better. ## Evidence statement R4.23b As well as making personal changes, such 'social health' encouraged changes within the family, within the local community and within the wider social and political community. Despite this, one study suggests that men remain less likely to use health services. ## Evidence statement R4.24a Nine studies discuss community perceptions of CVD risk factors. ## Evidence statement R4.24b Six studies report high levels of understanding about CVD risk among the target population while two suggest limited understanding and two suggest challenges in turning knowledge into action. ## Evidence statement R4.24c One study suggests that different types of knowledge are at play (theoretical, practical, experiential and intuitive), and where there is a discrepancy between theoretical and experiential knowledge, the latter influences what participants do. These links might be challenged by cues to action (health belief model) – most significantly breakdown of self-image and social networks. ## Evidence statement R4.24d One study develops a typology of six 'ideal types' of functional and dysfunctional attitude among programme participants who see it as a blessing, an opportunity, a confirmation, a watchman, a disappointment or an insult. The latter two are negative or 'dysfunctional' in terms of positive health choices and more men have these attitudes. ## Evidence statement R4.25a Nine study reports discuss people's motivations for, or resistance to, adopting risk reduction behaviours. ## Evidence statement R4.25b Two studies report that health concerns, sometimes serious, were motivating factors to participate and two that feedback of physiological test results was motivating. ## Evidence statement R4.25c Women may be targeted to take heart health practices home, however, two studies report on difficulties initiating or maintaining family interest and that resistance from family members was a barrier to adopting healthier behaviour. It is difficult to maintain behaviour changes amidst the usual business of family commitments. ## Evidence statement R4.25d One study suggests that there is a need for ongoing support in order for behavioural changes to be made and maintained. ## Evidence statement R4.25e One study found that secondary school pupils enjoyed the freedom to make food choices not available at primary school – pupils' food choices, and those of the wider population, may reflect issues other than health. ## Evidence statement R4.26a Six studies report on participant perceptions of programmes in which they were involved. ## Evidence statement R4.26b In two studies participants reported improving heart health through weight loss, increased exercise, as well as increased awareness and use of services and programme activities. One study also suggests that networks providing community support was a benefit. ## Evidence statement R4.26c One study found that practical demonstrations were much more successful than information provision alone. ## Evidence statement R4.26d Two studies suggest that the participants may doubt the credibility of health messages, with so many sources of, sometimes contradictory, information available. Matching the characteristics of the community may be important. ## Evidence statement R5.2 Community engagement: Positive community engagement requires trusting, respectful relationships to be built which motivate and support change. Community engagement should be an ongoing and dynamic partnership which responds to community needs. As CVD may not be seen as an immediate concern within targeted communities, staff may first need to listen and respond to the existing concerns of the community. This may be done through participating in existing networks and forums, or creating forums that have more open agendas, at least to start with. Sufficient time is needed to ensure that this is done appropriately and also to ensure that changes become adopted by the community so that they are empowered to continue, even if the project itself comes to an end. Information and education is likely to be more effective if it relates to the experiences of the community, and if those that deliver it are seen as part of that community. Appropriately skilled staff are needed for effective community engagement. Greater levels of participation, that involve community members as partners or devolve power to them, may have additional benefits – ensuring that programmes are truly responsive to community needs, involving local people in the complexities of planning and delivering such programmes and so facilitating understanding within the community. Done well, community engagement may create a positive feedback loop which motivates change, improving health which produces greater motivation. However, care needs to be taken to ensure that those adopting behaviour change are not just those already motivated to change, thereby increasing, rather than lessening, health inequalities. ## Evidence statement R5.3 Staffing – leadership: Strong, inspirational leadership may be important to initiate, coordinate and drive complex programmes and motivate and encourage cooperation among multiple staff across a number of agencies with a range of responsibilities. To fulfil this, staff are needed whose role is dedicated to the programme and those with multiple roles need to have appropriate time freed up. Leaders may be needed for the project over all, but also for specific elements of the project, for example, to encourage primary care participation or ensure local political or funding support. Leaders from within the community are also needed to champion the project and facilitate engagement. Expectations of leadership roles should be matched by appropriate control and responsibility, and given the necessary training and support. ## Evidence statement R5.4 Staffing – staff engagement: To ensure that staff are engaged with the aims of a CVD prevention progamme, they require appropriate training and resources, a good understanding of how their role fits into the programme overall and a clear understanding of the extent of their roles and responsibilities. ## Evidence statement R5.5 Staffing – GPs: The role of primary care was complicated and sometimes contradictory. Some GPs may be more comfortable with a secondary, rather than primary, prevention role, which may explain why some participants found it difficult to engage them in CVD prevention programmes. Conversely, other participants viewed primary care as crucial partners in CVD prevention. Advocacy among other local organisations may be a key role. Where primary care is involved in CVD prevention programmes, they need to receive appropriate resources to free-up staff time. Engaging primary care and keeping them appropriately informed may require tailored approaches. ## Evidence statement R5.6 Staffing – volunteers: Volunteers from within the community may be particularly effective at informing, motivating and engaging their peers in the community and enhance community empowerment. Volunteer workers need to be properly trained and supported to ensure that they continue to be involved and don't get burnt out. The issues of paying those involved should be considered carefully. ## Evidence statement R5.7 Staffing – multi-agency, multi-disciplinary teams: Public health work to reduce CVD is likely to require the involvement of multiple agencies and disciplines. Coordination and cooperation is required to build trust and a sense of shared purpose through aligning the goals and activities of different agencies involved, and assigning clear roles and responsibilities to participating organisations and staff within them. Joint appointments may facilitate this. Ongoing feedback and communication is vital. Sufficient time is needed to successfully negotiate and accommodate different expectations and bureaucracies. ## Evidence statement R5.8 Legacy: CVD reduction programmes may enhance their longer-term impact through ensuring that programme activities are embedded within organisations and the community. Appropriate training and support for key staff, and community members, from project inception may help to ensure activities become 'institutionalised'. Ongoing sources of funding should also be identified. Programme impacts should be regularly assessed and results fed back to staff and organisations so that successful activities are recognised and adopted. This will require the identification of appropriate resources. Early and ongoing community engagement may ensure ongoing changes in healthy behaviours, empowering the community to maintain positive changes. Short-term projects often fail to leave lasting benefits to a community as their short-term goal setting may preclude the necessary engagement required. ## Evidence statement R5.9 Short time frames: Short time frames for CVD prevention programmes may threaten success at a number of levels: implementation, staff engagement and training, community engagement, evaluation and legacy. It is difficult for such programmes to meet community needs, staff needs or to permit changes to become embedded in the community. This may lead communities and local agencies to lose faith in such interventions, further hampering the ability of future work to be successful in those areas. ## Evidence statement R5.10 Structural barriers: At a macro-level, changes in the broader political environment can have dramatic effects on the adoption and continuation of prevention activities. Support for CVD prevention programmes may be affected by changing political priorities around prevention and treatment of illness. ## Evidence statement R5.11 Piloting and monitoring: Cyclical approaches to monitoring and evaluation, such as piloting, process evaluation and action research, allow project to be responsive to local needs, adapting or removing inappropriate projects and allowing successful projects to be rolled out. Information from this process fed back to staff in a timely way can help develop a sense of ownership and cooperation and motivate good practice. Organisations and individuals should also learn from the experiences of previous projects. ## Evidence statement R5.12 Challenges of evaluation: Commissioners and funders may need to allow flexibility in programme evaluation designs to allow them to adapt to local needs, rather than requiring fixed plans prior to funding. In addition, programmes and evaluations should allow sufficient time for outcomes to be achieved. Multiple methods may be needed to evaluate important aspects of CVD prevention programmes, such as community empowerment, that are not all easily captured through numerical outcome data. Programmes that measure only population-level changes may not capture large impacts for some individuals, and this may be important, especially where health inequalities are addressed. ## Evidence statement CE1 Three studies gave results in cost per life-year gained for population-based programmes compared to no intervention. The results ranged from cost-saving to £240,000 per life-year gained. ## Evidence statement CE2 Two studies gave results in cost per QALY or DALY (disability-adjusted life years) for population-based programmes compared to no intervention. Results ranged from £10 per QALY to £96 per DALY. ## Evidence statement CE3 Two studies gave results in cost per case prevented for population-based programmes compared to no intervention. Results ranged from cost saving to £22,000 per case prevented. ## Evidence statement CE4 Five studies reported results in cost per life-year gained for some form of screening strategy compared to no intervention. Results ranged from cost saving to £140,000 per life-year gained. ## Evidence statement CE5 Two studies gave results in cost per case prevented for screening compared to no intervention. Results ranged from £10,000 to £730,000 per case prevented. ## Evidence statement CE6 Two studies gave results per 1% reduction in coronary risk for screening compared to no intervention. Results ranged from £2.25 to £5.30 per 1% reduction for one person. ## Evidence statement CE7 One study gave a result of £0.80 per pound weight lost for a screening programme compared to no intervention. ## Evidence statement CE8 One study gave results ranging from £12,000 to £120,000 per life-year gained and £100,000 to £230,000 per QALY for screening compared to a population-based approach. ## Evidence statement CE9 One study gave results from cost saving to £39,000 per life-year gained for some form of exercise training. # Additional evidence Expert reports: ER 1: 'The effectiveness of physical activity promotion interventions' ER 3: 'Expert testimony on salt and cardiovascular disease' ER 4: 'The relationship between commercial interests and risk of cardiovascular disease' ER 5: 'Regional development of a population-based collaborative CVD prevention strategy: the experience of NHS West Midlands' ER 6: 'NICE guidance on the prevention of CVD at population level: evidence from the Co-operative Group' ER 7: 'Population and community programmes addressing multiple risk factors to prevent cardiovascular disease (CVD): addendum to qualitative study produced by Peninsula Technology Assessment Group for NICE: CVD programme – Heart of Mersey (HoM)' ER 8: 'Expert testimony paper on the independent evaluation of 'have a heart Paisley' phase one (Scotland's national CHD prevention demonstration project)' ER 9: 'Expert testimony on the public health harm caused by industrially produced trans fatty acids and actions to reduce and eliminate them from the food system in the UK' ER 10: 'Prevention of cardiovascular disease at a population level: evidence on interventions to address dietary fats' ER 11: 'CVD risk factors: paradigms and pathways' ER 12: 'CVD prevention in populations: lessons from other countries' ER 13: 'Will CVD prevention widen health inequalities?' 'Obesity'. NICE clinical guideline 43 (2006): (1) Section 7.4.1.3 Evidence of corroboration (2) Evidence statement 5, Section 12 Prevention evidence summary: broader community interventions (Community 2) (3) Evidence statement 6, Section 12 Prevention evidence summary: broader community interventions (Community 2) (4) Evidence statement 2, Section 10 Prevention evidence summary: broader community interventions (Community 2) # Cost-effectiveness evidence The economic analysis consisted of a review of economic evaluations and a cost-effectiveness analysis. 'Prevention of cardiovascular disease at population level (question 1; cost-effectiveness)' 'Prevention of cardiovascular disease at population level: modelling strategies for primary prevention of cardiovascular disease'. Some primary prevention programmes involving education, mass media and screening with a general population were found to be effective and cost effective. They may reduce some of the risk factors for CVD, including changing behaviours which increase the risk. However, when the findings from all programmes were summarised, the overall effect on health outcomes was uncertain. In addition, as these programmes were conducted many years ago, the findings may not be generally applicable in the UK now. The cost-effectiveness analysis strongly suggests that legislation likely to reduce the risk of CVD can be expected to produce a net cost saving to the public sector – as well as improving health. (Unless a very large sum of money needs to be spent on implementation.) For example, implementing a CVD prevention programme based on the North Karelia project would result in an incremental cost-effectiveness ratio of approximately £7000 per quality-adjusted life year (QALY). For the Stanford Five City Project, the total healthcare cost savings almost equal the estimated cost of the project. The benefits of reducing the prevalence of smoking would also make the programme cost saving. At the request of the Programme Development Group (PDG), the scope of the modelling was extended beyond programmes for which there was direct evidence of effectiveness. Interventions modelled included: The North Karelia project – including the effect of a net percentage reduction in serum cholesterol of 3% for men and 1% for women, and a reduction in systolic blood pressure of 3% for men and 5% for women. The Stanford Five City Project – the effect of a 4% reduction in systolic blood pressure and a 2% decrease in serum cholesterol among the general population. Legislation to ban trans fats and so reduce trans fatty acid (TFA) levels in the population so that it only accounts for approximately 0.7% of total energy intake. Legislation to reduce the population's salt intake by 3 g and 6 g per day. The modelling made a number of conservative assumptions. It found that halving CVD events across the entire England and Wales population of 50 million would result in discounted savings of approximately £14 billion per year. Reducing mean population cholesterol or blood pressure levels by 5% would result in discounted annual savings of approximately £0.7 billion and £0.9 billion respectively. Reducing population cardiovascular risk by even 1% would generate discounted savings of approximately £260 million per year. Additional benefits to existing CVD patients, and reductions in other diseases, were not quantified. As the model is based on a series of conservative assumptions, it probably seriously underestimates the true health benefits to be gained from the recommendations. # Fieldwork findings Fieldwork aimed to test the relevance, usefulness and feasibility of putting the recommendations into practice. The PDG considered the findings when developing the final recommendations. For details, go to the fieldwork section in appendix B and online. Feedback to the recommendations varied. ## Food industry recommendations (1, 2, 3, 4, 5 and 10 in the consultation document) It was indicated, particularly by some food industry stakeholders, that: the recommendations were 'out of date' and did not reflect the current situation within the food industry it was not feasible to implement parts of the recommendations and their impact would be minimal some of the advice was already covered by other government agencies, as well as at European level the role of these recommendations was questionable, particularly where they were quoting differences in target values from those agreed with the FSA. It was felt that NICE has 'a lot less weight' in the food and planning sectors and that we would need to work much more closely with them to gain support for the recommendations. Food industry representatives generally (but not unanimously) indicated that trans fats were 'no longer an issue' and should, therefore, not be included in the recommendations. They also questioned the levels of saturated fat and salt recommended, as they were unaware of the evidence to support a reduction to these levels. Catering industry recommendations (6, 14 and 15 in the consultation document) In general, stakeholders felt that the catering recommendations demonstrated how to follow good practice. Local authority planning recommendations (7, 8, 9, 12, 13, 16, 17 and 18 in the consultation document) Local planning and policy representatives stated that the recommendations needed to become part of national planning policy or law. Otherwise, it would not be possible to implement them. ## Communications recommendation (number 11 in the consultation document) There was limited feedback from the industry as some of the target organisations disputed that it was relevant to them and declined the opportunity to be interviewed. ## CVD programme recommendations (19 to 24 in the consultation document) In general, representatives from the NHS and PCTs indicated that the regional CVD prevention recommendations were appropriate and that they supported current work on CVD prevention.# Appendix D: Gaps in the evidence The Programme Development Group (PDG) identified a number of gaps in the evidence related to the programmes under examination based on an assessment of the evidence, stakeholder and expert comment and fieldwork. These gaps are set out below. There is a lack of UK studies on the effectiveness of programmes to prevent CVD among black and minority ethnic groups living in the UK. There is a lack of evidence on the effectiveness of interventions targeting those with high risk factors who believe their health is bad. There is a lack of evidence on the effectiveness of providing emotional support and help to develop general coping skills as part of interventions to prevent CVD. There is a lack of evidence on the effectiveness of CVD prevention programmes involving the families of those at risk. There is a lack of controlled comparison studies looking at the effectiveness of lay health advisers in helping to prevent CVD. The Group made 6 recommendations for research. These are listed in section 5.# Appendix E: supporting documents Supporting documents are available online. These include the following: Evidence reviews: Review 1: 'Prevention of cardiovascular disease at population level (Question 1; phase 1)' Review 2: 'Prevention of cardiovascular disease at population level (Question 1; phase 2)' Review 3: 'Prevention of cardiovascular disease at population level (Question 1; phase 3)' Review 4: 'Barriers to, and facilitators for, multiple risk factor programmes aimed at reducing cardiovascular disease within a given population: a systematic review of qualitative research'. Primary research: Review 5: 'Population and community programmes addressing multiple risk factors to prevent cardiovascular disease: A qualitative study into how and why some programmes are more successful than others'. Economic analysis: Review 6: 'Prevention of cardiovascular disease at population level (Question 1; cost-effectiveness)' 'Prevention of cardiovascular disease at population level: modelling strategies for primary prevention of cardiovascular disease'. Expert reports: Report 1: 'The effectiveness of physical activity promotion interventions' Report 2: 'Health policy analysis' Report 3: 'Expert testimony on salt and cardiovascular disease' Report 4: 'The relationship between commercial interests and risk of cardiovascular disease' Report 5: 'Regional development of a population-based collaborative CVD prevention strategy: the experience of NHS West Midlands' Report 6: 'NICE guidance on the prevention of CVD at population level: evidence from the Co-operative Group' Report 7: 'Population and community programmes addressing multiple risk factors to prevent cardiovascular disease (CVD): addendum to qualitative study produced by Peninsula Technology Assessment Group for NICE: CVD programme – Heart of Mersey (HoM)' Report 8: 'Expert testimony paper on the independent evaluation of "have a heart Paisley" phase one (Scotland's national CHD prevention demonstration project)' Report 9: 'Expert testimony on the public health harm caused by industrially produced trans fatty acids and actions to reduce and eliminate them from the food system in the UK' Report 10: 'Prevention of cardiovascular disease at a population level: evidence on interventions to address dietary fats' Report 11: 'CVD risk factors: paradigms and pathways' Report 12: 'CVD prevention in populations: lessons from other countries' Report 13: 'Will CVD prevention widen health inequalities?' Report 14: 'Food manufacturer's perspective'. Fieldwork report: 'Fieldwork on prevention of cardiovascular disease at population level'. A quick reference guide for professionals whose remit includes public health and for interested members of the public. For information on how NICE public health guidance is developed see: 'Methods for development of NICE public health guidance (second edition, 2009)' 'The NICE public health guidance development process: An overview for stakeholders including public health practitioners, policy makers and the public (second edition, 2009)'.# Changes after publication February 2012: minor maintenance. January 2013: minor maintenance# About this guidance NICE public health guidance makes recommendations on the promotion of good health and the prevention of ill health. This guidance was developed using the NICE public health programme guidance process. The recommendations from this guidance have been incorporated into the NICE Pathways diet and physical activity. Tools to help you put the guidance into practice and information about the evidence it is based on are also available. Your responsibility This guidance represents the views of the Institute and was arrived at after careful consideration of the evidence available. Those working in the NHS, local authorities, the wider public, voluntary and community sectors and the private sector should take it into account when carrying out their professional, managerial or voluntary duties. Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties. Copyright © National Institute for Health and Clinical Excellence 2010. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE. Contact NICE National Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BTwww.nice.org.uknice@nice.org.uk0845 033 7780	{'Introduction': "The Department of Health (DH) asked the National Institute for Health and Clinical Excellence (NICE) to produce public health guidance on the prevention of cardiovascular disease (CVD) at population level.\n\nCVD includes coronary heart disease (CHD), stroke and peripheral arterial disease. These conditions are frequently brought about by the development of atheroma and thrombosis (blockages in the arteries). They are also linked to conditions such as heart failure, chronic kidney disease and dementia.\n\nThe guidance is for government, the NHS, local authorities, industry and all those whose actions influence the population's cardiovascular health. This includes commissioners, managers and practitioners working in local authorities and the wider public, private, voluntary and community sectors. It may also be of interest to members of the public.\n\nThe guidance complements, but does not replace, NICE guidance on: smoking cessation and prevention and tobacco control, physical activity, obesity, hypertension and maternal and child nutrition (for further details, see section 7). It will also complement NICE guidance on alcohol misuse. The Programme Development Group (PDG) developed the recommendations on the basis of reviews of the evidence, economic modelling, expert advice, stakeholder comments and fieldwork.\n\nMembers of the PDG are listed in appendix A. The methods used to develop the guidance are summarised in appendix B.\n\nSupporting documents used to prepare this document are listed in appendix E. Full details of the evidence collated, including fieldwork data and activities and stakeholder comments, are available on the NICE website, along with a list of the stakeholders involved and NICE's supporting process and methods manuals.", 'Recommendations ': "This is NICE's formal guidance on preventing cardiovascular disease (CVD) at population level. When writing the recommendations, the Programme Development Group (PDG) (see appendix A) considered the evidence of effectiveness (including cost effectiveness), fieldwork data and comments from stakeholders and experts. Full details are available online.\n\nThe evidence statements underpinning the recommendations are listed in appendix C. The evidence reviews, supporting evidence statements and economic modelling report are available online.\n\n# Recommendations for policy: a national framework for action\n\nChanges in cardiovascular disease (CVD) risk factors can be brought about by intervening at the population and individual level. Government has addressed – and continues to address – the risk factors at both levels.\n\nInterventions focused on changing an individual's behaviour are important and are supported by a range of existing NICE guidance (see section 7, 'Related NICE guidance').\n\nChanges at the population-level could lead to further substantial benefits and this guidance breaks new ground for NICE, by focusing on action to bring about such changes. They may be achieved in a number of ways but national or regional policy and legislation are particularly powerful levers. (For more on the importance of interventions aimed at the whole population, see considerations 3.12, 3.13, 3.14 and 3.15.)\n\nThis guidance makes the case that CVD is a major public health problem.\n\nRecommendations 1 to 12 are based on extensive and consistent evidence. This suggests that the policy goals identified provide the outline for a sound, evidence-based national framework for action which is likely to be the most effective and cost-effective way of reducing CVD at population level.\n\nIt would require a range of legislative, regulatory and voluntary changes including the further development of existing policies.\n\nThe framework would be established through policy, led by the Department of Health. It would involve government, government agencies, industry and key, non-governmental organisations working together.\n\nThe final decision on whether these policy options are adopted – and how they are prioritised – will be determined by government through normal political processes.\n\nThe recommendations for practice (recommendations 13 to 24) support and complement – and are supported by – these policy options.\n\n## Who should take action?\n\nAs well as the Department of Health, the following should be involved:\n\n\n\nChief Medical Officer\n\nNational Clinical Director for Coronary Heart Disease\n\nGovernment Chief Scientific Adviser\n\nDepartment of Health Chief Scientist\n\nAdvertising Standards Authority\n\nDepartment for Business, Innovation and Skills\n\nDepartment for Culture, Media and Sport\n\nDepartment for Education\n\nDepartment for Environment, Food and Rural Affairs\n\nDepartment for Transport\n\nDepartment of Communities and Local Government\n\nFood Standards Agency\n\nHM Treasury\n\nNational Institute for Health Research\n\nOfcom\n\n\n\nOther research organisations (for example, the Medical Research Council and the Economic and Social Research Council).\n\nOther key players include:\n\n\n\ncaterers\n\nfood and drink producers\n\nfood and drink retailers\n\nmarketing and media industries\n\nnational, non-governmental organisations including, for example, the British Heart Foundation, Cancer Research UK, Diabetes UK, National Heart Forum, the Stroke Association and other chronic disease charities\n\nthe farming sector.\n\n\n\n## Recommendation 1 Salt\n\nHigh levels of salt in the diet are linked with high blood pressure which, in turn, can lead to stroke and coronary heart disease. High levels of salt in processed food have a major impact on the total amount consumed by the population.\n\nOver recent years the food industry, working with the Food Standards Agency, has made considerable progress in reducing salt in everyday foods. As a result, products with no added salt are now increasingly available. However, it is taking too long to reduce average salt intake among the population. Furthermore, average intake among children is above the recommended level – and some children consume as much salt as adults. Progress towards a low-salt diet needs to be accelerated as a matter of urgency.\n\nReduce population-level consumption of salt. To achieve this, the evidence suggests that the following are among the measures that should be considered.\n\nAccelerate the reduction in salt intake among the population. Aim for a maximum intake of 6\xa0g per day per adult by 2015 and 3\xa0g by 2025.\n\nEnsure children's salt intake does not exceed age-appropriate guidelines (these guidelines should be based on up-to-date assessments of the available scientific evidence).\n\nPromote the benefits of a reduction in the population's salt intake to the European Union (EU). Introduce national legislation if necessary.\n\nEnsure national policy on salt in England is not weakened by less effective action in other parts of the EU.\n\nEnsure food producers and caterers continue to reduce the salt content of commonly consumed foods (including bread, meat products, cheese, soups and breakfast cereals). This can be achieved by progressively changing recipes, products and manufacturing and production methods.\n\nEstablish the principle that children under 11 should consume substantially less salt than adults. (This is based on advice from the Scientific Advisory Committee on Nutrition.)\n\nSupport the Food Standards Agency so that it can continue to promote – and take the lead on – the development of EU-wide salt targets for processed foods.\n\nEstablish an independent system for monitoring national salt levels in commonly consumed foods.\n\nEnsure low-salt products are sold more cheaply than their higher salt equivalents.\n\nClearly label products which are naturally high in salt and cannot meaningfully be reformulated. Use the Food Standards Agency-approved traffic light system. The labels should also state that these products should only be consumed occasionally.\n\nDiscourage the use of potassium and other substitutes to replace salt. The aim of avoiding potassium substitution is twofold: to help consumers' readjust their perception of 'saltiness' and to avoid additives which may have other effects on health.\n\nPromote best practice in relation to the reduction of salt consumption, as exemplified in these recommendations, to the wider EU.\n\n## Recommendation 2 Saturated fats\n\nReducing general consumption of saturated fat is crucial to preventing CVD. Over recent years, much has been done (by the Food Standards Agency, consumers and industry) to reduce the population's intake. Consumption levels are gradually moving towards the goal set by the Food Standards Agency: to reduce population intake of saturated fat from 13.3% to below 11% of food energy.\n\nHowever, a further substantial reduction would greatly reduce CVD and deaths from CVD. Taking the example of Japan (where consumption of saturated fat is much lower than in the UK), halving the average intake (from 14% to 6–7% of total energy) might prevent approximately 30,000 CVD deaths annually. It would also prevent a corresponding number of new cases of CVD annually. (Note that low-fat products are not recommended for children under 2 years, but are fine thereafter.)\n\nReduce population-level consumption of saturated fat. To achieve this, the evidence suggests that the following are among the measures that should be considered.\n\nEncourage manufacturers, caterers and producers to reduce substantially the amount of saturated fat in all food products. If necessary, consider supportive legislation. Ensure no manufacturer, caterer or producer is at an unfair advantage as a result.\n\nCreate the conditions whereby products containing lower levels of saturated fat are sold more cheaply than high saturated fat products. Consider legislation and fiscal levers if necessary.\n\nCreate favourable conditions for industry and agriculture to produce dairy products for human consumption that are low in saturated fat.\n\nContinue to promote semi-skimmed milk for children aged over 2 years. This is in line with the American Heart Association's pediatric dietary strategy.\n\n## Recommendation 3 Trans fats\n\nIndustrially-produced trans fatty acids (IPTFAs) constitute a significant health hazard. In recent years many manufacturers and caterers, with the encouragement of the Food Standards Agency and other organisations, have considerably reduced the amount of IPTFAs in their products. However, certain sections of the population may be consuming a substantially higher amount of IPTFAs than average (for instance, those who regularly eat fried fast-food). It is important to protect all social groups from the adverse effects of IPTFAs.\n\nIn some countries and regions (for instance, Denmark, Austria and New York), IPTFAs have been successfully banned. A study for the European Parliament recently recommended that it, too, should consider an EU-wide ban. In the meantime, some large UK caterers, retailers and producers have removed IPTFAs from their products.\n\nEnsure all groups in the population are protected from the harmful effects of IPTFAs. To achieve this, the evidence suggests that the following are among the measures that should be considered.\n\nEliminate the use of IPTFAs for human consumption.\n\nIn line with other EU countries (specifically, Denmark and Austria), introduce legislation to ensure that IPTFA levels do not exceed 2% in the fats and oils used in food manufacturing and cooking.\n\nDirect the bodies responsible for national surveys to measure and report on consumption of IPTFAs by different population subgroups – rather than only by mean consumption across the population as a whole.\n\nEstablish guidelines for local authorities to monitor independently IPTFA levels in the restaurant, fast-food and home food trades using existing statutory powers (in relation to trading standards or environmental health).\n\nCreate and sustain local and national conditions which support a reduction in the amount of IPTFAs in foods, while ensuring levels of saturated fat are not increased. Encourage the use of vegetable oils high in polyunsaturated and monounsaturated fatty acids to replace oils containing IPTFAs. Saturated fats should not be used as an IPTFA substitute.\n\nDevelop UK-validated guidelines and information for the food service sector and local government on removing IPTFAs from the food preparation process. This will support UK-wide implementation of any legislation produced on IPTFAs.\n\n## Recommendation 4 Marketing and promotions aimed at children and young people\n\nEating and drinking patterns get established at an early age so measures to protect children from the dangers of a poor diet should be given serious consideration.\n\nCurrent advertising restrictions have reduced the number of advertisments for foods high in fat, salt or sugar during television programmes made for children and young people. However, advertisements, promotions, product placements and sponsorship shown between programmes for older audiences also have a powerful influence on children and young people. Marketing bans have been successfully introduced in several other countries; evidence shows that a 9pm watershed for such TV advertisements would reduce children and young people's exposure to this type of advertising by 82%.\n\nEnsure children and young people under 16 are protected from all forms of marketing, advertising and promotions (including product placements) which encourage an unhealthy diet. To achieve this, the evidence suggests that the following are among the measures that should be considered.\n\nDevelop a comprehensive, agreed set of principles for food and beverage marketing aimed at children and young people. This could be similar to the 'Sydney principles'. They should be based on a child's right to a healthy diet.\n\nExtend TV advertising scheduling restrictions on food and drink high in fat, salt or sugar (as determined by the Food Standards Agency's nutrient profile) up to 9pm.\n\nDevelop equivalent standards, supported by legislation, to restrict the marketing, advertising and promotion of food and drink high in fat, salt or sugar via all non-broadcast media. This includes manufacturers' websites, use of the Internet generally, mobile phones and other new technologies.\n\nEnsure restrictions for non-broadcast media on advertising, marketing and promotion of food and drink high in fat, salt or sugar are underpinned by the Food Standards Agency nutrient profiling system.\n\n## Recommendation 5 Commercial interests\n\nIf deaths and illnesses associated with CVD are to be reduced, it is important that food and drink manufacturers, retailers, caterers, producers and growers, along with associated organisations, deliver goods that underpin this goal. Many commercial organisations are already taking positive action.\n\nEnsure dealings between government, government agencies and the commercial sector are conducted in a transparent manner that supports public health objectives and is in line with best practice. (This includes full disclosure of interests.) To achieve this, the following are among the measures that should be considered.\n\nEncourage best practice for all meetings, including lobbying, between the food and drink industry and government (and government agencies). This includes full disclosure of interests by all parties. It also involves a requirement that information provided by the food and drink, catering and agriculture industries is available for the general public and is auditable.\n\n## Recommendation 6 Product labelling\n\nClear labelling which describes the content of food and drink products is important because it helps consumers to make informed choices. It may also be an important means of encouraging manufacturers and retailers to reformulate processed foods high in saturated fats, salt and added sugars. Evidence shows that simple traffic light labelling consistently works better than more complex schemes.\n\nEnsure the Food Standards Agency's integrated front-of-pack labelling system is rapidly implemented.\n\nEnsure labelling regulations in England are not adversely influenced by EU regulation.To achieve this, the evidence suggests that the following are among the measures that should be considered.\n\nEstablish the Food Standards Agency's single, integrated, front-of-pack traffic light colour-coded system as the national standard for food and drink products sold in England. This includes the simple, traffic light, colour-coding visual icon and text which indicates whether food or drink contains a 'high', 'medium' or 'low' level of salt, fat or sugar. It also includes text to indicate the product's percentage contribution to the guideline daily amount (GDA) from each category.\n\nConsider using legislation to ensure universal implementation of the Food Standards Agency's front-of-pack traffic light labelling system.\n\nDevelop and implement nutritional labelling for use on shelves or packaging for bread, cakes, meat and dairy products displayed in a loose or unwrapped state or packed on the premises. The labelling should be consistent with the Food Standards Agency's traffic light labelling system.\n\nEnsure food and drink labelling is consistent in format and content. In particular, it should refer to salt (as opposed to sodium), the content per 100\xa0g and use kcals as the measure of energy.\n\nContinue to support the Food Standards Agency in providing clear information about healthy eating.\n\nEnsure the UK continues to set the standard of best practice by pursuing exemption from potentially less effective EU food labelling regulations when appropriate.\n\n## Recommendation 7 Health impact assessment (see also recommendation 22)\n\nPolicies in a wide variety of areas can have a positive or negative impact on CVD risk factors – and frequently the consequences are unintended. The Cabinet Office has indicated that, where relevant, government departments should assess the impact of policies on the health of the population. Well-developed tools and techniques exist for achieving this.\n\nEnsure government policy is assessed for its impact on CVD.\n\nEnsure any such assessments are adequately incorporated into the policy making process. To achieve this, the following are among the measures that should be considered.\n\nAssess (in line with the Cabinet Office requirement) all public policy and programmes for the potential impact (positive and negative) on CVD and other related chronic diseases. In addition, assess the potential impact on health inequalities. Assessments should be carried out using health and policy impact assessment and other similar, existing tools.\n\nMonitor the outcomes of policy and programmes after the assessment and use them to follow up and amend future plans.\n\nMake health impact assessment mandatory in specific scenarios. (Note that strategic environmental assessment, environmental impact assessment and regulatory impact assessment are already mandatory in certain contexts.)\n\n## Recommendation 8 Common agricultural policy\n\nThe common agricultural policy (CAP) is the overarching framework used by EU member countries to form their own agricultural policies. The burden of diet-related disease has grown considerably since CAP was first implemented.\n\nCAP reform offers a significant opportunity to address the burden of CVD. However, there are still a number of significant 'distortions' in relation to certain food prices and production processes which potentially increase the burden of disease. Further reform should aim to remove these distortions to promote health and wellbeing and to provide a basis for UK government action to prevent CVD.\n\nThe CAP has two main 'pillars': market measures (first pillar) and rural development policy (second pillar). Recent CAP reform has shifted money from the first to the second pillar which now focuses more on 'public goods'. However, health has not been formally recognised as a 'public good'.\n\nCAP reforms have begun to address this issue, but a clearer focus on CVD and its antecedents (that is, the production of foods high in fat, sugar or salt) is needed.\n\nEnsure promoting health and reducing disease is made an explicit part of the CAP's 'public goods' so that European money promotes the wellbeing of EU citizens.\n\nEnsure CAP spending takes adequate account of its potential impact on CVD risk factors and is used in a way that optimises the public health outcomes.\n\nTo achieve this, the following are among the measures that should be considered.\n\nNegotiate at EU and national level to ensure the CAP takes account of public health issues. Health benefits should be an explicit, legitimate outcome of CAP spending. This can be achieved through formal recognition of health as a 'public good'.\n\nProgressively phase out payments under 'pillar one' so that all payments fall under 'pillar two'. This will allow for better protection of health, climate and the environment. It will also improve and stimulate economic growth.\n\nEncourage the principle that future 'pillar two' funds should reward or encourage the production of highly nutritious foods such as fruit, vegetables, whole grains and leaner meats.\n\nNegotiate to ensure the European Commission's impact assessment procedure takes cardiovascular health and other health issues into account. (Impact assessment is part of the European Commission's strategic planning and programming cycle.)\n\n## Recommendation 9 Physically active travel (see also recommendation 21)\n\nTravel offers an important opportunity to help people become more physically active. However, inactive modes of transport have increasingly dominated in recent years. In England, schemes to encourage people to opt for more physically active forms of travel (such as walking and cycling) are 'patchy'.\n\nEnsure government funding supports physically active modes of travel.To achieve this, the evidence suggests that the following are among the measures that should be considered.\n\nEnsure guidance for local transport plans supports physically active travel. This can be achieved by allocating a percentage of the integrated block allocation fund to schemes which support walking and cycling as modes of transport.\n\nCreate an environment and incentives which promote physical activity, including physically active travel to and at work.\n\nConsider and address factors which discourage physical activity, including physically active travel to and at work. An example of the latter is subsidised parking.\n\n## Recommendation 10 Public sector catering guidelines (see also recommendations 19 and 20)\n\nPublic sector organisations are important providers of food and drink to large sections of the population. It is estimated that they provide around one in three meals eaten outside the home. Hence, an effective way to reduce the risk of CVD would be to improve the nutritional quality of the food and drink they provide.\n\nEnsure publicly funded food and drink provision contributes to a healthy, balanced diet and the prevention of CVD.\n\nEnsure public sector catering practice offers a good example of what can be done to promote a healthy, balanced diet.\n\nTo achieve this, the evidence suggests that the following are among the measures that should be considered.\n\nEnsure all publicly funded catering departments meet Food Standards Agency-approved dietary guidelines. This includes catering in schools, hospitals and public sector work canteens.\n\nAssess the effectiveness of the 'Healthier food mark' pilot. If successful, develop a timetable to implement it on a permanent basis.\n\n## Recommendation 11 Take-aways and other food outlets (see also recommendations 23 and 24)\n\nFood from take-aways and other outlets (the 'informal eating out sector') comprises a significant part of many people's diet. Local planning authorities have powers to control fast-food outlets.\n\nEmpower local authorities to influence planning permission for food retail outlets in relation to preventing and reducing CVD. To achieve this, the following are among the measures that should be considered.\n\nEncourage local planning authorities to restrict planning permission for take-aways and other food retail outlets in specific areas (for example, within walking distance of schools). Help them implement existing planning policy guidance in line with public health objectives. (See also recommendation 12.)\n\nReview and amend 'classes of use' orders for England to address disease prevention via the concentration of outlets in a given area. These orders are set out in the Town and Country Planning (Use Classes) Order 1987 and subsequent amendments.\n\n## Recommendation 12 Monitoring\n\nCVD is responsible for around 33% of the observed gap in life expectancy among people living in areas with the worst health and deprivation indicators compared with those living elsewhere in England. Independent monitoring, using a full range of available data, is vital when assessing the need for additional measures to address such health inequalities, including those related to CVD.\n\nEnsure all appropriate data are available for monitoring and analysis to inform CVD prevention policy.\n\nTo achieve this, the evidence suggests that the following are among the measures that should be considered.\n\nEnsure data on CVD prevention is available for scrutiny by the public health community as a whole.\n\nEnsure new econometric data (including pooled consumer purchasing data) are rapidly made available by industry for monitoring and analysis by independent agencies.\n\nUse population surveys (including the 'National diet and nutrition survey' [NDNS] and the 'Low income diet and nutrition survey' [LIDNS]) and data from all relevant sources to monitor intake of nutrients for all population groups. (Sources include: the Food Standards Agency, Department of Health, Department for Environment, Food and Rural Affairs, Office for National Statistics, the Public Health Observatories, academic and other researchers.)\n\nMonitor the intake of salt, trans fatty acids, saturated fatty acids and mono and polyunsaturated fatty acids among different population groups and report the findings for those groups.\n\nSupport the 'National diet and nutrition survey' and the 'Low income diet and nutrition survey'.\n\nEnsure the CVD module (including lipid profile measures) routinely appears in the 'Health surveys for England'.\n\nDevelop an international public health information system (resembling GLOBALink) for CVD prevention and use it to ensure widespread dissemination of these data.\n\n# Recommendations for practice\n\n## Recommendations 13–18 Regional CVD prevention programmes\n\nRecommendations13–18 provide for a comprehensive regional and local CVD prevention programme. They should all be implemented, following the order set out below and in conjunction with recommendations 1–12, which they support. The aim is to plan, develop and maintain effective programmes. The target population for recommendations 13–18 and the list of who should take action is outlined below. This is followed by the specific actions to be taken in relation to each element of the programme.\n\nThe population that falls within a local authority, primary care trust (PCT) area or across combined PCT and local authority areas or within a particular region of the country.\n\nCommissioners and providers of public health intervention programmes within:\n\ncity region partnerships\n\ngovernment regional offices\n\nlocal authorities\n\nlocal strategic partnerships\n\nnon-governmental organisations, including charities and community groups\n\nPCTs\n\nstrategic health authorities.\n\n## Recommendation 13 Regional CVD prevention programmes – good practice principles\n\nEnsure a CVD prevention programme comprises intense, multi-component interventions.\n\nEnsure it takes into account issues identified in recommendations 1 to 12.\n\nEnsure it includes initiatives aimed at the whole population (such as local policy and regulatory initiatives) which complement existing programmes aimed at individuals at high risk of CVD.\n\nEnsure it is sustainable for a minimum of 5 years.\n\nEnsure appropriate time and resources are allocated for all stages, including planning and evaluation.\n\n## Recommendation 14 Regional CVD prevention programmes – preparation\n\nGain a good understanding of the prevalence and incidence of CVD in the community. Find out about any previous CVD prevention initiatives that have been run (including any positive or negative experiences).\n\nConsider how existing policies relating to food, tobacco control and physical activity, including those developed by the local authority, may impact on the prevalence of CVD locally.\n\nGauge the community's level of knowledge of, and beliefs about, CVD risk factors. This includes beliefs that smoking is the only solace in life for people with little money, or that only people who have a lot of money eat salad.\n\nGauge how confident people in the community are that they can change their behaviour to reduce the risks of CVD. (See 'Behaviour change' [NICE public health guidance 6].)\n\nIdentify groups of the population who are disproportionately affected by CVD and develop strategies with them to address their needs.\n\nTake into account the community's exposure to risk factors (factors currently facing adults and those emerging for children and younger people).\n\n## Recommendation 15 Regional CVD prevention programmes – programme development\n\nDevelop a population-based approach.\n\nEnsure a 'programme theory' is developed and used to underpin the programme. This should cover the reasons why particular actions are expected to have particular outcomes.\n\nEnsure the programme helps address local area agreement targets and acts as a local incentive for world class commissioning in the NHS. Also ensure it tackles health inequalities.\n\nLink the programme with existing strategies for targeting people at particularly high risk of CVD and take account of ongoing, accredited screening activities by GPs and other healthcare professionals. This includes the NHS Health Checks programme.\n\nWork closely with regional and local authorities and other organisations to promote policies which are likely to encourage healthier eating, tobacco control and increased physical activity. Policies may cover spatial planning, transport, food retailing and procurement. Organisations that may get involved could include statutory, public sector and civil society groups (examples of the latter are charities, clubs, self-help and community groups).When developing CVD programmes, take account of relevant recommendations made within the following NICE guidance:\n\n\n\n'Brief interventions and referrals for smoking cessation' (NICE public health guidance 1)\n\n'Four commonly used methods to increase physical activity' (NICE public health guidance 2)\n\n'Workplace interventions to promote smoking cessation' (NICE public health guidance 5)\n\n'Behaviour change' (NICE public health guidance 6)\n\n'Physical activity and the environment' (NICE public health guidance 8)\n\n'Community engagement' (NICE public health guidance 9)\n\n'Smoking cessation services' (NICE public health guidance 10)\n\n'Maternal and child nutrition' (NICE public health guidance 11)\n\n'Promoting physical activity in the workplace' (NICE public health guidance 13)\n\n'Identifying and supporting people most at risk of dying prematurely' (NICE public health guidance 15)\n\n'Physical activity and children' (NICE public health guidance 17)\n\n'Obesity' (NICE clinical guideline 43).\n\n\n\nOnly develop, plan and implement a strategic, integrated media campaign as part of a wider package of interventions to address CVD risk factors. Media campaigns should be based on an acknowledged theoretical framework.\n\n## Recommendation 16 Regional CVD prevention programmes – resources\n\nEnsure the programme lasts a minimum of 5 years (while subject to annual evaluation reports) to maximise its potential impact.\n\nProduce a long-term plan – and gain political commitment – for funding to ensure the programme has adequate resources and is sustainable beyond the end of the research or evaluation period.\n\nEnsure the programme is adequately staffed. Avoid adding CVD prevention to the workload of existing staff without relieving them of other tasks.\n\nEnsure volunteers are an additional (rather than a core) resource and that their training and support is adequately resourced.\n\nEnsure steps are taken to retain staff.\n\nWhere staff are recruited from the local community ensure, as far as possible, that they reflect the local culture and ethnic mix.\n\nEnsure there are effective links with other existing and relevant community initiatives.\n\n## Recommendation 17 Regional CVD prevention programmes – leadership\n\nAct as leader and governor of CVD prevention. Identify and articulate local community needs and aspirations and how these may impact on the community's risk of CVD. Reconcile these needs and aspirations or arbitrate on them to help prevent CVD.\n\nIdentify senior figures within PCTs and local authorities as champions for CVD prevention.\n\nIdentify people to lead the CVD programme, including members of the local community. Identify in advance – and provide for – the training and other needs of these potential leaders.\n\nDevelop systems within local strategic partnerships and other subregional or regional partnerships for agreeing shared priorities with other organisations involved in CVD prevention. Ensure senior staff are involved, as appropriate.\n\n## Recommendation 18 Regional CVD prevention programmes – evaluation\n\nEstablish baseline measures before the CVD programme begins. These should include lifestyle and other factors that influence cardiovascular risk, as well as figures on CVD prevalence and mortality. The establishment of such measures should be budgeted for as part of the programme.\n\nEnsure evaluation is built in (in line with 'Behaviour change' [NICE public health guidance 6].). It should include the policies and activities of partner organisations which are likely to influence CVD prevalence.\n\nEnsure appropriate methods (using multiple approaches and measures) are used to evaluate the programme's processes, outcomes and measures or indicators. Evaluation should include determining how acceptable the programme is to the local community or the groups targeted.\n\nEnsure the results of evaluation are freely available and shared with partner organisations. Use the findings to inform future activities.\n\n## Recommendation 19 Children and young people\n\nChildren and young people aged under 16 years.\n\nParents and carers of children and young people under the age of 16.\n\nLocal authorities (providers of cultural and leisure services).\n\nSchools (governors and teachers).\n\nCatering staff.\n\nNursery nurses and workers in pre-school day care settings such as nurseries.\n\nManagers of children's centres.\n\nHelp children and young people to have a healthy diet and lifestyle. This includes helping them to develop positive, life-long habits in relation to food. This can be achieved by ensuring the messages conveyed about food, the food and drink available – and where it is consumed – is conducive to a healthy diet. (For more details see 'Maternal and child nutrition' [NICE public health guidance 11] and 'Physical activity and children' [NICE public health guidance 17].)\n\nWhen public money is used to procure food and drink in venues outside the direct control of the public sector, ensure those venues provide a range of affordable healthier options (including from vending machines). Ideally, the healthier options should be cheaper than the less healthy alternatives. For instance, carbonated or sweetened drinks should not be the only options and fruit and water should be available at an affordable price. (Examples of when public money is used in this way include school visits to museums, sports centres, cinemas and fun parks.)\n\nEncourage venues frequented by children and young people and supported by public money to resist sponsorship or product placement from companies associated with foods high in fat, sugar or salt. (This includes fun parks and museums.)\n\nOrganisations in the public sector should avoid sponsorship from companies associated with foods high in fat, sugar or salt.\n\n## Recommendation 20 Public sector food provision\n\nAnyone who eats food provided by public sector organisations.\n\nEducation authorities.\n\nGovernment departments and agencies.\n\nLocal authorities.\n\nNHS organisations.\n\nPrison services.\n\nThe armed forces.\n\nThe emergency services.\n\nEnsure all food procured by, and provided for, people working in the public sector and all food provided for people who use public services:\n\n\n\nis low in salt and saturated fats\n\nis nutritionally balanced and varied, in line with recommendations made in the 'eatwell plate'\n\n\n\ndoes not contain industrially produced trans fatty acids (IPTFAs).\n\n## Recommendation 21 Physical activity\n\nEveryone.\n\nLocal authorities.\n\nPCTs.\n\nEnsure the physical environment encourages people to be physically active (see 'Physical activity and the environment' [NICE public health guidance 8]). Implement changes where necessary. This includes prioritising the needs of pedestrians and cyclists over motorists when developing or redeveloping highways. It also includes developing and implementing public sector workplace travel plans that incorporate physical activity (see 'Promoting physical activity in the workplace' [NICE public health guidance 13]). Encourage and support employers in other sectors to do the same.\n\nEnsure the need for children and young people to be physically active is addressed (see 'Promoting physical activity for children and young people' [NICE public health guidance 17]). This includes providing adequate play spaces and opportunities for formal and informal physical activity.\n\nAudit bye-laws and amend those that prohibit physical activity in public spaces (such as those that prohibit ball games).\n\nConsider offering free swimming to parents and carers who accompany children aged under 5 years to swimming facilities.\n\nApportion part of the local transport plan (LTP) block allocation to promote walking, cycling and other forms of travel that involve physical activity. The proportion allocated should be in line with growth targets for the use of these modes of transport.\n\nEnsure cycle tracks created under the Cycle Tracks Act 1984 are part of the definitive map (the legal record of public rights of way).\n\nAlign all 'planning gain' agreements with the promotion of heart health to ensure there is funding to support physically active travel. (For example, Section 106 agreements are sometimes used to bring development in line with sustainable development objectives.)\n\n## Recommendation 22 Health impact assessments of regional and local plans and policies\n\nEveryone.\n\nLocal policy makers.\n\nPCTs.\n\nRegional and local government.\n\nUse a variety of methods to assess the potential impact (positive and negative) that all local and regional policies and plans may have on rates of CVD and related chronic diseases. Take account of any potential impact on health inequalities.\n\nIdentify those policies and plans that are likely to have a significant impact on CVD rates. This can be achieved by using screening questions that cover the social, economic and environmental determinants of CVD.\n\nMonitor the outcomes following an assessment and use this to follow up and amend plans.\n\nIdentify where expertise is required to carry out assessments and where this is available locally.\n\nIdentify the training and support needs of staff involved in carrying out assessments and provide the necessary resources.\n\n## Recommendation 23 Take-aways and other food outlets\n\nEveryone but particularly those who frequently use these food outlets.\n\n## Who should take action?\n\nEnvironmental health officers.\n\nLocal government planning departments.\n\nPublic health nutritionists.\n\nTrading standards officers.\n\nUse bye-laws to regulate the opening hours of take-aways and other food outlets, particularly those near schools that specialise in foods high in fat, salt or sugar.\n\nUse existing powers to set limits for the number of take-aways and other food outlets in a given area. Directives should specify the distance from schools and the maximum number that can be located in certain areas.\n\nHelp owners and managers of take-aways and other food outlets to improve the nutritional quality of the food they provide. This could include monitoring the type of food for sale and advice on content and preparation techniques.\n\n## Recommendation 24 Nutrition training\n\nPeople eating snacks and meals provided by public sector services.\n\nCaterers.\n\nChartered Institute of Environmental Health (CIEH).\n\nLocal authorities.\n\nProviders of hygiene training.\n\nThe food and farming network (Feast).\n\nEnsure the links between nutrition and health are an integral part of training for catering managers. In particular, they should be made aware of the adverse effect that frying practices and the use of salt, industrial trans fats and saturated fats can have on health.\n\nEnsure they are aware of the healthy alternatives to frying and to using salt and sugar excessively, based on the 'eatwell plate'.\n\nThe PDG considers that all the recommended measures are cost effective.\n\nFor the research recommendations and gaps in research, see section 5 and appendix D respectively.\n\n Blas E, Gilson L, Kelly MP et al. (2008) Addressing social determinants of health inequities: what can the state and civil society do? The Lancet 372: 1684–9. Kelly MP, Stewart E, Morgan A et al. (2009a) A conceptual framework for public health: NICE's emerging approach. Public Health 123: e14–20. Marmot M (2010) Fair society, healthy lives: strategic review of health inequalities in England post 2010. Rose G (2008) Rose's strategy of preventive medicine. Commentary by Khaw KT, Marmot M. Oxford: Oxford University Press.\n\n American Heart Association (2005) Dietary recommendations for children and adolescents. A guide for practitioners: consensus statement from the American Heart Association. Circulation 112: 2061–75.\n\n Office of Communications (2006) Annex 7 – impact assessment. Annex to consultation on television advertising of food and drink to children.\n\n Swinburn B, Sacks G, Lobstein T et al. (2007) The 'Sydney principles' for reducing the commercial promotion of foods and beverages to children. Public Health Nutrition 11 (9): 881–6.\n\n Kelly B, Hughes C, Chapman K et al. (2009b) Consumer testing of the acceptability and effectiveness of front-of-pack food labelling systems for the Australian grocery market. Health Promotion International 24 (2): 120–9.\n\n Lloyd Williams F, Mwatsama M, Birt C et al. (2008) Estimating the cardiovascular mortality burden attributable to the European Common Agricultural Policy on dietary saturated fats. Geneva: World Health Organization. Lock K, Pomerleau J (2005) Fruit and vegetable policy in the European Union: its effect on cardiovascular disease. Brussels: European Health Network.\n\n The scope of what are regarded as 'European public goods' in the EU is broader than the strict definition of a 'public good' used by some economists.\n\n Pawson R (2001) Evidence based policy: 2. The promise of 'realist synthesis'.\n\n HM Government; Communities and Local Government (2008) Creating strong, safe and prosperous communities. Statutory guidance. London: Community and Local Government Publications.", 'Public health need and practice': "Cardiovascular disease (CVD) is generally due to reduced blood flow to the heart, brain or body caused by atheroma or thrombosis. It is increasingly common after the age of 60, but rare below the age of 30. Plaques (plates) of fatty atheroma build up in different arteries during adult life. These can eventually cause narrowing of the arteries, or trigger a local thrombosis (blood clot) which completely blocks the blood flow.\n\nThe main types of CVD are: coronary heart disease (CHD), stroke and peripheral arterial disease (PVD) (British Heart Foundation 2009a).\n\nGlobally, CVD is the leading cause of death (World Health Organization 2007). It is also associated with a large burden of preventable illnesses.\n\n# CVD in England and the UK\n\nIn England in 2007, CVD led to nearly 159,000 deaths (accounting for nearly 34% of all deaths in England). This includes 74,185 deaths from coronary heart disease (CHD) and 43,539 from stroke (British Heart Foundation 2009b).\n\nMost premature deaths from CVD – that is, among people aged less than 75 – are preventable. In 2006, CVD accounted for around 30% of premature deaths among men and 21% among women, accounting for just over 40,000 premature deaths in that year. The purpose of preventing premature death from CVD is to enable high quality life for as long as possible.\n\nAn estimated 2.8 million men and 2.8 million women in the UK are living with CVD. The British Heart Foundation estimates that around 111,000 people have a stroke for the first time every year. (Its report notes that national stroke audit data is more conservative, putting the estimated 'first time' strokes a year at approximately 72,000 [33,000 among men and 39,000 among women] (British Heart Foundation 2009c).\n\nIn addition, there are an estimated 96,000 new cases of angina in the UK each year (52,000 among men and about 43,000 among women) and around 113,000 heart attacks per year (67,000 among men and 46,000 among women) (British Heart Foundation 2009c). New cases of heart failure total around 68,000 a year (about 38,000 among men and 30,000 among women).\n\nOverall, CVD costs the UK approximately £30 billion annually (Luengo-Fernandez et al. 2006).\n\nDespite recent improvements, death rates in the UK from CVD are relatively high compared with other developed countries (only Ireland and Finland have higher rates). There is also considerable variation within the UK itself – geographically, ethnically and socially. For instance, premature death rates from CVD are up to six times higher among lower socioeconomic groups than among more affluent groups (O'Flaherty et al. 2009). In addition, death rates from CVD are approximately 50% higher than average among South Asian groups (Allender et al. 2007).\n\nThe reduction in CVD-related risks among younger men (and perhaps women) over previous years seems to have stalled in England from around 2003. This is also the case in a number of other countries including Scotland (O'Flaherty et al. 2009), Australia (Wilson and Siskind 1995) and the United States (Ford and Capewell 2007).\n\nThe higher incidence of CVD is a major reason why people living in areas with the worst health and deprivation indicators have a lower life expectancy compared with those living elsewhere in England. For males, it accounts for 35% of this gap in life expectancy (of that, approximately 25% is due to CHD and 10% due to other forms of CVD). Among females, it accounts for 30% of the gap (DH 2008a).\n\n# Risk factors for CVD\n\nLifetime risk of CVD is strongly influenced by diet and physical activity levels since childhood (National Heart Forum 2003). The risk among adults is determined by a variety of 'upstream' factors (such as food production and availability, access to a safe environment that encourages physical activity and access to education). It is also influenced by 'downstream' behavioural issues (such as diet and smoking).\n\nIn more than 90% of cases, the risk of a first heart attack is related to nine potentially modifiable risk factors (Yusuf et al. 2004):\n\nsmoking/tobacco use\n\npoor diet\n\nhigh blood cholesterol\n\nhigh blood pressure\n\ninsufficient physical activity\n\noverweight/obesity\n\ndiabetes\n\npsychosocial stress (linked to people's ability to influence the potentially stressful environments in which they live)\n\nexcess alcohol consumption.\n\nOther factors, such as maternal nutrition and air pollution may also be linked to the disease (Allender et al. 2007).\n\n# How these risk factors cause many other illnesses\n\nAddressing diet, physical inactivity, smoking and excessive alcohol consumption to reduce CVD will also help reduce a wide range of other chronic conditions. This includes many of the other main causes of death and illness in England such as type 2 diabetes and many common cancers (see also 3.73).\n\nType 2 diabetes, which affects over two million people in the UK, is associated with being overweight and sedentary. (It also accounts for an estimated 5% of UK healthcare expenditure.) Between 8% and 42% of certain cancers (endometrial, breast, and colon) are attributable to excess body fat.\n\nThe report 'Food matters' (Cabinet Office 2008) estimates that a total of around 70,000 lives would be saved each year in the UK if people's diet matched the nutritional guidelines on fruit and vegetable consumption and saturated fat, added sugar and salt intake.\n\n# Tackling the risk factors\n\nReducing the risks, for example, by quitting tobacco or improving the diet (so reducing cholesterol or blood pressure levels) can rapidly reduce the likelihood of developing CVD. Actions which impact on the whole population most effectively reduce these risk factors (Kelly et al. 2009a).\n\nSome population-based prevention programmes have been accompanied by a substantial reduction in the rate of CVD deaths. However, the degree to which these are attributable to the programme is contested. This is due to a number of reasons including:\n\nIt is difficult to design studies which evaluate entire cities, regions or countries or are of sufficient duration.\n\nControl sites can become 'contaminated' (that is, if the intervention affects people living in the control area).\n\nThere may be unreasonable expectations about the speed of change.\n\nBehaviour change is often erratic or slow.\n\nFailure to address 'upstream' influences such as policy or manufacturing and commercial practices.\n\nThe crucial importance of using policy to modify population-wide CVD risk factors has been recognised on an international, European and national level. For example, the World Health Organization's (WHO) first global treaty on health, the 'Framework convention on tobacco control' (2003) undertook to enact key tobacco control measures, such as tobacco tax increases, smokefree public places and tobacco advertising controls. Parties to the treaty included the UK.\n\nIn 2004, WHO member states also agreed to a non-binding global strategy on diet, physical activity and health. In addition, since 1993 the European Union (EU) has legislated on issues such as advertising and the labelling of consumer products like food and tobacco.\n\nIn 2009, the Cardio and Vascular Coalition published 'Destination 2020', the voluntary sector's plan for cardiac and vascular health in England (Cardio and Vascular Coalition 2009).\n\n# Government policy\n\nGovernment policy in many areas influences CVD. The 'Choosing health' white paper (DH 2004) set priorities for action on nutrition, physical activity, obesity and tobacco control. It was supported by delivery plans on food, physical activity and tobacco control, including the provision of NHS Stop Smoking Services.\n\nSince that time, a wide variety of policy documents have been published including:\n\n'Active travel strategy' (Department for Transport 2010)\n\n'A smokefree future: a comprehensive tobacco control strategy for England' (DH 2010)\n\n'Be active be healthy. A plan for getting the nation moving' (DH 2009a)\n\n'Commissioning framework for health and well-being' (DH 2007a)\n\n'Delivering choosing health: making healthier choices easier' (DH 2005a)\n\n'Food 2030' (Department for Environment, Food and Rural Affairs 2010)\n\n'Health challenge England – next steps for choosing health' (DH 2006a)\n\n'Health inequalities: progress and next steps' (DH 2008b)\n\n'Healthy weight, healthy lives: a cross-government strategy for England' (DH 2008c)\n\n'National stroke strategy' (DH 2007b)\n\n'NHS 2010 – 2015: from good to great. Preventative, people-centred, productive' (DH 2009b)\n\n'Our health, our care, our say' (DH 2006b)\n\n'Putting prevention first – vascular checks: risk assessment and management' (DH 2008d)\n\n'Tackling health inequalities – a programme for action' (DH 2003)\n\n'Tackling health inequalities: what works' (DH 2005b)\n\n'Tackling health inequalities: 2007 status report on the programme for action' (DH 2008a)\n\n'The NHS in England: the operating framework for 2006/7' (DH 2006c)\n\n'The NHS in England: the operating framework for 2008/9' (DH 2007c)\n\n'Wanless report: securing good health for the whole population' (Wanless 2004).", 'Considerations': "The Programme Development Group (PDG) took account of a number of factors and issues when developing the recommendations.\n\n# Introduction\n\nEvidence was presented on how to prevent or reduce the combination of modifiable risk factors that can cause cardiovascular disease (CVD). The PDG also considered evidence and expert testimony on separate key risk factors. The reviews, together with the expert testimonies, are listed in appendix A. Relevant existing NICE guidance was also summarised.\n\nThe key CVD risk factors that can be modified are: smoking, a poor diet, obesity, lack of physical activity and high alcohol consumption (Emberson et al. 2004; Yusuf et al. 2004). CVD risk factors tend to 'cluster together'. Thus people who smoke are more likely to have a poor diet and exercise less. This 'clustering' also tends to have a disproportionate effect on people who are disadvantaged, further accentuating health inequalities.\n\nThe PDG noted that approximately 100,000 people die from smoking-related diseases in the UK every year. Tobacco accounts for approximately 29% of deaths from cancer, 13% of cardiovascular deaths and 30% of deaths from respiratory disease (Action on Smoking and Health 2008). It also acknowledged that smoking accounts for over half the disproportionate burden of illnesses experienced by disadvantaged groups. The PDG strongly endorsed the national tobacco control measures set out in 'Beyond smoking kills' (Action on Smoking and Health 2008).\n\nApproaches to helping people quit smoking, or to stop using other forms of tobacco, are covered by recommendations made in other NICE guidance. This includes: 'Smoking cessation services' (NICE public health guidance 10); 'Workplace interventions to promote smoking cessation' (NICE public health guidance 5) and 'Brief interventions and referral for smoking cessation' (NICE public health guidance 1). As a result, tobacco issues are not covered in this guidance.\n\nThe PDG noted that nicotine replacement therapy (NRT) can help to reduce CVD among people who are addicted to nicotine. It fully endorses the Tobacco Advisory Group's recommendations on the regulation and marketing of NRT (Royal College of Physicians 2007). (The report advocates making NRT more acceptable and accessible to people who smoke and who find it impossible to quit.)\n\nTaking a population-based approach, the PDG focused on the major contributors to CVD risk found in the typical UK diet. These include: a high intake of saturated and industrially-produced trans fatty acids and salt. It acknowledged and supports the work of the Food Standards Agency and other organisations (such as the Advertising Standards Authority) in helping to reduce general consumption of these products. However, it believes further action is essential to achieve greater reductions in premature death and disease and to reduce health inequalities.\n\nA consistent message on lifestyle risk factors related to CVD is important.\n\nThe recommendations made in this guidance are not intended to replace existing advice to the public on diet. Rather, they will support the next stage of policy development to tackle the substantial burden of ill health from CVD and other chronic diseases (see also section 2). This includes the development of effective local and regional, population-level programmes to prevent CVD, diabetes, obesity, kidney disease and some common cancers.\n\nIn response to stakeholder feedback, the PDG considered the evidence on interventions targeting specific CVD risk factors. For example, in relation to salt, saturated fats and trans fatty acids.\n\nPolicies to promote physical activity were considered. However, physical activity, smoking and obesity have all been covered by other NICE guidance. In addition, as policies to increase the consumption of fresh fruit and vegetables are already agreed and widely implemented, the PDG did not consider them in detail. (See section 7.)\n\n# Population versus individual approach\n\nCVD risk factors can be reduced in a number of ways. Two different (and frequently, complementary) approaches are often described as 'individual-' and 'population-based'. The former involves interventions which tend to give people direct encouragement to change their behaviour. It may involve providing information about the health risks of their current behaviour, advice (such as to be more active) or prescribing a treatment. Alternatively, it may involve altering the way the NHS and other organisations deliver prevention or healthcare services. Population-based interventions, on the other hand, aim to change the risks from the social, economic, material and environmental factors that affect an entire population. This can be achieved through regulation, legislation, subsidy and taxation or rearranging the physical layout of communities. The PDG focused on population-based approaches.\n\nThe NHS Health Check programme, which was being rolled out as this guidance was published, is aimed at all those aged 40–74. It will ensure everyone in this age range is assessed to determine their risk of heart disease, stroke, kidney disease and diabetes. It will also help them to reduce or manage that risk by providing individually tailored advice. This guidance complements the NHS Health Check programme by focusing on the CVD risk factors for an entire population. It will benefit the NHS, local authorities and industry, as well as individuals, by substantially reducing the number of people who need statin or anti-hypertensive medication. It will also enable services to focus more on those who still need treatment.\n\nThe PDG recognised that smoking cessation and other services that focus on helping individuals to change their behaviour have an important role to play in preventing CVD. Many of these services or approaches have been the focus of earlier NICE guidance (see section 7).\n\nPreviously in the UK, interventions focused on individuals have tended to dominate CVD prevention activities and it is important to identify and treat those who are at higher risk. However, a much larger overall benefit could be achieved by making changes (albeit small ones) among any given population as a whole. As indicated by the Rose hypothesis, a small reduction in risk among a large number of people may prevent many more cases, rather than treating a small number at higher risk. A whole-population approach explicitly focuses on changing everyone's exposure to risk (Rose 2008).\n\nThere is growing evidence in support of the Rose hypothesis (see point above). For instance, data were recently pooled from six general population cohort studies involving 109,954 European participants. These data were analysed to compare different CVD strategies. The analysis found that a 10%, population-wide reduction in blood cholesterol, blood pressure and smoking prevalence would save approximately 9120 lives per million population over 10 years. In contrast, treating 40% of high-risk individuals with a 'polypill' (containing a statin, three half-dose anti-hypertensives and aspirin) would save about 3720 lives per million, even assuming complete, long-term adherence (Cooney et al. 2009).\n\nIt should be noted that, as indicated above, population- and individual-based approaches are both important and can be complementary. They do not have to be considered as alternatives for CVD prevention.\n\n# Population-based approaches: health inequalities\n\nBoth population- and individual-based approaches can influence health inequalities. However, population-based approaches may be more likely to reduce health inequalities. That is because there are many reasons why people who are disadvantaged might find it more difficult to change their behaviour than those who are affluent (Swann et al. 2009). As a result, some activities aimed at individuals may inadvertently increase health inequalities.\n\n'Upstream', population-level interventions include: fiscal measures (such as taxation), national or regional policy and legislation (such as legislation on smokefree public places or the way food is produced); and environmental changes. They are not reliant on an individual's knowledge or ability to choose healthier options. Social and economic action can also change people's risk of CVD (in such cases, the health outcomes are side effects – albeit desirable).\n\nThe recommendations in this guidance do not, in the main, rely on individual choice. Rather, they aim to improve social environments and thus ensure the healthy choice is the easy choice. The emphasis is on changing policies, systems, regulations, the physical environment and other 'upstream' factors. This approach is likely to reduce, rather than increase, health inequalities and is congruent with NICE's guidance on behaviour change (see section 7).\n\n# Population-level approaches: cost effectiveness\n\nThe financial modelling for this guidance shows that considerable cost savings could be made. Using a number of conservative assumptions, it found that halving CVD events across England and Wales (a population of 50 million) would result in discounted savings in healthcare costs of approximately £14 billion per year. Reducing mean population cholesterol or blood pressure levels by 5% would result in discounted annual savings of approximately £0.7 billion and £0.9 billion respectively. Reducing population cardiovascular risk by even 1% would generate discounted savings of approximately £260 million per year.\n\nA 3\xa0g reduction in mean daily salt intake by adults (to achieve a target of 6\xa0g daily) would lead to around 14–20,000 fewer deaths from CVD annually (Strazzullo et al. 2009). Using conservative assumptions, this means approximately £350 million in healthcare costs would be saved. In addition, approximately 130,000 quality-adjusted life years (QALYs) would be gained. A mean reduction of 6\xa0g per day would double the benefits: an annual saving of £700 million in healthcare costs and a gain of around 260,000 QALYs. A 3\xa0g reduction in daily salt intake (a reasonably conservative estimate of what could be achieved) would reduce systolic blood pressure by approximately 2\xa0mmHg. This would equate to a 2% decrease in the risk reduction model. Similarly, a reduction of IPTFA intake to approximately 0.7% of total fat energy might save approximately 571,000 life years – and some £2\xa0billion.\n\n# Epidemiology\n\nThe PDG noted that CVD death rates are no longer falling among young and middle aged people in the UK (for instance, they are no longer falling among those aged 35–54 in the most socially disadvantaged groups in Scotland), the USA and Australia. This reflects a combination of adverse risk factors including smoking, a poor diet and disadvantage (O'Flaherty et al. 2009).\n\nThe prevalence of obesity and over weight continues to rise (National Heart Forum 2010). This, in turn, will lead to a rise in Type 2 diabetes which can increase the risk of CVD. The risk of CHD is particularly high among women with diabetes (Barrett-Connor et al. 1991).\n\nEpidemiological studies indicate that approximately 45–75% of the recent fall in CVD deaths in Westernised industrialised countries was the result of a reduction in the major risk factors. This includes a reduction in smoking prevalence and salt and saturated fat consumption.\n\nThe decline in CVD deaths noted above began long before effective treatments were introduced. In Finland and Iceland, coronary heart disease mortality rates declined by 63% between 1982 and 1997. Seventy five per cent of this was attributed to a reduction in smoking, blood pressure and cholesterol levels (Aspelund et al. 2009; Laatikainen et al. 2005). Sweden also observed a large reduction in CVD-related mortality. This was attributed to dietary reductions in cholesterol and blood pressure. In contrast, blood pressure and cholesterol levels in the UK have, thus far, only fallen a modest amount (Unal et al. 2005).\n\nThe fall in blood pressure and cholesterol levels seen in many Western populations are mainly attributable to lifestyle changes and changes in the wider determinants of health – rather than to medication. Changes to the wider determinants of health have often been as a consequence of public health policy. Preventive services are unlikely to tackle these wider determinants unless supported by national policies and systems (Capewell and O'Flaherty 2008).\n\nData from 'natural experiments' in a whole population (where there were no randomised controlled trials to assess the results) provide compelling evidence of the links between CVD and diet. Rapid and large falls in CVD deaths have been observed in diverse populations including those living in Poland, Mauritius, Finland, Iceland and Norway. In Poland, a 26% decrease in coronary deaths followed a substantial reduction in the consumption of animal fats and increased consumption of vegetable oils and fruit after the break-up of the Soviet Union (Zatonski and Willett 2005). In Mauritius, CVD deaths fell following the introduction of legislation to make it mandatory to use polyunsaturated oils as a substitute for highly saturated cooking oils (Dowse et al. 1995). A substantial fall in CVD deaths also followed a reduction in saturated fat intake in Finland, Iceland, Norway and elsewhere (Zatonski and Willet 2005, Laatikainen et al. 2005.) Conversely, rapid rises in CVD mortality have been seen in China and elsewhere, principally due to the adoption of a Western diet rich in saturated fats (Critchley et al. 2004).\n\nThe PDG discussed the nature and quality of evidence relevant to CVD prevention in whole populations. As indicated in consideration 3.71, this evidence is not drawn from randomised trials alone. The PDG felt it important to consider natural experiments and observational studies as well. The studies had to include a known cause–effect mechanism and an association which was both strong and consistent.\n\n# Primordial prevention\n\nThe PDG noted the importance of taking action to prevent the elevation of CVD risk factors among children, by ensuring they have a healthy, balanced diet and are physically active. This supports the principle of 'primordial prevention'. In this context, this means ensuring the low cholesterol and blood pressure levels seen in normal childhood are maintained throughout life (Labarthe 1999). This is crucial to prevent risk factor 'tracking' whereby, for instance, children with obesity, elevated blood pressure or raised cholesterol are very likely to become adults with above-average risk-factor levels. There is also a strong association between early abuse and neglect and subsequent depression, drug abuse and ischemic heart disease. In addition, some evidence suggests that childhood maltreatment, including both abuse and neglect, influences depression and heart disease in ways that are gender-dependent.\n\nMaternal and fetal nutrition may have an important influence on whether or not people develop CVD later in life. Some evidence suggests that breastfeeding may protect against the development of risk factors for CVD. For example, it is associated with small reductions in blood pressure (Martin et al. 2005) and serum cholesterol. It is also associated with a reduced risk of being overweight (Harder et al. 2005) or having type 2 diabetes. However, the evidence on breastfeeding per se as a means of preventing CVD is weak (Owen et al. 2006; 2008).\n\nThe PDG recognised the many benefits of breastfeeding (including the benefits of continuing to breastfeed beyond the recommended first 6 months after birth). However, it concluded that there was insufficient evidence to make a recommendation related to CVD prevention. Note: NICE's guidance on maternal and child nutrition (NICE public health guidance 11) is referred to in the recommendations.\n\n# Single risk factors\n\nThe Strategy Unit report 'Food matters' (2008) concluded that some 70,000 premature UK deaths could be avoided with a healthier diet. More recently, the Food Standards Agency suggested that poor dietary health in the UK could contribute to up to 150,000 CVD deaths – and a further 155,000 cancer deaths – per year (Food Standards Agency 2009).\n\nMuch of the observational evidence that links diet to CVD is based on individual nutrients. However, the PDG recognised that their impact should also be considered in the context of the whole diet. It recognised that a 'healthier' diet is likely to comprise a favourable balance of food and nutrients and a reduction in the intake of harmful elements. In a typical Western diet, the latter include substantial amounts of salt, saturated fat and trans fats (Hu 2008).\n\nA 'healthier' diet based on fruit, legumes, pulses, other vegetables, wholegrain foods, fish and poultry is consistently associated with lower levels of CVD risk factors (Fung et al. 2001; Lopez-Garcia et al. 2004) and lower CVD mortality (Heidemann et al. 2008; Osler et al. 2001). Vegetarian and 'Mediterranean' diets are also consistently associated with lower CVD mortality (Hu 2008; Mann et al. 2009). Interventions promoting these types of 'healthier' diet have been shown to be highly effective in reducing blood pressure, cholesterol and subsequently CVD (Appel et al. 1997; de Lorgeril et al. 1999).\n\nThe PDG emphasised its support for a healthy diet, as advocated in the 'eatwell' plate (Food Standards Agency 2007).\n\nThe PDG discussed whether it would be feasible for food labels to present calorie content in terms of the hours of physical activity required to use them up. There was no evidence to support this approach. However, there is evidence that presenting the total calorific content on food labels might help reduce intake (Ludwig and Brownell 2009).\n\nSalt intake is a major determinant of CVD in the UK, mainly due to its effect on blood pressure. On average, 70%–90% of people's intake comes from salt added during the manufacturing process; only 10–30% comes from adding it during cooking or at the table. Reducing the population's salt intake will, therefore, involve encouraging the food industry to reduce the salt used in processed foods – as well as encouraging people to reduce the salt they add themselves. The PDG believes the former will best be achieved by using a combination of voluntary and regulatory action.\n\nThe UK population's per capita daily salt intake has fallen by 0.9\xa0g in the last 5 years (a reduction of around 2% per year). This means people are consuming an average 8.6\xa0g of salt per day. The reduction has mainly come about as a result of public awareness campaigns and a voluntary code of practice for industry, led by the Food Standards Agency. The voluntary agreement came into force in 2004 and was followed by progressive targets (in 2006 and 2009). The campaigns, which cost just £15 million, led to approximately 6000 fewer CVD deaths per year, saving the UK economy approximately £1.5 billion per annum. The PDG noted the new targets for 2010 and 2012.\n\nRecent evidence shows that it is feasible to reduce the salt content of foods even further and that this would lead to substantial health benefits (Appel and Anderson 2010). For example, a 10% reduction in the salt content of items like bread and soup is not detected by consumers and does not, therefore, affect consumer choice. This would reduce both strokes and cardiovascular events. A reduction in mean salt intake of 3\xa0g per day for adults (to achieve a target of 6\xa0g daily) would lead to around 14–20,000 fewer deaths from CVD annually (Strazzullo et al. 2009). Using conservative assumptions, this means approximately 130,000 quality-adjusted life years (QALYs) would be gained and around £350 million would be saved in healthcare costs. A reduction of 6\xa0g per day would lead to twice the gain: some 260,000 QALYs and an annual saving of £700 million in healthcare costs.\n\nMany children in the UK may be consuming as much salt as adults (He et al. 2008). Indeed, single helpings of soup or 'meal deals' may contain as much as 3\xa0g of salt. Currently, it is recommended that: children aged from 1 to 3 years should consume no more than 2\xa0g salt a day (0.8\xa0g sodium); from 4 to 6 years they should consume no more than 3\xa0g salt a day (1.2\xa0g sodium); and from 7 to 10 years a maximum of 5\xa0g salt a day (2\xa0g sodium) (Scientific Advisory Committee on Nutrition 2003).\n\nThe PDG discussed the benefits of substituting mono-unsaturated or polyunsaturated fats for saturated fats (Hu 2008) and of reducing total fat consumption. Evidence suggests that reducing saturated fat intake from 14% to 7% of energy intake (to reach the levels seen in Japan) might prevent around 30,000 CVD deaths annually. Changes in CVD deaths are also addressed in consideration 3.27.\n\nThe PDG discussed whether to recommend 'low' rather than 'full-fat' products as there is a risk that if saturated fat is removed to create a 'low-fat' product, it could still be used in another product, with no overall reduction in the population's fat consumption. In addition, the Group felt that there was a risk that some fat content would be replaced with high levels of sugar – so losing some of the benefit of reducing calorie intake.\n\nThe PDG discussed the potential problems that might arise if low-fat milk was made cheaper than full-fat milk. In general, most of the population should aim for a low-fat diet. However, full-fat products are the 'healthier' choice for some groups. Children aged under 2, for instance, may need the additional calories and fat-soluble vitamins found in full-fat milk and the PDG noted that full-fat milk is recommended for this group when cow's milk is being used. The Group was concerned that increasing the relative price of full-fat milk (to make lower-fat milk a more attractive option) could place an added financial burden on disadvantaged groups. However, it also believed that this added burden could be addressed by the tax and benefits system.\n\nThe PDG agreed with the 2009 World Health Organization (WHO) review of industrially-produced trans fatty acids (IPTFAs) – also known as partially hydrogenated vegetable oils (PHVOs). In line with the WHO review, the PDG concluded that IPTFAs are unnecessary and 'toxic' and should be eliminated from foodstuffs. The WHO review states that because IPTFAs are produced by partial hydrogenation they are not normally present naturally in foods and have no known health benefits. The review defined them as 'industrial additives'. It recommended that food services, restaurants, and food and cooking fat manufacturers should avoid their use (Uauy et al. 2009). A recent study commissioned by the European Parliament advocated that an EU-wide ban on IPTFAs should be considered. The PDG noted that IPTFAs have been successfully banned in Denmark and New York City.\n\nThe WHO review of industrially-produced trans fatty acids noted that people who use partially hydrogenated vegetable oils (PHVOs) for cooking would have mean trans fatty acids intakes considerably higher than the national average. The same would be true for those who eat a high proportion of industrially processed or 'fast food'. The review noted that '…replacing TFAs [trans fatty acids] with vegetable oils high in polyunsaturated fatty acids (PUFA) and monounsaturated fatty acids (MUFA) is the preferred option for health benefits… Eliminating use of TFA-containing PHVO [partially hydrogenated vegetable oils] should be considered as hazard removal, in line with risk management models used to address many other food safety issues.' The PDG concurred.\n\nAssuming a linear dose response, if less than 1% of food energy came from IPTFAs, between 4500 and nearly 7000 lives might be saved in England.\n\nThe PDG commended the substantial efforts made by much of the UK-based food industry and the Food Standards Agency to remove IPTFAs from the UK food chain. It also noted the review of trans fats by the Scientific Advisory Committee on Nutrition (SACN). New concerns have now emerged, particularly in relation to imported products and fried food prepared in some settings. People from disadvantaged groups are likely consume more of these products which, in turn, could be an important contributory factor to health inequalities.\n\nSome products (this includes fried food from take-away venues) may contain substantial levels of IPTFAs. The PDG noted that some people may be consuming this sort of meal on a frequent basis. Hence, it considered that IPTFA consumption across different population groups is relevant – and that simply looking at average intake will not suffice.\n\nThe Group discussed the links between sedentary behaviour and CVD – and the need to encourage people to be more physically active. However, evidence on how to address sedentary behaviour is not well developed and remains an area for further study.\n\nThe PDG noted the importance of ensuring physical activity is enjoyable and can be incorporated into daily life. Effective interventions to encourage physical activity are possible both nationally and locally. For example, NICE has made recommendations on how to help people to be physically active in: 'Four commonly used methods to promote physical activity' (NICE public health guidance 2); 'Physical activity and the environment' (NICE public health guidance 8); 'Promoting physical activity in the workplace' (NICE public health guidance 13); and 'Promoting physical activity for children and young people' (NICE public health guidance 17).\n\n# Achieving change: national level\n\nPublic, private, voluntary and community sector organisations all have a role to play in preventing CVD at national level. For example, measures to encourage commercial markets to be health promoting could be highly cost saving (Abelson 2003; Catford 2009; Trust for America's Health 2008; Wanless 2004). Such measures might include: improving the content of products (re-formulation); controls on the marketing of energy-dense, nutrient-poor foods, foods high in fat, salt or sugar and processed foods; and package labelling.\n\nThose preparing, producing and selling food have a particularly important role in improving the diet of the nation. Although such organisations must consider their commercial interests, the PDG considers it also reasonable to expect them to work with others to help prevent CVD. It takes this view in light of the diseases and deaths caused by CVD (and the consequent costs to the exchequer and society). The PDG recognised that many responsible commercial organisations are already taking positive action. Many organisations, for instance, have taken praiseworthy action to reduce the salt or saturated fat content of food, or to remove industrially-produced trans fats from their processes (Brownell and Warner 2009)..\n\nThe PDG believes that more could be done to assist those sectors which have, for a variety of reasons, been unable or unwilling to take positive action. Such action would not only benefit the population, but would also help provide a 'level playing field', where all businesses work to the same standard. Brownell and Warner (2009) state: 'there is an opportunity if the industry chooses to seize it – an opportunity to talk about the moral high ground and to occupy it'.\n\nAdvertising and other marketing activities have an important influence on consumption patterns. They encourage people to change brands and they also encourage overall increases in consumption of related brands.\n\nThe PDG noted the work of the Advertising Standards Authority and others to develop the existing overarching regulatory system that controls food advertising aimed at children. Furthermore, the Group noted and praised the important work involved in developing the current UK advertising regulations. The Ofcom/Food Standards Agency restrictions on TV advertisements for foods high in salt, fat or sugar aimed at children are a good example of these regulations being put into practice. However, the PDG felt that children are particularly vulnerable and need further protection from commercial pressures. The 'Sydney principles' (developed by the International Obesity Taskforce Working Group in Sydney, Australia [Swinburn et al. 2007]) provide for the type of protection that it believes is still needed in the UK. The principles state that any action to reduce marketing to children should: support their rights; afford them substantial protection; be statutory in nature; take a wide definition of commercial promotion; guarantee commercial-free childhood settings; include cross-border media; and be evaluated, monitored and enforced. In other words, the PDG considers that a comprehensive model which includes marketing, advertising, promotion and product placement would provide the necessary protection.\n\nAdvertising restrictions are gaining support. In 2007, WHO called for recommendations to restrict food marketing to children. Examples of jurisdictions that have successfully introduced such restrictions now include Norway, Sweden, Belgium, Greece, Romania and Quebec.\n\nNational policy has an important role in changing the risk factors faced by a population (both direct, indirect and unintentional). However, the PDG recognised that developing and implementing such policy is a highly complex process: it is not linear and rarely moves simply from design to implementation. In addition, the Group acknowledged that evidence alone is rarely sufficient to bring about policy change.\n\nThe way research evidence influences the policy process and gets translated into action can be explained by a model such as Kingdon's (1995) 'policy windows'. This suggests that 'windows' open (and close) by the coupling (or de-coupling) of three 'streams': problems, policies and politics. It can be applied nationally and locally (Exworthy et al. 2002). Other policy models also provide a potentially valuable insight into this complex, non-linear process. Whichever model is applied, however, all parties concerned need to acknowledge that the problem is important. In addition, it has to be possible to devise policies to remedy it – and there has to be a political willingness to act. Examples from other countries of where policy has been successfully used to reduce CVD are particularly valuable in showing what could be achieved in the UK.\n\nThis guidance has made the case unequivocally that CVD is a major and, most significantly, a preventable problem. It has also identified policy options which would be effective at the population level.\n\nNationally, the campaigning activities of charities such as the British Heart Foundation, the National Heart Forum and others focused on chronic diseases are particularly influential.\n\nVoluntary action may be effective. However, if the pace of change is insufficient mandatory measures may be needed. The success of legislation banning tobacco advertising and smoking in public places followed unsuccessful voluntary agreements with industry. This also demonstrates the effectiveness of national government action to improve the public's health.\n\n# Achieving change: the regional, community and private sectors\n\nRegional government offices and strategic health authorities could make an important contribution to CVD prevention. For example, they could negotiate to maximise the number of local area agreements (LAAs) that include 'stretch' targets related to CVD. They could also ensure all PCT 'world class commissioning' strategies for healthcare adequately address CVD prevention at a population and individual level. This involves having long-term strategies for sustainable change that avoid an over-dependence on medical solutions. There is also scope for effective action by public sector bodies at a sub-regional level. This was the case in Merseyside where, prior to the national ban on smoking in public places, a private members bill supporting local smoking restrictions had been developed in case national legislation was delayed.\n\nLocal authorities and PCTs, working with the private and 'the third sector' in local strategic partnerships (LSPs), have demonstrated their commitment to CVD prevention. (The third sector includes voluntary and community groups, social enterprises, charities, cooperatives and mutual organisations.) For example, many have established health and wellbeing partnerships. In addition, 5 of the 15 most popular improvement targets in LSP local area agreements relate directly or indirectly to CVD prevention. Fifty-one LSPs have also selected national indicator (NI) 121 (mortality rate from all circulatory diseases for those aged under 75) as an indicator for the current round of local area agreements, which runs to 2011.\n\nOnly 5 (6.7%) of the 74 green flags awarded to the 152 LSPs in England as part of their first comprehensive area assessment related to public health (green flags represent exceptional performance or outstanding improvement); 19 (30.6%) of the 62 red flags awarded related to public health. Of these, 15 (24.2%) related directly or indirectly to CVD prevention. (Red flags indicate the need to improve outcomes.) The first comprehensive area assessment reports were published in December 2009.\n\nLocal advocacy by 'third sector' groups and organisations, including the voluntary sector, is an important part of CVD prevention activities. For example, it could have an impact on planning applications for fast-food outlets.\n\nAddressing the needs of disadvantaged groups involves working beyond geographical boundaries with different communities. The leaders of some communities may be able to deliver CVD prevention programmes effectively. However, it should not be assumed that all community leaders will be able or willing to participate – or that it would be appropriate.\n\n# Evidence\n\nMany studies considered in the reviews of effectiveness for this guidance were carried out some years ago (that is, studies reporting on regional, population-level programmes).The majority were published before 2000, with a substantial number published before 1990. This reflects, in part, the decision to include studies such as the North Karelia and HeartBeat Wales CVD population programmes which took place in the 1970s and 1980s. The age of the studies means a number of factors have to be taken into account when considering effectiveness. In particular:\n\nThe risk factor levels for CVD are likely to have changed. For instance, intake of salt and saturated fat and the prevalence of smoking may have fallen, while a sedentary lifestyle and rates of obesity may have increased.\n\nThe political and cultural environments which potentially influence the effectiveness of interventions may have changed substantially.\n\nA number of issues have to be taken into account when considering evidence of the effectiveness of population-level interventions:\n\nChanges may have come about inadvertently, for instance, as a result of a change in agriculture practice following economic developments. Any evaluation of such changes is likely to have been carried out after the event, using proxy data.\n\nIt is often difficult to find a suitable control population where conditions are relatively similar to those in the intervention group. Where a control group is used, there is often contamination between the two groups which can lead to an underestimation of any beneficial effects.\n\nIt is ethically wrong – and practically impossible – to randomly allocate country-wide populations to controlled trials. The best evidence available has to be gleaned from other research designs – in particular, natural experiments, epidemiological models and cost effectiveness and cost–benefit analyses.\n\nThe potential effect of any intervention may change according to the initial level of risk. For instance, it may be easier to reduce salt consumption among a population with a high intake than among a population where intakes of salt are lower. However, epidemiological modelling suggests that substantial reductions in CVD rates can be achieved by reducing the major risk factors as much as possible. This is the case even in countries where CVD mortality rates are already relatively low, such as Italy (Palmieri et al. 2009).\n\nThe economic modelling used for this guidance was based on conservative assumptions. Nevertheless, it suggested that the recommended population-based approaches are likely to be consistently cost saving (see considerations 3.33 and 3.45 and appendix C).\n\n# Interpreting the evidence\n\nThe PDG recognised that empirical data alone, even from the best conducted investigation, seldom provides a sufficient or complete basis for making recommendations. Rather, it requires interpretation and analysis. Therefore, the PDG developed its recommendations using the best available empirical data and inductive and deductive reasoning, using prior knowledge and understanding and existing models and theories. The development of policy to reduce mortality and morbidity from CVD flow from these inductive and deductive interpretations.\n\nThe PDG acknowledged that the traditional hierarchy of evidence does not resolve all the problems associated with empirical data. For example, while it explicates the degree of bias attributable to poor internal validity, it does not answer it completely. Nor does it deal with external validity, that is, the degree to which findings are transferable to other experimental settings or to practice. The PDG therefore, took a broad approach to the evidence available to it. (For further details, see chapters 3 and 7 of 'Methods for development of NICE public health guidance [second edition, 2009]'.)\n\n# Other issues\n\nMany of the risk factors that the PDG considered are also associated with other health-related conditions including some common cancers, chronic respiratory disease, obesity, diabetes, kidney disease and mental wellbeing. The strategies discussed in this guidance are likely to help prevent some of these other health conditions. (Certainly, they are not likely to increase the risk of any common chronic diseases.) However, it was not possible to consider each of these other health conditions in detail.\n\nDaily consumption of products containing plant sterols and stanols may reduce blood cholesterol by about 10% – and so may reduce CVD mortality substantially. However, it was not clear how a recommendation on their use might impact on inequalities in health. The PDG believes this issue deserves further attention.\n\nAgricultural and transport policy and practice (and associated issues) has a powerful impact on people's diet and physical activity levels. It also has an impact on climate change and sustainable development (which, in turn, can affect health). An analysis of transport patterns in London and how they could be changed indicates the extent of this synergy (Woodcock et al. 2009). One scenario described a 'sustainable transport future' featuring more physically active travel and low-emission vehicles to cut CO2 emissions by three-fifths. The report points out that physically active travel could bring substantial benefits: the incidence of heart disease and stroke could fall by 10–20%, with reductions in breast cancer (12–13%), dementia (8%) and depression (5%). Reductions in air pollution would bring additional health benefits.\n\nAgriculture and food production account for 10–12% of greenhouse gas emissions (Friel et al. 2009). Livestock farming is responsible for four-fifths of these emissions (including methane). A 30% fall in adult consumption of saturated fat from animal sources (and an associated fall in livestock-related greenhouse gas emissions) would reduce heart disease by around 15% in the UK. If additional, positive effects are taken into account (such as a reduction in the prevalence of obesity and diet-related cancers) the health gains might been even more substantial.\n\nMonitoring is crucial. The PDG commended the regular Food Standards Agency/Department of Health-sponsored surveys. These include the 'National diet and nutrition survey' (NDNS) and the 'Low income diet and nutrition survey' (LIDNS).", 'Recommendations for research': "The Programme Development Group (PDG) recommends that the following research questions should be addressed. It notes that 'effectiveness' in this context relates not only to the size of the effect, but also to cost effectiveness rapidity and duration of effect. It also takes into account any harmful/negative side effects.\n\nWhat has been the impact of marketing bans on foods high in fat, sugar or salt in Norway, Sweden, Romania and Quebec? What lessons can the UK learn?\n\nHow do inequalities contribute to:\n\n\n\n\n\n\n\nthe consumption of trans fats, poly-unsaturated and mono-unsaturated fats, fresh fruit and vegetables and stanols?\n\nvariations in physical activity levels among different population groups?\n\n\n\n\n\n\n\nCVD prevention aimed at individuals tends to widen health inequalities. Is there any effective way to ameliorate this? Conversely, is there any further empirical evidence that population-wide policy interventions or CVD preventive strategies narrow the inequalities gap?\n\nWhat impact would food taxes and subsidies, particularly in relation to salt, saturated fats and fruit and vegetable consumption, have on CVD risk and health inequalities?\n\nCould 'natural' experiments aid understanding of the impact that 'upstream' factors such as the social, economic and physical environment have on the incidence and rates of cardiovascular disease (CVD)? How could CVD modelling be developed in the UK, particularly to examine health inequalities?\n\nWhat effect would a regular daily intake of 2.5\xa0g of stanols or sterols have on the incidence of cardiac and stroke events? How can we best evaluate stanols in terms of their acceptability, affordability, effectiveness, cost-effectiveness and impact on health inequalities?\n\nMore detail on the gaps in the evidence identified during development of this guidance is provided in appendix D.", 'Updating the recommendations ': 'This guidance will be reviewed at 3 and 5 years after publication to determine whether all or part of it should be updated. Information on the progress of any update will be posted on our website.', 'Related NICE guidance': 'Alcohol-use disorders: preventing harmful drinking. NICE public health guidance 24 (2010).\n\nPromoting physical activity for children and young people. NICE public health guidance 17 (2009).\n\nCardiovascular risk assessment and the modification of blood lipids for the primary and secondary prevention of cardiovascular disease. NICE clinical guideline 67 (2008).\n\nIdentifying and supporting people most at risk of dying prematurely. NICE public health guidance 15 (2008).\n\nPreventing the uptake of smoking by children and young people. NICE public health guidance 14 (2008).\n\nPromoting physical activity in the workplace. NICE public health guidance 13 (2008).\n\nMaternal and child nutrition. NICE public health guidance 11 (2008).\n\nSmoking cessation services. NICE public health guidance 10 (2008).\n\nCommunity engagement. NICE public health guidance 9 (2008).\n\nPhysical activity and the environment. NICE public health guidance 8 (2008).\n\nBehaviour change. NICE public health guidance 6 (2007).\n\nWorkplace interventions to promote smoking cessation. NICE public health guidance 5 (2007).\n\nFour commonly used methods to increase physical activity. NICE public health guidance 2 (2006).\n\nBrief interventions and referral for smoking cessation in primary care and other settings. NICE public health guidance 1 (2006).\n\nObesity: the prevention, identification, assessment and management of overweight and obesity in adults and children. NICE clinical guideline 43 (2006).\n\nHypertension: management of hypertension in adults in primary care. NICE clinical guideline 34 (2006) [Replaced by NICE clinical guideline 127]', 'References': "Abelson P (2003) Returns on investment in public health. Canberra: Department of Health and Ageing\n\nAction on Smoking and Health (2008) Beyond smoking kills. London: Action on Smoking and Health\n\nAllender S, Peto V, Scarborough P et al. (2007) Coronary heart disease statistics 2007 edition. 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American Journal of Epidemiology 162: 397–403\n\nHe FJ, Marrero NM, MacGregor GA (2008) Salt and blood pressure in children and adolescents. Journal of Human Hypertension 22: 4–11\n\nHeidemann C, Schulze MB, Franco OH et al. (2008) Dietary patterns and risk of mortality from cardiovascular disease, cancer and all causes in a prospective cohort of women. Circulation 118: 230–7\n\nHM Government; Communities and Local Government (2008) Creating strong, safe and prosperous communities. Statutory guidance. London: Community and Local Government Publications\n\nHu FB (2008) Globalization of food patterns and cardiovascular disease risk. Circulation 118: 1913–4\n\nKelly MP, Stewart E, Morgan A et al. (2009a) A conceptual framework for public health: NICE's emerging approach. Public Health 123: e14–20\n\nKelly B, Hughes C, Chapman K et al. (2009b) Consumer testing of the acceptability and effectiveness of front-of-pack food labelling systems for the Australian grocery market. 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London: Cabinet Office\n\nStrazzullo P, D'Elia L, Kandala N et al. (2009) Salt intake, stroke, and cardiovascular disease: meta-analysis of prospective studies. BMJ 339: 4567\n\nSwann C, Owen L, Carmona C et al. (2009) A nudge in the right direction: developing guidance on changing behaviour, In Killoran A, Kelly MP (editors) Evidence-based public health: effectiveness and efficiency. Oxford : Oxford University Press\n\nSwinburn B, Sacks G, Lobstein T et al. (2007) The 'Sydney principles' for reducing the commercial promotion of foods and beverages to children. Public Health Nutrition: 11 (9): 881–6\n\nTrust for America's Health (2008) Prevention for a healthier America: investments in disease prevention yield significant savings, stronger communities\n\nUauy R, Aro A, Clark R et al. (2009) WHO scientific update on trans fatty acids: summary and conclusions. European Journal of Clinical Nutrition (63): 68–75\n\nUnal B, Critchley J, Capewell S (2005) Modelling the decline in coronary heart disease deaths in England and Wales, 1981–2000: comparing contributions from primary prevention and secondary prevention. BMJ 331: 614–5\n\nWanless D (2004) Securing good health for the whole population. London: HM Treasury\n\nWilson A, Siskind V (1995) Coronary heart disease mortality in Australia: is mortality starting to increase among young men? International Journal of Epidemiology (24): 678-84\n\nWoodcock J, Edwards P, Tonne C et al. (2009) Public health benefits of strategies to reduce greenhouse-gas emissions: urban land transport. Lancet 374 (9705): 1930–43\n\nWorld Health Organization (2003) Framework convention on tobacco control\n\nWorld Health Organization (2007) Prevention of CVD: guidelines for assessment and management of total cardiovascular risk. Geneva: World Health Organization\n\nYusuf S, Hawken S, Ôunpuu T et al. (2004) Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the INTERHEART study): case-control study. The Lancet 364: 937–52\n\nZatonski WA, Willett W (2005) Changes in dietary fat and declining coronary heart disease in Poland: population based study. BMJ 331: 187–9", 'Appendix B: Summary of the methods used to develop this guidance': "# Introduction\n\nThe reviews, expert reports and economic analysis include full details of the methods used to select the evidence (including search strategies), assess its quality and summarise it.\n\nThe minutes of the PDG meetings provide further detail about the Group's interpretation of the evidence and development of the recommendations.\n\nAll supporting documents are listed in appendix E and are available online.\n\n# Guidance development\n\nThe stages involved in developing public health programme guidance are outlined in the box below.\n\n. Draft scope released for consultation\n\n. Stakeholder meeting about the draft scope\n\n. Stakeholder comments used to revise the scope\n\n. Final scope and responses to comments published on website\n\n. Evidence reviews, economic modelling and expert testimony undertaken and submitted to PDG\n\n. PDG produces draft recommendations\n\n. Draft guidance (and evidence) released for consultation and for field testing\n\n. PDG amends recommendations\n\n. Final guidance published on website\n\n. Responses to comments published on website\n\n# Key questions\n\nThe key questions were established as part of the scope. They formed the starting point for the reviews of evidence and were used by the PDG to help develop the recommendations.\n\nThe overarching questions were:\n\nWhich multiple risk-factor interventions are effective and cost effective in preventing the onset of cardiovascular disease (CVD) within a given population (primary prevention)?\n\nHow does effectiveness and cost effectiveness vary between different population groups?\n\nThe subsidiary question was:\n\nWhat barriers and facilitators influence the effectiveness of multiple risk-factor programmes aimed at reducing CVD (or the risk factors associated with CVD) among a given population (including subgroups experiencing health inequalities, where the data allows)?\n\nThese questions were made more specific for each review (see reviews for further details).\n\nSingle risk factors were considered using expert testimony. See appendix C for details.\n\n# Reviewing the evidence\n\nThree reviews of effectiveness (reviews 1,2 and 3), one qualitative review (review 4), one primary study of barriers and facilitators (review 5) and one review of cost effectiveness (review 6) were conducted.\n\n## Identifying the evidence\n\nThe following databases were searched for randomised controlled trials (RCTs); controlled before-and-after trials; cohort studies; case–control studies; before-and-after studies; and interrupted time series (from 1970 onwards):\n\nASSIA (Applied Social Science Index and Abstracts)\n\nCINAHL (Cumulative Index of Nursing and Allied Health Literature)\n\nCochrane Database of Systematic Reviews (CDSR)\n\nCochrane Library (Wiley)\n\nDatabase of Abstracts of Reviews of Effects (DARE)\n\nDH-Data\n\nEMBASE\n\nHealth Management Information Service (HELMIS)\n\nHealth Technology Assessment (HTA)\n\nHMIC (Health Management Information Consortium)\n\nKing's Fund Database\n\nMEDLINE\n\nMEDLINE In Process\n\nPsycINFO\n\nThe following websites were also searched:\n\nCentre for the Evaluation of Public Health Interventions, London School of Hygiene & Tropical Medicine\n\nCochrane Public Health Group\n\nHealth evidence\n\nThe Campbell Collaboration\n\nThe Evidence for Policy and Practice Information and Coordinating Centre\n\nFurther details of the databases, search terms and strategies used are included in the review reports.\n\n## Selection criteria\n\nStudies were included in the effectiveness reviews if they:\n\nInvolved a population at least the size of one covered by a UK primary care trust.\n\nWere based in an Organisation for Economic Co-operation and Development (OECD) country, another developed country or within a World Health Organization region.\n\nIncluded primary prevention strategies to tackle at least two of the key risk factors for CVD.\n\nStudies were excluded if they were:\n\nConfined to populations clinically diagnosed as being at high risk of CVD or diagnosed with CVD.\n\nPublished before 1970.\n\nNot published in English.\n\n## Quality appraisal\n\nIncluded papers were assessed for methodological rigour and quality using the NICE methodology checklist, as set out in the NICE technical manual 'Methods for the development of NICE public health guidance' (see appendix E). Each study was graded (++, +, –) to reflect the risk of potential bias arising from its design and execution.\n\n++ All or most of the checklist criteria have been fulfilled. Where they have not been fulfilled, the conclusions are very unlikely to alter.\n\n+ Some of the checklist criteria have been fulfilled. Those criteria that have not been fulfilled or not adequately described are unlikely to alter the conclusions.\n\n– Few or no checklist criteria have been fulfilled. The conclusions of the study are likely or very likely to alter.\n\n# Economic analysis\n\nThe economic analysis consisted of a review of economic evaluations (review 6) and a cost effectiveness analysis.\n\n## Review of economic evaluations\n\nThe same protocol was used to conduct the literature reviews for all phases of the review. In a minor departure from the protocol, the list of included study designs was extended to include cost-consequences.\n\nThe following databases were searched from 1970 to August 2008:\n\nECONLIT\n\nEMBASE\n\nMEDLINE\n\nNHS EED database (Cochrane Library, Wiley).\n\nThe search was limited to articles published from 1970 onwards and in the English language.\n\nIn addition to the general bibliographic database searches, specific searches were conducted for each programme found during the general searches to ensure all published evaluations, particularly economic evaluations, were identified.\n\nStudy quality was assessed using an evidence form based on the 'Methods for the development of NICE public health guidance' (second edition 2009) and adapted to reflect the parameters of this review. It was supplemented with questions from the Drummond checklist (Drummond MF Guidelines for authors and peer reviewers of economic submissions to the BMJ. London: BMJ).\n\nThe selection criteria were the same as for the effectiveness reviews (see pages 53–54). The following study types were included: cost–benefit, cost-effectiveness and cost–utility analyses.\n\n## Modelling\n\nAn economic model was constructed to incorporate data from the reviews of effectiveness and cost effectiveness. The results are reported in: 'Prevention of cardiovascular disease at population level: modelling strategies for primary prevention of cardiovascular disease'.\n\n# Fieldwork\n\nFieldwork was carried out to evaluate how relevant and useful NICE's recommendations are for practitioners and how feasible it would be to put them into practice. It was conducted with practitioners and commissioners who are involved in activities relevant to cardiovascular disease. They included those working in the food industry (such as food retailers, food producers and trade associations), local planning departments, local authority catering representatives and representatives from the NHS and PCTs.\n\nThe fieldwork comprised:\n\nEight half-day workshops.\n\nNine case studies (interviews involving practitioners, commissioners and professionals). Each reviewed recommendations made in the following specific areas:\n\n\n\nhealth impact assessments\n\nCVD prevention programmes (two case studies)\n\ntake-away planning\n\ntraining caterers\n\npublic sector food provision\n\nphysically active travel\n\nthe dairy industry\n\nreformulation of food.\n\n\n\nTelephone interviews covering the following topics: mass media, government departments, and key food industry producers.\n\nThe studies were commissioned to ensure there was ample geographical coverage. The main issues arising from these studies are set out in appendix C under fieldwork findings. The full fieldwork report, 'Fieldwork on prevention of cardiovascular disease at population level' is available online.\n\n# How the PDG formulated the recommendations\n\nAt its meetings between September 2008 and July 2009, the PDG considered the evidence of effectiveness, expert reports and cost effectiveness to determine:\n\nwhether there was sufficient evidence (in terms of strength and applicability) to form a judgement\n\nwhere relevant, whether (on balance) the evidence demonstrates that the intervention or programme/activity can be effective or is inconclusive\n\nwhere relevant, the typical size of effect (where there is one)\n\nWhether the evidence is applicable to the target groups and context covered by the guidance.\n\nThe PDG developed draft recommendations through informal consensus, based on the following criteria:\n\nStrength (type, quality quantity and consistency) of the evidence.\n\nThe applicability of the evidence to the populations/settings referred to in the scope.\n\nEffect size and potential impact on the target population's health.\n\nImpact on inequalities in health between different groups of the population.\n\nEquality and diversity legislation.\n\nEthical issues and social value judgements.\n\nCost effectiveness (for the NHS and other public sector organisations).\n\nBalance of harms and benefits.\n\nEase of implementation and any anticipated changes in practice.\n\nWhere possible, recommendations were linked to evidence statements (see appendix C for details). Where a recommendation was inferred from the evidence, this was indicated by the reference 'IDE' (inference derived from the evidence).\n\nThe draft guidance, including the recommendations, was released for consultation in October 2009. At its meeting in December 2009, the PDG amended the guidance in light of comments from stakeholders and experts and the fieldwork. The guidance was signed off by the NICE Guidance Executive in May 2010.", 'Appendix C: The evidence ': "This appendix lists the evidence statements from four reviews, a cost-effectiveness review and a primary research study provided by external contractors (see appendix A) and links them to the relevant recommendations. (See appendix B for the key to quality assessments.)\n\nThe evidence statements are presented here without references – these can be found in the full reviews (see appendix E for details).\n\nThe appendix also sets out a brief summary of findings from the economic analysis.\n\nThe four reviews (reviews 1–4), the primary research study (review 5) and the cost-effectiveness review (review 6) are:\n\nEvidence reviews:\n\n\n\nReview 1: 'Prevention of cardiovascular disease at population level (Question 1; phase 1)'\n\nReview 2: 'Prevention of cardiovascular disease at population level (Question 1; phase 2)'\n\nReview 3: 'Prevention of cardiovascular disease at population level (Question 1; phase 3)'\n\nReview 4: 'Barriers to, and facilitators for, multiple risk factor programmes aimed at reducing cardiovascular disease within a given population: a systematic review of qualitative research'\n\n\n\nPrimary research:\n\n\n\nReview 5: 'Population and community programmes addressing multiple risk factors to prevent cardiovascular disease: A qualitative study into how and why some programmes are more successful than others'\n\n\n\nCost-effectiveness review:\n\n\n\nReview 6: 'Prevention of cardiovascular disease at population level (Question 1; cost-effectiveness)'\n\n\n\nEvidence statement R3.E1a indicates that the linked statement is numbered E1a in review 3. Evidence statement R5.12 indicates that the linked statement is numbered 12 in the primary research study (review 5). Evidence statement ER1 indicates that the linked statement is from expert report 1 (see additional evidence). Evidence statement CE1 indicates that the linked statement is numbered 1 in the cost-effectiveness review (review 6). '\n\nThe reviews, economic analysis and additional evidence are available online where a recommendation is not directly taken from the evidence statements, but is inferred from the evidence, this is indicated by IDE (inference derived from the evidence).\n\nWhere the PDG has considered other evidence, it is linked to the appropriate recommendation below. It is also listed in the additional evidence section of this appendix. This includes evidence used to develop other NICE guidelines and guidance.\n\nRecommendation 1: evidence statement R3.E1m; additional evidence ER3\n\nRecommendation 2: evidence statements R3.E1b; R3E1h; R3.E1i; R3.E1j; R3.E1k; additional evidence ER10\n\nRecommendation 3: additional evidence ER9; ER10\n\nRecommendation 4: additional evidence ER4; ER6; CG43 (1)\n\nRecommendation 5: additional evidence ER4\n\nRecommendation 6: additional evidence ER3; ER4; ER6; CG43 (2)\n\nRecommendation 7: additional evidence ER1; ER10; ER13\n\nRecommendation 8: additional evidence ER10; ER13\n\nRecommendation 9: additional evidence ER1; CG43 (3)\n\nRecommendation 10: additional evidence CG43 (4)\n\nRecommendation 11: evidence statements R4.18a; R4.18b\n\nRecommendation 12: IDE\n\nRecommendation 13: evidence statements R3.E2a–f, R4.2a–c, R4.17a–d, R4.18a–c, R4.19a, R4.20a, R4.21a–c, R4.22a, R4.23a–b, R4.24a–d, R4.25a–d, R4.26a–d, R5.2\n\nRecommendation 14: evidence statements R3.E1a–o, R3.E2a–f, R3.E3a–c, R4.14a–b, R5.5, R5.7, R5.10, CE 1–9; additional evidence ER 7, ER 8, ER 13\n\nRecommendation 15: evidence statements R4.3a, R4.3b, R4.10a–d, R4.11a, R4. 11b, R4.12a, R4.13a–d, R4.15a, R4.15b, R5.2, R5.4, R5.6, R5.7\n\nRecommendation 16: evidence statements R4.1b, R4.7c, R4.10d, R5.2, R5.3\n\nRecommendation 17: evidence statements R4.16a–c, R5.12\n\nRecommendation 18: evidence statements R3.E1n, R3.E3c, R4.4a, R4.9f, R4.18a, R4.18c; additional evidence ER 1\n\nRecommendation 19: evidence statements R3.E5c, R4.18a–c; additional evidence ER 4\n\nRecommendation 20: evidence statements R3.E1a–m, R3.E3c, R4.4a, R4.9e, R4.18a, R4.18b, R4.25e; additional evidence ER 3, ER 9, ER 10\n\nRecommendation 21: evidence statements R4.1b, R4.3a, R4.3b, R4.7a–c, R4.8a–d, R4.16a–c, R4.17a–d, R5.3, R5.7, R5.8, R5.9, R5.11, R5.12; additional evidence ER 5, ER 7, ER 8\n\nRecommendation 22: evidence statements R4.3a, R4.18a, R4.18c, R5.10; additional evidence ER 1, ER 5, ER 7, ER 8, ER 12, IDE\n\nRecommendation 23: evidence statements R3.E3a, R3.E3c, R4.18a, R4.18b; additional evidence ER 3, ER 4, ER 9, ER 10\n\nRecommendation 24: evidence statements R4.9e; additional evidence ER 3, ER 9, ER 10\n\nIn addition, the approach taken in recommendations 1 to 12 is supported by the following evidence statements: R4.3a, R4.3b, R4.4a, R4.18a, R418b, R418c, R5.9 and additional evidence ER10, ER11, ER12, ER13.\n\n# Evidence statements\n\nPlease note that the wording of some evidence statements has been altered slightly from those in the evidence reviews to make them more consistent with each other and NICE's standard house style.\n\n## Evidence statement R3.E1a\n\nCVD mortality and morbidity: Limited evidence from 3 out of 38 programme evaluations using different summary effect measures demonstrate a mixed effect of multiple risk factor interventions (MRFI) on CVD mortality (the majority of programmes were beneficial) with two controlled before-and-after (CBA) studies demonstrating a net decrease in CVD mortality and one randomised controlled trial (RCT) demonstrating no net change. Limited evidence from 4 out of 38 programme evaluations, using different summary effect measures, demonstrate a mixed effect of MRFI on CVD morbidity (the majority disbeneficial) with one CBA study and one RCT demonstrating a net increase in morbidity and one RCT demonstrating no net change in morbidity. The effect of one programme on morbidity and mortality is unclear.\n\n## Evidence statement R3.E1b\n\nBlood cholesterol: A large body of evidence from 15 CBA studies and 5 RCTs demonstrates a mixed direction of effect (majority of programmes beneficial) of MRFI programmes on blood cholesterol. Fourteen studies (nine CBA and five RCTs) demonstrate a beneficial net effect. Four CBA studies demonstrate no net effect or inconclusive net effects and two CBA studies demonstrate a disbeneficial net effect. The most optimistic result was from a CBA study, reporting a 0.7mmol/l net reduction in blood cholesterol. The least optimistic result was from a CBA study, reporting a +0.5mmol/l net increase in blood cholesterol.\n\n## Evidence statement R3.E1c\n\nDiastolic and systolic blood pressure: A large body of evidence demonstrates a mixed direction of effect (majority of programmes beneficial) in favour of MRFI programmes on diastolic and systolic blood pressure. Fourteen CBA studies and five RCTs demonstrate a mixed direction of effect (majority of programmes beneficial) on diastolic blood pressure. Twelve studies (seven CBA studies and five RCTs) demonstrate a beneficial net effect. Five CBA studies demonstrate no net effect or inconclusive net effects and two CBA studies demonstrate a disbeneficial net effect. The most optimistic result was from a CBA study, reporting a 5.5mmHg net reduction in diastolic blood pressure. The least optimistic result was from a CBA study, reporting a 6mmHg net increase in diastolic blood pressure. Fourteen CBA studies and five RCTs demonstrate a mixed effect (majority of programmes beneficial) on systolic blood pressure. Ten studies (five CBA studies and five RCTs) demonstrate a beneficial net effect. Five CBA studies demonstrate no net effect or inconclusive net effects and four CBA studies demonstrate a disbeneficial net effect. The most optimistic result was from a CBA study, reporting an 11.8 mmHg net reduction in systolic blood pressure. The least optimistic result was from a CBA study, reporting a 5mmHg net increase in systolic blood pressure.\n\n## Evidence statement R3.E1d\n\nSmoking: A large body of evidence from twenty CBA studies and four RCTs demonstrate a mixed effect of MRFI on smoking prevalence (the majority of programmes beneficial). Twelve studies (nine CBA studies and three RCTs) demonstrate a beneficial net effect. Seven studies (six CBA studies and one RCT) demonstrate no net effect or inconclusive net effects and five CBA studies demonstrate a disbeneficial net effect. The most optimistic result was from a CBA study, reporting an 18.6% net reduction in smoking prevalence. The least optimistic result was from a CBA study, reporting a 12.8% net increase in smoking prevalence.\n\n## Evidence statement R3.E1e\n\nBMI: A large body of evidence from fourteen CBA studies and three RCTs demonstrate a mixed effect of MRFI programmes on body mass index (BMI) (the majority of programmes beneficial). Ten studies (seven CBA studies and three RCTs) demonstrate a beneficial net effect. Four CBA studies demonstrate no net effect or inconclusive net effects and three CBA studies demonstrate a disbeneficial net effect. The most optimistic result was from a CBA study, reporting a 1.3kg/m2 net reduction in BMI. The least optimistic result was from a CBA study, reporting a 0.7kg/m2 net increase in BMI.\n\n## Evidence statement R3.E1f\n\nBlood glucose: Limited evidence from 3 out of 38 programme evaluations, using different summary effect measures, demonstrate a mixed effect of MRFI on blood glucose. One RCT and one CBA study report mixed results: net decreases in men and net increases in women, whilst one CBA study demonstrates no net effect.\n\n## Evidence statement R3.E1g\n\nTriglyceride levels, high-density lipoprotein/low-density lipoprotein (HDL/LDL) ratio or lipid levels: No evidence has been identified on the effects of MRFI programmes on triglyceride levels, HDL/LDL ratio or lipid levels.\n\n## Evidence statement R3.E1h\n\nDietary change – low versus high fat spreads: Five CBA studies and one RCT (+) demonstrate a mixed effect of MRFI programmes on consumption or low versus high fat spreads (the majority of programmes beneficial). Four studies (three CBA studies and one RCT) demonstrate a beneficial net effect. One CBA study demonstrates an inconclusive net effect and one CBA study demonstrates an unfavourable net effect. The most optimistic result was from a CBA study, reporting a 24% net reduction in the number of people with high consumption of fat spread on bread. The least optimistic result was from a CBA study, reporting a 3.3% net decrease in the use of unsaturated spreading fats.\n\n## Evidence statement R3.E1i\n\nDietary change – vegetable versus animal fats for cooking: Four CBA studies demonstrate a mixed effect of MRFI programmes on the use of vegetable versus animal fat for cooking (the majority of programmes beneficial). Three CBA studies demonstrate a beneficial net effect and one CBA study demonstrates an inconclusive net effect. The most optimistic result was from a CBA study, reporting a 6% net increase in the use of unsaturated fats for cooking. The least optimistic result was from a CBA study, reporting a 2% net decrease in the use of vegetable fats for cooking.\n\n## Evidence statement R3.E1j\n\nDietary change – low versus high fat milk: Five CBA studies and one RCT (+) demonstrate a mixed effect of MRFI programmes on the consumption of low- versus high-fat milk (the majority of programmes beneficial). Three CBA studies and one RCT demonstrate a beneficial net effect and two CBA studies demonstrate an inconclusive net effect. The most optimistic result was from a CBA study, reporting a 9% net increase in the use of low fat milk in men. The least optimistic result was from a CBA study, reporting a 1% net decrease in the use of low fat milk in women.\n\n## Evidence statement R3.E1k\n\nDietary change – consumption high fat foods: Six CBA studies demonstrate a mixed effect of MRFI programmes on the percentage of high-fat foods in the diet (the majority of programmes beneficial). Three CBA studies demonstrate a beneficial net effect, two CBA studies demonstrate no net effect or inconclusive net effects and one CBA study demonstrates a disbeneficial net effect. The most optimistic result was from a CBA study, reporting a 24% net decrease in saturated fat intake. The least optimistic result was from a CBA study, reporting a 3.4% net increase in high-fat/junk food consumption.\n\n## Evidence statement R3.E1l\n\nDietary change – consumption of fruit and vegetables and wholemeal bread: Limited evidence is available on the effects of MRFI programmes on the consumption of fruit and vegetables and wholemeal bread (the majority of programmes beneficial). Three CBA studies demonstrate a mixed effect of MRFI programmes on the consumption of fruit and vegetables. Two CBA studies demonstrate a beneficial net effect and one CBA study demonstrates an inconclusive net effect. The most optimistic result is from a CBA study, reporting a 9% net increase in the number of people consuming five portions of fruit and vegetables per day. The least optimistic result is from a CBA study, reporting a 0.2% net decrease in fruit consumption. Two CBA studies demonstrate a mixed effect on the consumption of wholemeal bread. One CBA study demonstrates a beneficial net effect and one CBA study demonstrates an inconclusive effect. The most optimistic result is from a CBA study, reporting a 3% increase in children. The least optimistic result is from the same CBA study, reporting a 0.3% net decrease in adults.\n\n## Evidence statement R3.E1m\n\nDietary change – salt intake: Two CBA studies (one [+] and one [-]) provide mixed results for the effects of MRFI programmes on salt intake. One CBA study demonstrates a beneficial net treatment effect and one CBA demonstrates an inconclusive net treatment effect.\n\n## Evidence statement R3.E1n\n\nPhysical activity: Evidence from 11 CBA studies and one RCT (+) provide a mixed pattern for the effect of MRFI programmes on physical activity (the majority of studies are disbeneficial). Three CBA studies and two RCTs demonstrate a favourable net effect. Three CBA studies demonstrate inconclusive net effects and four CBA studies demonstrate a disbeneficial net effect. The most optimistic result is from a CBA study, reporting an 11.5% net increase in the number of people doing strenuous physical activity more than three times per week. The least optimistic result is from a CBA study, reporting a 6% net decrease in the number of people who were physically active.\n\n## Evidence statement R3.E1o\n\nAttitudes, knowledge and intentions relating to CVD risk factors: Limited evidence is available on the effects of MRFI programmes on CVD risk factor attitudes, knowledge and intention to change. One CBA study and one uncontrolled before-and-after study suggest beneficial changes in CVD knowledge following MRFI programmes. One of these studies showed a net increase in the number of individuals intending to lose weight. No evidence has been identified on the effects of MRFI programmes on CVD risk factor attitudes.\n\n## Evidence statement R3.E2a\n\nGeneral: Evidence for variation in effectiveness in subgroups of the population is limited and inconsistently reported across included programmes. There is no clear pattern with respect to gender, age, ethnicity or measures of deprivation which may be the result of the limited information available, confounding and selective reporting.\n\n## Evidence statement R3.E2b\n\nEthnicity: Three programmes report the results of subgroup analysis of effectiveness according to ethnicity. One uncontrolled before-and-after study reports lower effectiveness in ethnic minorities in acquisition of CVD knowledge. One CBA study reports lower effectiveness in ethnic minority groups for reducing smoking prevalence, reducing BMI and increasing fruit and vegetable intake and one CBA study reports no difference in effectiveness according to ethnic group.\n\n## Evidence statement R3.E2c\n\nAge: Six programmes report results of subgroup analysis according to age. Two uncontrolled before-and-after studies report a reduction in effectiveness in acquisition of CVD knowledge in younger participants and one uncontrolled before-and-after study reports a reduction in effectiveness in reducing salt intake in younger participants. One CBA study reports a reduction in effectiveness in promoting CVD awareness in older participants. Two CBA studies report no differences in effectiveness according to age.\n\n## Evidence statement R3.E2d\n\nGender: Seven programmes report results of subgroup analysis according to gender. Four programmes report a reduction in effectiveness in women compared to men. One RCT reports a reduction in effectiveness in increasing physical activity in women compared to men. One uncontrolled before-and- after study and two CBA studies report a reduction in effectiveness in reducing smoking prevalence in women compared to men. One CBA study reports a reduction in effectiveness in reducing cholesterol in women compared to men. One CBA study reports a reduction in effectiveness in drinking low-fat compared to high-fat milk in women compared to men. Two programmes report a reduction in effectiveness in men compared to women. Two CBA studies report a reduction in effectiveness in promoting CVD awareness and acquisition of CVD knowledge in men compared to women and one CBA study reports a reduction in effectiveness in reducing CVD morbidity and mortality in men compared to women. One CBA study reports no differences in effectiveness according to gender.\n\n## Evidence statement R3.E2e\n\nSocial class: Two programmes report results of subgroup analysis according to social class. One CBA study reports a reduction in effectiveness in reducing smoking in lower social classes compared to higher social classes. One CBA study reports no differences in effectiveness according to social class.\n\n## Evidence statement R3.E2f\n\nLevel of education: One programme reports results of subgroup analysis according to level of education. One CBA study reports a reduction in effectiveness in CVD awareness in those relatively more educated.\n\n## Evidence statement R3.E3a\n\nNature of the interventions: Thirty one programmes were concerned with the effectiveness of population programmes using education and mass media, and seven with screening programmes directed at large populations in the community or primary care. However, 16 of the education and mass-media programmes contained screening components. Counselling was a key process in many programmes, undertaken individually in 24 programmes and amongst groups in 16 programmes. The 38 programmes varied in many other ways. Programme length ranged from one to over 20 years. The size of the population addressed ranged from approximately 2500 to over 1 million. Fourteen of the programmes implemented changes to the environment. Health departments (n=23) [where n is the number of programmes in which the organisations indicated were involved], local health committees (n=12), voluntary organisations (n=11) and community volunteers (n=9) had roles in programme delivery. Programmes were delivered in a variety of settings including workplaces (n=12) and schools (n=18).\n\n## Evidence statement E.3b\n\nEducation and mass-media based programmes compared to screening based: As indicated this was the most marked contrast between the programmes. However comparing the effectiveness of the two groups is complicated:\n\nMany of the education and mass-media based programmes contain elements of screening.\n\nThere are many CVD screening programmes, particularly focused on moderate or high-risk populations which are not included in this review.\n\nThe comparison between the two groups is likely to be confounded by other factors, a very important one of which is that CBA studies are used to evaluate most of the education and mass-media based programmes, and RCTs all the screening based programmes.\n\nWith these provisos (and reference to pages 127–31 in report 3), the pattern of results for the risk factors of cholesterol, blood pressure (BP), smoking and BMI in the two different groups of programmes are summarised in the table below:\n\nProgramme type (n=38)\n\nProgramme result, based on direction of effect\n\nBeneficial\n\nInconclusive\n\nDisbenefical\n\nNo data\n\nNet change in mean total cholesterol in mmol/L\n\nEduc & MM 9\n\n\n\n\n\n\n\n\n\nScreening 5\n\n\n\n\n\n\n\n\n\n\n\nNet change in systolic BP in mmHg\n\nEduc & MM 6\n\n\n\n\n\n\n\n\n\nScreening 5\n\n\n\n\n\n\n\n\n\n\n\nNet change in diastolic BP in mmHg\n\nEduc & MM 7\n\n\n\n\n\n\n\n\n\nScreening 5\n\n\n\n\n\n\n\n\n\n\n\nNet change in BMI in kg/m2\n\nEduc & MM 8\n\n\n\n\n\n\n\n\n\nScreening 3\n\n\n\n\n\n\n\n\n\n\n\nNet change in smoking prevalence in %\n\nEduc & MM 9\n\n\n\n\n\n\n\n\n\nScreening 3\n\n\n\n\n\n\n\n\n\nAlthough the results are similar, there does appear to be a more consistent pattern of benefit in the programmes focusing on screening. As well as the provisos mentioned above, the following also need to be borne in mind when taking this observation at face value:\n\nWhether this difference could be accounted for by chance alone.\n\nWhether the difference would persist if the size of the effects could be taken into account.\n\nVote counting as a method of summarising the results in a systematic review is recognised to be the weakest approach.\n\n## Evidence statement R3.E3c\n\nPossible variations in effectiveness by other aspects of the nature of the intervention: Over the three reports, many other plausible reasons for the noted variation in effectiveness have been identified. These include:\n\nduration of programme\n\nintensity of programme\n\nuse of an underlying theoretical model to inform the design of the programme\n\npre-programme investigation of particular risk factors operating in a population\n\ncommunity involvement in planning and/or design of programme\n\nadaptability of the programme as new challenges emerge\n\nlevel of integration of the separate components of the programme\n\ninclusion of environmental changes as part of the programme.\n\nWhether any of these factors account for differences in effectiveness which could not arise by chance alone has not been fully explored, and their potential importance can neither be confirmed nor refuted. Unfortunately, the extent to which the differences could ever be satisfactorily explored using the results from these evaluations is debatable given noted limitations in the reporting of the precise differences in nature of the programmes and the amount of statistical information available.\n\n## Evidence statement R3.E5c\n\nAge: Fifteen programmes report participation in programme interventions and/or programme evaluation surveys according to age. One uncontrolled before-and-after study and 13 CBA studies report lower participation in evaluation surveys or programme interventions by those of younger age whilst one CBA study reports no difference in participation according to age.\n\n## Evidence statement R4.1b\n\nThese suggest that factors influencing success include: time limitations for projects, leadership, (including difficulties engaging community members at strategic levels), and cooperation between partner organisations.\n\n## Evidence statement R4.2a\n\nFour study reports show conflicting evidence about the degree and methods of community engagement important for success.\n\n## Evidence statement R4.2b\n\nFor programmes that were successful, one study reports that positive community expectations about the potential of the programme to effect wider change facilitated community engagement. It is suggested that insufficient community engagement did not significantly impact on another programme's success.\n\n## Evidence statement R4.2c\n\nFor programmes that were unsuccessful, one study reports that previous negative experiences of community programmes discouraged community engagement. Conversely, another study reports engagement in the programme increased willingness for future involvement.\n\n## Evidence statement R4.3a\n\nThere is evidence from five study reports that community programmes to address heart health can be affected by the broader political context.\n\n## Evidence statement R4.3b\n\nThis can effect diverse organisational elements such as: the availability of project funding, the development of partnerships between organisations and a sense of shared purpose at different administrative levels. Individual responses may also be affected through legislation incentives to healthier behaviours.\n\n## Evidence statement R4.4a\n\nThere is evidence from four study reports that high pricing can impact on people's ability and willingness to adopt healthy eating behaviours and to participate in organised physical activity.\n\n## Evidence statement R4.7a\n\nSix study reports discuss factors relating to organisational and strategic issues.\n\n## Evidence statement R4.7b\n\nThere is evidence from four studies that short time frames limit the ability to plan and develop the programme, engage the community, develop partnerships and communication, meet targets and leave a positive legacy.\n\n## Evidence statement R4.7c\n\nLeadership was identified as a key organisational benefit of programmes by three studies. It is required to develop partnerships and collaborations within communities, and is important at all levels, from volunteers to with senior administrators. One study failed to see the desired shift in leadership to the community itself.\n\n## Evidence statement R4.8a\n\nEvidence from six study reports is related to the organisational culture and partnerships of those involved in CVD programme services.\n\n## Evidence statement R4.8b\n\nThree studies note differences in culture between partner organisations including frames of reference, terminology and programme expectations although this didn't always lead to conflict.\n\n## Evidence statement R4.8c\n\nFour studies suggest that CVD programmes are enhanced where partner organisations have aligned values, priorities, focus and goals between organisations.\n\n## Evidence statement R4.8d\n\nPartnerships may have positive effects through interagency learning, increasing the visibility of smaller organisations and enhanced funding opportunities.\n\n## Evidence statement R4.9e\n\nTwo studies note that to sustain the provision of healthier food options, communities need to take them up and so they need to be made attractive and clear.\n\n## Evidence statement R4.9f\n\nOne study found that community projects were largely unwilling address smoking, preferring to promote physical activity.\n\n## Evidence statement R4.10a\n\nFive studies reported on staffing successful programmes.\n\n## Evidence statement R4.10b\n\nThree studies report difficulties in recruitment and retention.\n\n## Evidence statement R4.10c\n\nPositive staff contributions were defined in three studies where successful networking allowed staff to use their time effectively because they were not duplicating activities; where they were assisted by structures that focus on heart health issues and where flexibility allowed them to spend significant periods of time with participants.\n\n## Evidence statement R4.10d\n\nPositive staff characteristics included knowledge and interest in heart health and being upbeat and friendly. A range of specialist staff should be involved.\n\n## Evidence statement R4.11a\n\nSix study reports make specific comments about funding and resource requirements.\n\n## Evidence statement R4 11.b\n\nFive study reports note the need for those with existing roles and responsibilities to be given resources to take on additional CVD programme work, or for dedicated positions to be created. Limited time for school-based staff may be a particular problem.\n\n## Evidence statement R4.12a\n\nTwo studies identify effective communication between organisations, staff and the community, to be important, but use different mechanisms to achieve this: lay health advisers or having a full time project coordinator.\n\n## Evidence statement R4.13a\n\nFour study reports discuss recruiting and retaining programme volunteers.\n\n## Evidence statement R4.13b\n\nVolunteers need adequate resourcing and leadership, and may be motivated by witnessing positive changes in the community.\n\n## Evidence statement R4.13c\n\nOne study suggests that volunteers find health promotion less satisfying than traditional patient service roles.\n\n## Evidence statement R4.13d\n\nTwo study reports about the same programme note that lay health advisers, recruited from the target community, were key.\n\n## Evidence statement R4.14a\n\nTwo study reports mention the role of GPs in community CVD projects.\n\n## Evidence statement R4.14b\n\nGP uptake was slow and it is suggested that GPs may be less comfortable in health promotion roles than their traditional role of secondary prevention.\n\n## Evidence statement R4.15a\n\nEvidence relating to staff training were identified by six study reports.\n\n## Evidence statement R4.15b\n\nWhile skills training is needed, involvement in the programme itself increases skills and knowledge through sharing information and implementing theoretical knowledge.\n\n## Evidence statement R4.16a\n\nFive study reports relate to the evaluation of CVD prevention programmes.\n\n## Evidence statement R4.16b\n\nTwo study reports found that process evaluation and action research raised self-awareness among staff and promoted programme improvement. While a third reports that time limited projects limit the possibility of such learning.\n\n## Evidence statement R4.16c\n\nData management was a challenge in long-term projects and those with multiple strands across a number of organisations.\n\n## Evidence statement R4.17a\n\nThere is evidence from eight study reports about community engagement in CVD prevention programmes.\n\n## Evidence statement R4.17b\n\nTwo study reports suggest that successful community engagement requires multiple approaches across populations.\n\n## Evidence statement R4.17c\n\nTwo study reports suggest that successful programmes need to be sensitive to communities' habits and cultural patterns, while a further three describe the important of matching programme staff to the social and/or ethnic characteristics of the target communities.\n\n## Evidence statement R4.17d\n\nChallenges to community engagement include engaging community representatives at strategic levels; building confidence in community leaders; difficulties breaking into existing networks; competing with other community events; reaching young people; reluctance due to the legacy of negative experiences with previous initiatives; lack of enthusiasm in the community.\n\n## Evidence statement R4.18a\n\nSeven studies report that the local physical environment had important effects on the ability of community CVD risk-reduction projects to be successful.\n\n## Evidence statement R4.18b\n\nFive studies reported that access to healthy food options was limited, while unhealthy food was more visible, both in the community and in school-based programmes.\n\n## Evidence statement R4.18c\n\nLocal barriers to physical activity including no sidewalks, unmetalled roads or loose dogs; lack of school provision to secure bikes or store kit which discourages extra-curricular exercise; and local availability of gyms or other facilities.\n\n## Evidence statement R4.19a\n\nCommunity and familial norms: There is evidence from one study report among British Asians that stress from a variety of sources was a noted problem among both men and women and this might lead to inability to access essential services or to communicate with professionals.\n\n## Evidence statement R4.20a\n\nAttitudes to food and cooking: There is evidence from three study reports that specific foods and eating patterns may be regarded as important expressions of cultural identity. Cultural norms about food types and their preparation may not be the most healthy from a CVD prevention perspective.\n\n## Evidence statement R4.21a\n\nThere is evidence from three study reports about cultural attitudes to weight and exercise.\n\n## Evidence statement R4.21b\n\nThese suggest that, among some groups, understandings of greater weight as a sign of wealth and health may persist which may challenge successful adoption of CVD prevention activities.\n\n## Evidence statement R4.21c\n\nFurther, specific connotations of language used to describe weight and physical activities may exist, so shared understandings between clinical and community meanings should not be assumed.\n\n## Evidence statement R4.22a\n\nFatalism and health: There is evidence from three study reports, among three different ethnic groups, of fatalistic attitudes where one's state of health is the will of God.\n\n## Evidence statement R4.23a\n\nThere is evidence from six study reports to suggest that a benefit of community CVD programmes is in providing leadership that encourages local attitudes to change for the better.\n\n## Evidence statement R4.23b\n\nAs well as making personal changes, such 'social health' encouraged changes within the family, within the local community and within the wider social and political community. Despite this, one study suggests that men remain less likely to use health services.\n\n## Evidence statement R4.24a\n\nNine studies discuss community perceptions of CVD risk factors.\n\n## Evidence statement R4.24b\n\nSix studies report high levels of understanding about CVD risk among the target population while two suggest limited understanding and two suggest challenges in turning knowledge into action.\n\n## Evidence statement R4.24c\n\nOne study suggests that different types of knowledge are at play (theoretical, practical, experiential and intuitive), and where there is a discrepancy between theoretical and experiential knowledge, the latter influences what participants do. These links might be challenged by cues to action (health belief model) – most significantly breakdown of self-image and social networks.\n\n## Evidence statement R4.24d\n\nOne study develops a typology of six 'ideal types' of functional and dysfunctional attitude among programme participants who see it as a blessing, an opportunity, a confirmation, a watchman, a disappointment or an insult. The latter two are negative or 'dysfunctional' in terms of positive health choices and more men have these attitudes.\n\n## Evidence statement R4.25a\n\nNine study reports discuss people's motivations for, or resistance to, adopting risk reduction behaviours.\n\n## Evidence statement R4.25b\n\nTwo studies report that health concerns, sometimes serious, were motivating factors to participate and two that feedback of physiological test results was motivating.\n\n## Evidence statement R4.25c\n\nWomen may be targeted to take heart health practices home, however, two studies report on difficulties initiating or maintaining family interest and that resistance from family members was a barrier to adopting healthier behaviour. It is difficult to maintain behaviour changes amidst the usual business of family commitments.\n\n## Evidence statement R4.25d\n\nOne study suggests that there is a need for ongoing support in order for behavioural changes to be made and maintained.\n\n## Evidence statement R4.25e\n\nOne study found that secondary school pupils enjoyed the freedom to make food choices not available at primary school – pupils' food choices, and those of the wider population, may reflect issues other than health.\n\n## Evidence statement R4.26a\n\nSix studies report on participant perceptions of programmes in which they were involved.\n\n## Evidence statement R4.26b\n\nIn two studies participants reported improving heart health through weight loss, increased exercise, as well as increased awareness and use of services and programme activities. One study also suggests that networks providing community support was a benefit.\n\n## Evidence statement R4.26c\n\nOne study found that practical demonstrations were much more successful than information provision alone.\n\n## Evidence statement R4.26d\n\nTwo studies suggest that the participants may doubt the credibility of health messages, with so many sources of, sometimes contradictory, information available. Matching the characteristics of the community may be important.\n\n## Evidence statement R5.2\n\nCommunity engagement: Positive community engagement requires trusting, respectful relationships to be built which motivate and support change. Community engagement should be an ongoing and dynamic partnership which responds to community needs.\n\nAs CVD may not be seen as an immediate concern within targeted communities, staff may first need to listen and respond to the existing concerns of the community. This may be done through participating in existing networks and forums, or creating forums that have more open agendas, at least to start with.\n\nSufficient time is needed to ensure that this is done appropriately and also to ensure that changes become adopted by the community so that they are empowered to continue, even if the project itself comes to an end.\n\nInformation and education is likely to be more effective if it relates to the experiences of the community, and if those that deliver it are seen as part of that community. Appropriately skilled staff are needed for effective community engagement.\n\nGreater levels of participation, that involve community members as partners or devolve power to them, may have additional benefits – ensuring that programmes are truly responsive to community needs, involving local people in the complexities of planning and delivering such programmes and so facilitating understanding within the community.\n\nDone well, community engagement may create a positive feedback loop which motivates change, improving health which produces greater motivation. However, care needs to be taken to ensure that those adopting behaviour change are not just those already motivated to change, thereby increasing, rather than lessening, health inequalities.\n\n## Evidence statement R5.3\n\nStaffing – leadership: Strong, inspirational leadership may be important to initiate, coordinate and drive complex programmes and motivate and encourage cooperation among multiple staff across a number of agencies with a range of responsibilities.\n\nTo fulfil this, staff are needed whose role is dedicated to the programme and those with multiple roles need to have appropriate time freed up.\n\nLeaders may be needed for the project over all, but also for specific elements of the project, for example, to encourage primary care participation or ensure local political or funding support. Leaders from within the community are also needed to champion the project and facilitate engagement.\n\nExpectations of leadership roles should be matched by appropriate control and responsibility, and given the necessary training and support.\n\n## Evidence statement R5.4\n\nStaffing – staff engagement: To ensure that staff are engaged with the aims of a CVD prevention progamme, they require appropriate training and resources, a good understanding of how their role fits into the programme overall and a clear understanding of the extent of their roles and responsibilities.\n\n## Evidence statement R5.5\n\nStaffing – GPs: The role of primary care was complicated and sometimes contradictory. Some GPs may be more comfortable with a secondary, rather than primary, prevention role, which may explain why some participants found it difficult to engage them in CVD prevention programmes. Conversely, other participants viewed primary care as crucial partners in CVD prevention. Advocacy among other local organisations may be a key role.\n\nWhere primary care is involved in CVD prevention programmes, they need to receive appropriate resources to free-up staff time.\n\nEngaging primary care and keeping them appropriately informed may require tailored approaches.\n\n## Evidence statement R5.6\n\nStaffing – volunteers: Volunteers from within the community may be particularly effective at informing, motivating and engaging their peers in the community and enhance community empowerment.\n\nVolunteer workers need to be properly trained and supported to ensure that they continue to be involved and don't get burnt out.\n\nThe issues of paying those involved should be considered carefully.\n\n## Evidence statement R5.7\n\nStaffing – multi-agency, multi-disciplinary teams: Public health work to reduce CVD is likely to require the involvement of multiple agencies and disciplines.\n\nCoordination and cooperation is required to build trust and a sense of shared purpose through aligning the goals and activities of different agencies involved, and assigning clear roles and responsibilities to participating organisations and staff within them. Joint appointments may facilitate this. Ongoing feedback and communication is vital.\n\nSufficient time is needed to successfully negotiate and accommodate different expectations and bureaucracies.\n\n## Evidence statement R5.8\n\nLegacy: CVD reduction programmes may enhance their longer-term impact through ensuring that programme activities are embedded within organisations and the community.\n\nAppropriate training and support for key staff, and community members, from project inception may help to ensure activities become 'institutionalised'. Ongoing sources of funding should also be identified.\n\nProgramme impacts should be regularly assessed and results fed back to staff and organisations so that successful activities are recognised and adopted. This will require the identification of appropriate resources.\n\nEarly and ongoing community engagement may ensure ongoing changes in healthy behaviours, empowering the community to maintain positive changes. Short-term projects often fail to leave lasting benefits to a community as their short-term goal setting may preclude the necessary engagement required.\n\n## Evidence statement R5.9\n\nShort time frames: Short time frames for CVD prevention programmes may threaten success at a number of levels: implementation, staff engagement and training, community engagement, evaluation and legacy. It is difficult for such programmes to meet community needs, staff needs or to permit changes to become embedded in the community. This may lead communities and local agencies to lose faith in such interventions, further hampering the ability of future work to be successful in those areas.\n\n## Evidence statement R5.10\n\nStructural barriers: At a macro-level, changes in the broader political environment can have dramatic effects on the adoption and continuation of prevention activities.\n\nSupport for CVD prevention programmes may be affected by changing political priorities around prevention and treatment of illness.\n\n## Evidence statement R5.11\n\nPiloting and monitoring: Cyclical approaches to monitoring and evaluation, such as piloting, process evaluation and action research, allow project to be responsive to local needs, adapting or removing inappropriate projects and allowing successful projects to be rolled out.\n\nInformation from this process fed back to staff in a timely way can help develop a sense of ownership and cooperation and motivate good practice.\n\nOrganisations and individuals should also learn from the experiences of previous projects.\n\n## Evidence statement R5.12\n\nChallenges of evaluation: Commissioners and funders may need to allow flexibility in programme evaluation designs to allow them to adapt to local needs, rather than requiring fixed plans prior to funding. In addition, programmes and evaluations should allow sufficient time for outcomes to be achieved.\n\nMultiple methods may be needed to evaluate important aspects of CVD prevention programmes, such as community empowerment, that are not all easily captured through numerical outcome data.\n\nProgrammes that measure only population-level changes may not capture large impacts for some individuals, and this may be important, especially where health inequalities are addressed.\n\n## Evidence statement CE1\n\nThree studies gave results in cost per life-year gained for population-based programmes compared to no intervention. The results ranged from cost-saving to £240,000 per life-year gained.\n\n## Evidence statement CE2\n\nTwo studies gave results in cost per QALY or DALY (disability-adjusted life years) for population-based programmes compared to no intervention. Results ranged from £10 per QALY to £96 per DALY.\n\n## Evidence statement CE3\n\nTwo studies gave results in cost per case prevented for population-based programmes compared to no intervention. Results ranged from cost saving to £22,000 per case prevented.\n\n## Evidence statement CE4\n\nFive studies reported results in cost per life-year gained for some form of screening strategy compared to no intervention. Results ranged from cost saving to £140,000 per life-year gained.\n\n## Evidence statement CE5\n\nTwo studies gave results in cost per case prevented for screening compared to no intervention. Results ranged from £10,000 to £730,000 per case prevented.\n\n## Evidence statement CE6\n\nTwo studies gave results per 1% reduction in coronary risk for screening compared to no intervention. Results ranged from £2.25 to £5.30 per 1% reduction for one person.\n\n## Evidence statement CE7\n\nOne study gave a result of £0.80 per pound weight lost for a screening programme compared to no intervention.\n\n## Evidence statement CE8\n\nOne study gave results ranging from £12,000 to £120,000 per life-year gained and £100,000 to £230,000 per QALY for screening compared to a population-based approach.\n\n## Evidence statement CE9\n\nOne study gave results from cost saving to £39,000 per life-year gained for some form of exercise training.\n\n# Additional evidence\n\nExpert reports:\n\n\n\nER 1: 'The effectiveness of physical activity promotion interventions'\n\nER 3: 'Expert testimony on salt and cardiovascular disease'\n\nER 4: 'The relationship between commercial interests and risk of cardiovascular disease'\n\nER 5: 'Regional development of a population-based collaborative CVD prevention strategy: the experience of NHS West Midlands'\n\nER 6: 'NICE guidance on the prevention of CVD at population level: evidence from the Co-operative Group'\n\nER 7: 'Population and community programmes addressing multiple risk factors to prevent cardiovascular disease (CVD): addendum to qualitative study produced by Peninsula Technology Assessment Group for NICE: CVD programme – Heart of Mersey (HoM)'\n\nER 8: 'Expert testimony paper on the independent evaluation of 'have a heart Paisley' phase one (Scotland's national CHD prevention demonstration project)'\n\nER 9: 'Expert testimony on the public health harm caused by industrially produced trans fatty acids and actions to reduce and eliminate them from the food system in the UK'\n\nER 10: 'Prevention of cardiovascular disease at a population level: evidence on interventions to address dietary fats'\n\nER 11: 'CVD risk factors: paradigms and pathways'\n\nER 12: 'CVD prevention in populations: lessons from other countries'\n\nER 13: 'Will CVD prevention widen health inequalities?'\n\n\n\n'Obesity'. NICE clinical guideline 43 (2006):\n\n\n\n(1) Section 7.4.1.3 Evidence of corroboration\n\n(2) Evidence statement 5, Section 12 Prevention evidence summary: broader community interventions (Community 2)\n\n(3) Evidence statement 6, Section 12 Prevention evidence summary: broader community interventions (Community 2)\n\n(4) Evidence statement 2, Section 10 Prevention evidence summary: broader community interventions (Community 2)\n\n\n\n# Cost-effectiveness evidence\n\nThe economic analysis consisted of a review of economic evaluations and a cost-effectiveness analysis.\n\n'Prevention of cardiovascular disease at population level (question 1; cost-effectiveness)'\n\n'Prevention of cardiovascular disease at population level: modelling strategies for primary prevention of cardiovascular disease'.\n\nSome primary prevention programmes involving education, mass media and screening with a general population were found to be effective and cost effective. They may reduce some of the risk factors for CVD, including changing behaviours which increase the risk. However, when the findings from all programmes were summarised, the overall effect on health outcomes was uncertain. In addition, as these programmes were conducted many years ago, the findings may not be generally applicable in the UK now.\n\nThe cost-effectiveness analysis strongly suggests that legislation likely to reduce the risk of CVD can be expected to produce a net cost saving to the public sector – as well as improving health. (Unless a very large sum of money needs to be spent on implementation.)\n\nFor example, implementing a CVD prevention programme based on the North Karelia project would result in an incremental cost-effectiveness ratio of approximately £7000 per quality-adjusted life year (QALY). For the Stanford Five City Project, the total healthcare cost savings almost equal the estimated cost of the project. The benefits of reducing the prevalence of smoking would also make the programme cost saving.\n\nAt the request of the Programme Development Group (PDG), the scope of the modelling was extended beyond programmes for which there was direct evidence of effectiveness. Interventions modelled included:\n\nThe North Karelia project – including the effect of a net percentage reduction in serum cholesterol of 3% for men and 1% for women, and a reduction in systolic blood pressure of 3% for men and 5% for women.\n\nThe Stanford Five City Project – the effect of a 4% reduction in systolic blood pressure and a 2% decrease in serum cholesterol among the general population.\n\nLegislation to ban trans fats and so reduce trans fatty acid (TFA) levels in the population so that it only accounts for approximately 0.7% of total energy intake.\n\nLegislation to reduce the population's salt intake by 3\xa0g and 6\xa0g per day.\n\nThe modelling made a number of conservative assumptions. It found that halving CVD events across the entire England and Wales population of 50 million would result in discounted savings of approximately £14 billion per year. Reducing mean population cholesterol or blood pressure levels by 5% would result in discounted annual savings of approximately £0.7 billion and £0.9 billion respectively. Reducing population cardiovascular risk by even 1% would generate discounted savings of approximately £260 million per year.\n\nAdditional benefits to existing CVD patients, and reductions in other diseases, were not quantified.\n\nAs the model is based on a series of conservative assumptions, it probably seriously underestimates the true health benefits to be gained from the recommendations.\n\n# Fieldwork findings\n\nFieldwork aimed to test the relevance, usefulness and feasibility of putting the recommendations into practice. The PDG considered the findings when developing the final recommendations. For details, go to the fieldwork section in appendix B and online.\n\nFeedback to the recommendations varied.\n\n## Food industry recommendations (1, 2, 3, 4, 5 and 10 in the consultation document)\n\nIt was indicated, particularly by some food industry stakeholders, that:\n\n\n\nthe recommendations were 'out of date' and did not reflect the current situation within the food industry\n\nit was not feasible to implement parts of the recommendations and their impact would be minimal\n\nsome of the advice was already covered by other government agencies, as well as at European level\n\nthe role of these recommendations was questionable, particularly where they were quoting differences in target values from those agreed with the FSA.\n\n\n\nIt was felt that NICE has 'a lot less weight' in the food and planning sectors and that we would need to work much more closely with them to gain support for the recommendations.\n\nFood industry representatives generally (but not unanimously) indicated that trans fats were 'no longer an issue' and should, therefore, not be included in the recommendations. They also questioned the levels of saturated fat and salt recommended, as they were unaware of the evidence to support a reduction to these levels.\n\nCatering industry recommendations (6, 14 and 15 in the consultation document)\n\nIn general, stakeholders felt that the catering recommendations demonstrated how to follow good practice.\n\nLocal authority planning recommendations (7, 8, 9, 12, 13, 16, 17 and 18 in the consultation document)\n\nLocal planning and policy representatives stated that the recommendations needed to become part of national planning policy or law. Otherwise, it would not be possible to implement them.\n\n## Communications recommendation (number 11 in the consultation document)\n\nThere was limited feedback from the industry as some of the target organisations disputed that it was relevant to them and declined the opportunity to be interviewed.\n\n## CVD programme recommendations (19 to 24 in the consultation document)\n\nIn general, representatives from the NHS and PCTs indicated that the regional CVD prevention recommendations were appropriate and that they supported current work on CVD prevention.", 'Appendix D: Gaps in the evidence': 'The Programme Development Group (PDG) identified a number of gaps in the evidence related to the programmes under examination based on an assessment of the evidence, stakeholder and expert comment and fieldwork. These gaps are set out below.\n\nThere is a lack of UK studies on the effectiveness of programmes to prevent CVD among black and minority ethnic groups living in the UK.\n\nThere is a lack of evidence on the effectiveness of interventions targeting those with high risk factors who believe their health is bad.\n\nThere is a lack of evidence on the effectiveness of providing emotional support and help to develop general coping skills as part of interventions to prevent CVD.\n\nThere is a lack of evidence on the effectiveness of CVD prevention programmes involving the families of those at risk.\n\nThere is a lack of controlled comparison studies looking at the effectiveness of lay health advisers in helping to prevent CVD.\n\nThe Group made 6 recommendations for research. These are listed in section 5.', 'Appendix E: supporting documents': 'Supporting documents are available online. These include the following:\n\nEvidence reviews:\n\n\n\nReview 1: \'Prevention of cardiovascular disease at population level (Question 1; phase 1)\'\n\nReview 2: \'Prevention of cardiovascular disease at population level (Question 1; phase 2)\'\n\nReview 3: \'Prevention of cardiovascular disease at population level (Question 1; phase 3)\'\n\nReview 4: \'Barriers to, and facilitators for, multiple risk factor programmes aimed at reducing cardiovascular disease within a given population: a systematic review of qualitative research\'.\n\n\n\nPrimary research:\n\n\n\nReview 5: \'Population and community programmes addressing multiple risk factors to prevent cardiovascular disease: A qualitative study into how and why some programmes are more successful than others\'.\n\n\n\nEconomic analysis:\n\n\n\nReview 6: \'Prevention of cardiovascular disease at population level (Question 1; cost-effectiveness)\'\n\n\'Prevention of cardiovascular disease at population level: modelling strategies for primary prevention of cardiovascular disease\'.\n\n\n\nExpert reports:\n\n\n\nReport 1: \'The effectiveness of physical activity promotion interventions\'\n\nReport 2: \'Health policy analysis\'\n\nReport 3: \'Expert testimony on salt and cardiovascular disease\'\n\nReport 4: \'The relationship between commercial interests and risk of cardiovascular disease\'\n\nReport 5: \'Regional development of a population-based collaborative CVD prevention strategy: the experience of NHS West Midlands\'\n\nReport 6: \'NICE guidance on the prevention of CVD at population level: evidence from the Co-operative Group\'\n\nReport 7: \'Population and community programmes addressing multiple risk factors to prevent cardiovascular disease (CVD): addendum to qualitative study produced by Peninsula Technology Assessment Group for NICE: CVD programme – Heart of Mersey (HoM)\'\n\nReport 8: \'Expert testimony paper on the independent evaluation of "have a heart Paisley" phase one (Scotland\'s national CHD prevention demonstration project)\'\n\nReport 9: \'Expert testimony on the public health harm caused by industrially produced trans fatty acids and actions to reduce and eliminate them from the food system in the UK\'\n\nReport 10: \'Prevention of cardiovascular disease at a population level: evidence on interventions to address dietary fats\'\n\nReport 11: \'CVD risk factors: paradigms and pathways\'\n\nReport 12: \'CVD prevention in populations: lessons from other countries\'\n\nReport 13: \'Will CVD prevention widen health inequalities?\'\n\nReport 14: \'Food manufacturer\'s perspective\'.\n\n\n\nFieldwork report: \'Fieldwork on prevention of cardiovascular disease at population level\'.\n\nA quick reference guide for professionals whose remit includes public health and for interested members of the public.\n\nFor information on how NICE public health guidance is developed see:\n\n\'Methods for development of NICE public health guidance (second edition, 2009)\'\n\n\'The NICE public health guidance development process: An overview for stakeholders including public health practitioners, policy makers and the public (second edition, 2009)\'.', 'Changes after publication': 'February 2012: minor maintenance.\n\nJanuary 2013: minor maintenance', 'About this guidance': 'NICE public health guidance makes recommendations on the promotion of good health and the prevention of ill health.\n\nThis guidance was developed using the NICE public health programme guidance process.\n\nThe recommendations from this guidance have been incorporated into the NICE Pathways diet and physical activity. Tools to help you put the guidance into practice and information about the evidence it is based on are also available.\n\nYour responsibility\n\nThis guidance represents the views of the Institute and was arrived at after careful consideration of the evidence available. Those working in the NHS, local authorities, the wider public, voluntary and community sectors and the private sector should take it into account when carrying out their professional, managerial or voluntary duties.\n\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.\n\nCopyright\n\n© National Institute for Health and Clinical Excellence 2010. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.\n\nContact NICE\n\nNational Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BTwww.nice.org.uknice@nice.org.uk0845 033 7780'}	https://www.nice.org.uk/guidance/ph25	This guideline covers the main risk factors linked with cardiovascular disease: poor diet, physical inactivity, smoking and excessive alcohol consumption. It aims to reduce the high incidence of cardiovascular disease. This, in turn, will help prevent other major causes of death and illness, such as type 2 diabetes and many cancers.
654d7e20573aba7015704c709ced7dde86b3460a	nice	Alcohol-use disorders: prevention	Alcohol-use disorders: prevention This guideline covers alcohol problems among people over 10. It aims to prevent and identify such problems as early as possible using a mix of policy and practice. # Introduction The Department of Health asked NICE to produce public health guidance on the prevention and early identification of alcohol-use disorders among adults and adolescents. The guidance is for government, industry and commerce, the NHS and all those whose actions affect the population's attitude to – and use of – alcohol. This includes commissioners, managers and practitioners working in local authorities, education and the wider public, private, voluntary and community sectors. In addition, it may be of interest to members of the public. This is 1 of 3 pieces of NICE guidance addressing alcohol-related problems among people aged 10 years and older. The others are: NICE's guideline on alcohol-use disorders: diagnosis and management of physical complications (2010). A clinical guideline covering acute alcohol withdrawal including delirium tremens, alcohol-related liver damage, alcohol-related pancreatitis and management of Wernicke's encephalopathy. NICE's guideline on alcohol-use disorders: diagnosis, assessment and management of harmful drinking and alcohol dependence (2011). A clinical guideline covering identification, assessment, pharmacological and psychological/psychosocial interventions, and the prevention and management of neuropsychiatric complications. The guidance complements, but does not replace, NICE guidance on school-based interventions on alcohol. It will also complement NICE guidance on: personal, social and health education; prevention of cardiovascular disease; antenatal care; and associated guidance on alcohol-use disorders (management and dependence). The Programme Development Group (PDG) developed these recommendations on the basis of reviews of the evidence, an economic analysis, expert advice, stakeholder comments and fieldwork. Members of the PDG are listed in appendix A. The methods used to develop the guidance are summarised in appendix B. Supporting documents used to prepare this document are listed in appendix E. For more information see full details of the evidence collated, including fieldwork data and activities and stakeholder comments, along with a list of the stakeholders involved and NICE's supporting process and methods manuals.# Recommendations People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care. Making decisions using NICE guidelines has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding. This is NICE's formal guidance on the prefvention and early identification of alcohol-use disorders among adults and adolescents. When writing the recommendations, the Programme Development Group (PDG) (see appendix A) considered the evidence of effectiveness (including cost effectiveness), fieldwork data and comments from stakeholders and experts. The evidence statements underpinning the recommendations are listed in appendix C. The evidence reviews, supporting evidence statements and economic analysis are available. # Population versus individual approach A combination of interventions are needed to reduce alcohol-related harm – to the benefit of society as a whole. Population-level approaches are important because they can help reduce the aggregate level of alcohol consumed and therefore lower the whole population's risk of alcohol-related harm. They can help: those who are not in regular contact with the relevant services those who have been specifically advised to reduce their alcohol intake, by creating an environment that supports lower-risk drinking. They can also help prevent people from drinking harmful or hazardous amounts in the first place. Interventions aimed at individuals can help make people aware of the potential risks they are taking (or harm they may be doing) at an early stage. This is important, as they are most likely to change their behaviour if it is tackled early. In addition, an early intervention could prevent extensive damage. The government continues to use both individual and population approaches to address the harm caused by alcohol (for example, in its strategy 'Safe. Sensible. Social.' ). This NICE guidance provides authoritative recommendations, based on a robust analysis of the evidence, which support current government activities. The recommendations could form part of a national framework for action. As highlighted by the House of Commons Public Accounts Committee, national-level action to reduce the population's alcohol consumption requires coordinated government policy. It also needs government, industry and key non-governmental organisations to work together (House of Commons Public Accounts Committee – Reducing alcohol harm: health services in England for alcohol misuse). # Policy and practice This guidance makes the case that alcohol-related harm is a major public health problem. On the basis of the best available evidence, it also identifies the policy options that are most likely to be successful in combating such harm. The final decision on whether these policies are adopted – and how they are prioritised – will be determined by government and the normal political processes. The policy recommendations (recommendations 1 to 3) are based on extensive and consistent evidence which suggests that the issues identified deserve close attention. This evidence also suggests that policy change is likely to be a more effective – and more cost-effective – way of reducing alcohol-related harm among the population than actions undertaken by local health professionals. Many of the policy changes considered in this guidance are similar to those proposed by the House of Commons Health Select Committee (House of Commons Health Select Committee – Alcohol first report of session 2009–10). The recommendations for practice (recommendations 4 to 12) support, complement – and are reinforced by – these policy options. They include the use of screening and brief interventions. The latter includes structured brief advice and extended brief interventions. For the purposes of this guidance, screening involves identifying people who are not seeking treatment for alcohol problems but who, in the view of the professional, may have an alcohol-use disorder. Practitioners may use any contact with clients to carry out this type of screening. The term is not used here to refer to national screening programmes such as those recommended by the UK National Screening Committee (UK NSC). # Recommendations for policy ## Who should take action? The Chief Medical Officer should coordinate the alcohol harm-reduction strategy for England across government, supported by the Department of Health. The following departments and national agencies should also be involved: Advertising Standards Authority Department for Business, Innovation and Skills Department for Culture, Media and Sport Department for Education Department for Environment, Food and Rural Affairs Department of Communities and Local Government HM Treasury Home Office Ministry of Justice National Treatment Agency Ofcom Office of Fair Trading Organisations that should be consulted include: advertisers alcohol producers national non-governmental organisations (for example, Alcohol Concern and the Royal Medical Colleges) -ff- and on-sale retailers. ## Recommendation 1: price Making alcohol less affordable is the most effective way of reducing alcohol-related harm. The current excise duty varies for different alcoholic products (for historical reasons and under EU legislation). This means that the duty does not always relate directly to the amount of alcohol in the product. In addition, an increase in the duty levied does not necessarily translate into a price increase as retailers or producers may absorb the cost. There is extensive international and national evidence (within the published literature and from economic analyses) to justify reviewing policies on pricing to reduce the affordability of alcohol. Consider introducing a minimum price per unit. Set the level by taking into account the health and social costs of alcohol-related harm and its impact on alcohol consumption. Consider initiating a review of the excise duty regime with fellow EU member states. The aim would be to obtain a pan-EU agreement on harmonisation which links alcohol duty to the strength of each product. Regularly review the minimum price per unit to ensure alcohol does not become more affordable over time. Regularly review alcohol duties to make sure alcohol does not become more affordable over time. ## Recommendation 2: availability International evidence suggests that making it less easy to buy alcohol, by reducing the number of outlets selling it in a given area and the days and hours when it can be sold, is another effective way of reducing alcohol-related harm. In Scotland, protection of the public's health is part of the licensing objectives. Consider revising legislation on licensing to ensure: protection of the public's health is 1 of its objectives health bodies are responsible authorities licensing departments can take into account the links between the availability of alcohol and alcohol-related harm when considering a licence application (that is, they can take into account the number of alcohol outlets in a given area and times when it is on sale and the potential links to local crime and disorder and alcohol-related illnesses and deaths) immediate sanctions can be imposed on any premises in breach of their licence, following review proceedings. Consider reducing personal import allowances to support the introduction of a minimum price per unit of alcohol. ## Recommendation 3: marketing There is evidence that alcohol advertising does affect children and young people. It shows that exposure to alcohol advertising is associated with the onset of drinking among young people and increased consumption among those who already drink. All of the evidence suggests that children and young people should be protected as much as is possible by strengthening the current regulations. Ensure children and young people's exposure to alcohol advertising is as low as possible by considering a review of the current advertising codes. This review would ensure: the limits set by the Advertising Standards Authority (ASA) for the proportion of the audience under age 18 are appropriate where alcohol advertising is permitted there is adequate protection for children and young people all alcohol marketing, particularly when it involves new media (for example, web-based channels and mobile phones) and product placement, is covered by a stringent regulatory system which includes ongoing monitoring of practice. Ofcom, the ASA and the government should keep the current regulatory structure under review. Assess the potential costs and benefits of a complete alcohol advertising ban to protect children and young people from exposure to alcohol marketing. # Recommendations for practice ## Recommendation 4: licensing Alcohol licence-holders and designated supervisors of licensed premises. Local authorities. Trading standards officers. The police. Magistrates. Revenue and customs. Use local crime and related trauma data to map the extent of alcohol-related problems before developing or reviewing a licensing policy. If an area is saturated with licensed premises and the evidence suggests that additional premises may affect the licensing objectives, adopt a 'cumulative impact' policy. If necessary, limit the number of new licensed premises in a given area. Ensure sufficient resources are available to prevent under-age sales, sales to people who are intoxicated, proxy sales (that is, illegal purchases for someone who is under-age or intoxicated), non-compliance with any other alcohol licence condition and illegal imports of alcohol. Work in partnership with the appropriate authorities to identify and take action against premises that regularly sell alcohol to people who are under-age, intoxicated or making illegal purchases for others. Undertake test purchases (using 'mystery' shoppers) to ensure compliance with the law on under-age sales. Test purchases should also be used to identify and take action against premises where sales are made to people who are intoxicated or to those illegally purchasing alcohol for others. Ensure sanctions are fully applied to businesses that break the law on under-age sales, sales to those who are intoxicated and proxy purchases. This includes fixed penalty and closure notices (the latter should be applied to establishments that persistently sell alcohol to children and young people). ## Recommendation 5: resources for screening and brief interventions Professionals who have contact with those aged 16 and over. Chief executives of NHS and local authorities. Commissioners of NHS healthcare services. Commissioners from multi-agency joint commissioning groups. Managers of NHS-commissioned services. Chief executives of NHS and local authorities should prioritise alcohol-use disorder prevention as an 'invest to save' measure. Commissioners should ensure a local joint alcohol needs assessment is carried out in accordance with Public Health England's alcohol, drugs and tobacco: commissioning support pack and local alcohol services and systems improvement tool. They should also ensure locally defined integrated care pathways for alcohol treatment are reviewed. Commissioners should ensure their plans include screening and brief interventions for people at risk of an alcohol-related problem (hazardous drinkers) and those whose health is being damaged by alcohol (harmful drinkers). This includes people from disadvantaged groups. Commissioners should make provision for the likely increase in the number of referrals to services providing tier 2, 3 and 4 structured alcohol treatments as a result of screening. These services should be properly resourced to support the stepped care approach recommended in the Department of Health's Models of care for alcohol misusers. Commissioners should ensure at least 1 in 7 dependent drinkers can get treatment locally, in line with Signs for improvement. Commissioners should include formal evaluation within the commissioning framework so that alcohol interventions and treatment are routinely evaluated and followed up. The aim is to ensure adherence to evidence-based practice and to ensure interventions are cost effective. Managers of NHS-commissioned services must ensure an appropriately trained nurse or medical consultant, with dedicated time, is available to provide strategic direction, governance structures and clinical supervision to alcohol specialist nurses and care givers. Managers of NHS-commissioned services must ensure community and voluntary sector providers have an appropriately trained professional who can provide strategic direction, governance structures and supervision to those providing screening and brief interventions. Managers of NHS-commissioned services must ensure staff have enough time and resources to carry out screening and brief intervention work effectively. Staff should have access to recognised, evidence-based packs. These should include: a short guide on how to deliver a brief intervention, a validated screening questionnaire, a visual presentation (to compare the person's drinking levels with the average), practical advice on how to reduce alcohol consumption, a self-help leaflet and possibly a poster for display in waiting rooms. Managers of NHS-commissioned services must ensure staff are trained to provide alcohol screening and structured brief advice. If there is local demand, staff should also be trained to deliver extended brief interventions. ## Recommendation 6: supporting children and young people aged 10 to 15 years Children and young people aged 10 to 15 years who are thought to be at risk from their use of alcohol. Any professional with a safeguarding responsibility for children and young people and who regularly comes into contact with this age group. Use professional judgement to routinely assess the ability of these children and young people to consent to alcohol-related interventions and treatment. Some will require parental or carer involvement. Obtain a detailed history of their alcohol use (for example, using the Common Assessment Framework as a guide). Include background factors such as family problems and instances of child abuse or under-achievement at school. Use professional judgement to decide on the appropriate course of action. In some cases, it may be sufficient to empathise and give an opinion about the significance of their drinking and other related issues that may arise. In other cases, more intensive counselling and support may be needed. If there is a reason to believe that there is a significant risk of alcohol-related harm, consider referral to child and adolescent mental health services, social care or to young people's alcohol services for treatment, as appropriate and available. Ensure discussions are sensitive to the child or young person's age and their ability to understand what is involved, their emotional maturity, culture, faith and beliefs. The discussions (and tools used) should also take into account their particular needs (health and social) and be appropriate to the setting. ## Recommendation 7: screening young people aged 16 and 17 years Young people aged 16 and 17 years who are thought to be at risk from their use of alcohol. Health and social care, criminal justice and community and voluntary professionals in both NHS and non-NHS settings who regularly come into contact with this group. Complete a validated alcohol screening questionnaire with these young people. Alternatively, if they are judged to be competent enough, ask them to fill 1 in themselves. In most cases, AUDIT (alcohol use disorders identification test) should be used. If time is limited, use an abbreviated version (such as AUDIT-C, AUDIT-PC, CRAFFT, SASQ or FAST). Screening tools should be appropriate to the setting. For instance, in an emergency department, FAST or the Paddington Alcohol Test (PAT) would be most appropriate. Use professional judgement as to whether to revise the AUDIT scores downwards when screening people under 18. Focus on key groups that may be at an increased risk of alcohol-related harm. This includes those: who have had an accident or a minor injury who regularly attend genito-urinary medicine (GUM) clinics or repeatedly seek emergency contraception involved in crime or other antisocial behaviour who truant on a regular basis at risk of self-harm who are looked after involved with child safeguarding agencies. When broaching the subject of alcohol and screening, ensure discussions are sensitive to the young person's age and their ability to understand what is involved, their emotional maturity, culture, faith and beliefs. The discussions should also take into account their particular needs (health and social) and be appropriate to the setting. Routinely assess the young person's ability to consent to alcohol-related interventions and treatment. If there is doubt, encourage them to consider involving their parents in any alcohol counselling they receive. ## Recommendation 8: extended brief interventions with young people aged 16 and 17 years Young people aged 16 and 17 years who have been identified via screening as drinking hazardously or harmfully. Health and social care, criminal justice and community and voluntary sector professionals in both NHS and non-NHS settings who regularly come into contact with this group. Ask the young person's permission to arrange an extended brief intervention for them. Appropriately trained staff should offer the young person an extended brief intervention. Provide information on local specialist addiction services to those who do not respond well to discussion but who want further help. Refer them to these services if this is what they want. Referral must be made to services that deal with young people. Give those who are actively seeking treatment for an alcohol problem a physical and mental assessment and offer, or refer them for, appropriate treatment and care. ## Recommendation 9: screening adults Adults. Health and social care, criminal justice and community and voluntary sector professionals in both NHS and non-NHS settings who regularly come into contact with people who may be at risk of harm from the amount of alcohol they drink. NHS professionals should routinely carry out alcohol screening as an integral part of practice. For instance, discussions should take place during new patient registrations, when screening for other conditions and when managing chronic disease or carrying out a medicine review. These discussions should also take place when promoting sexual health, when seeing someone for an antenatal appointment and when treating minor injuries. Where screening everyone is not feasible or practicable, NHS professionals should focus on groups that may be at an increased risk of harm from alcohol and those with an alcohol-related condition. This includes people: with relevant physical conditions (such as hypertension and gastrointestinal or liver disorders) with relevant mental health problems (such as anxiety, depression or other mood disorders) who have been assaulted at risk of self-harm who regularly experience accidents or minor traumas who regularly attend GUM clinics or repeatedly seek emergency contraception. Non-NHS professionals should focus on groups that may be at an increased risk of harm from alcohol and people who have alcohol-related problems. For example, this could include those: at risk of self-harm involved in crime or other antisocial behaviour who have been assaulted at risk of domestic abuse whose children are involved with child safeguarding agencies with drug problems. When broaching the subject of alcohol and screening, ensure the discussions are sensitive to people's culture and faith and tailored to their needs. Complete a validated alcohol questionnaire with the adults being screened. Alternatively, if they are competent enough, ask them to fill 1 in themselves. Use AUDIT to decide whether to offer them a brief intervention (and, if so, what type) or whether to make a referral. If time is limited, use an abbreviated version (such as AUDIT-C, AUDIT-PC, SASQ or FAST). Screening tools should be appropriate to the setting. For instance, in an emergency department FAST or PAT would be most appropriate. Do not offer simple brief advice to anyone who may be dependent on alcohol. Instead, refer them for specialist treatment (see recommendation 12). If someone is reluctant to accept a referral, offer an extended brief intervention (see recommendation 11). Use professional judgement as to whether to revise the AUDIT scores downwards when screening: women, including those who are, or are planning to become, pregnant people aged 65 and over people from some black and minority ethnic groups.If in doubt, consult relevant specialists. Work on the basis that offering an intervention is less likely to cause harm than failing to act where there are concerns. Consult relevant specialists when it is not appropriate to use an English language-based screening questionnaire. (For example, when dealing with people whose first language is not English or who have a learning disability.) Biochemical measures should not be used as a matter of routine to screen someone to see if they are drinking hazardously or harmfully. (This includes measures of blood alcohol concentration .) Biochemical measures may be used to assess the severity and progress of an established alcohol-related problem, or as part of a hospital assessment (including assessments carried out in emergency departments). ## Recommendation 10: brief advice for adults Adults who have been identified via screening as drinking a hazardous or harmful amount of alcohol and who are attending NHS or NHS-commissioned services or services offered by other public institutions. Professionals who have received the necessary training and work in: primary healthcare emergency departments -ther healthcare services (hospital wards, outpatient departments, occupational health, sexual health, needle and syringe exchange programmes, pharmacies, dental surgeries, antenatal clinics and those commissioned from the voluntary, community and private sector) the criminal justice system social services higher education -ther public services. Offer a session of structured brief advice on alcohol. If this cannot be offered immediately, offer an appointment as soon as possible thereafter. Use a recognised, evidence-based resource that is based on FRAMES principles (feedback, responsibility, advice, menu, empathy, self-efficacy). It should take 5–15 minutes and should: cover the potential harm caused by their level of drinking and reasons for changing the behaviour, including the health and wellbeing benefits cover the barriers to change -utline practical strategies to help reduce alcohol consumption (to address the 'menu' component of FRAMES) lead to a set of goals. Where there is an ongoing relationship with the patient or client, routinely monitor their progress in reducing their alcohol consumption to a low-risk level. Where required, offer an additional session of structured brief advice or, if there has been no response, offer an extended brief intervention. ## Recommendation 11: extended brief interventions for adults Adults who have not responded to brief structured advice on alcohol and require an extended brief intervention or would benefit from an extended brief intervention for other reasons. NHS and other professionals in the public, private, community and voluntary sector who are in contact with adults and have received training in extended brief intervention techniques. Offer an extended brief intervention to help people address their alcohol use. This could take the form of motivational interviewing or motivational-enhancement therapy. Sessions should last from 20 to 30 minutes. They should aim to help people to reduce the amount they drink to low risk levels, reduce risk-taking behaviour as a result of drinking alcohol or to consider abstinence. Follow up and assess people who have received an extended brief intervention. Where necessary, offer up to 4 additional sessions or referral to a specialist alcohol treatment service (see recommendation 12). ## Recommendation 12: referral Those aged 16 years and over who attend NHS or other public services and may be alcohol-dependent. (For those under 16 see recommendation 6.) NHS and other professionals in the public, private, community and voluntary sector who have contact with anyone aged 16 and over. Consider making a referral for specialist treatment if 1 or more of the following has occurred. They: show signs of moderate or severe alcohol dependence have failed to benefit from structured brief advice and an extended brief intervention and wish to receive further help for an alcohol problem show signs of severe alcohol-related impairment or have a related co-morbid condition (for example, liver disease or alcohol-related mental health problems).# Public health need and practice In Britain, the amount of pure alcohol sold per adult rose from 9.53 litres in 1986/87 to a peak of 11.78 litres in 2004/05, before dropping to 11.53 litres in 2007/08 (HM Revenue and Customs 2008). This approximates to 22 units (176 g) per week for each person aged over 15 years. Levels of self-reported hazardous and harmful drinking are lowest in the central and eastern regions of England (21–24% of men and 10–14% of women). They are highest in the North East, North West and Yorkshire and Humber (26–28% of men, 16–18% of women) (North West Public Health Observatory 2007). A recent paper has also indicated that alcohol-related mortality within the UK varies according to a person's country of birth. For example, there is a higher alcohol-related mortality rate among those born in Ireland, Scotland and India compared to those born in Bangladesh, China, Hong Kong, Pakistan, the Middle East, West Africa and the West Indies (Bhala et al. 2009). Although the amount most people drink poses a relatively low risk to their health, an estimated 24% of adults drink a hazardous or harmful amount (The NHS Information Centre 2009). For definitions of harmful and hazardous drinking see the glossary. In 2007, 72% of men and 57% of women in England had an alcoholic drink on at least 1 day during the previous week (Robinson and Lader 2009). In addition, 41% of men and 35% of women exceeded the daily recommended limits on at least 1 day in the previous week (Robinson and Lader 2009). Among those aged 15 and under, 18% had drunk alcohol in the previous week (Diment et al. 2009). Although the proportion of schoolchildren who have never had an alcoholic drink has risen (from 39% in 2003 to 48% in 2008), those who do drink are consuming more. Between 2007 and 2008, mean alcohol consumption among young people aged 11 to 15 (specifically, those who had drunk alcohol in the previous week) increased from 12.7 units (102 g) to 14.6 units (117 g) (Diment et al. 2009). Regional analysis shows that consumption is highest among those living in the North East (17.7 units) and the North West (16.3 units). It is lowest in London (11.3 units) (The NHS Information Centre 2010). In addition, nearly 10,000 children and young people (under the age of 18) are admitted to hospital each year as a result of their drinking (Department for Children, Schools and Families 2009). # Trends in alcohol pricing and consumption In the past 20 years, the price of alcohol has been rising at around the same rate as for other consumer products. However, incomes have risen much faster. As a result, between 1980 and 2008 alcohol became 75% more affordable (The NHS Information Centre 2009). Since 1987, for example, beer and wine have become 139% and 124% more affordable respectively when bought from an off license (Booth et al. 2008). Overall, 80% of alcohol is purchased by 30% of the population (Booth et al. 2008). This suggests that the current low pricing policy in supermarkets mainly benefits those drinking at hazardous and harmful levels. In some cases, alcohol products are sold below cost. It is not possible to say exactly who pays for this subsidy, but it may be that moderate drinkers pay higher prices for other goods as a result. # Health and social problems Alcohol consumption is associated with many chronic health problems including psychiatric, liver, neurological, gastrointestinal and cardiovascular conditions and several types of cancer. It is also linked to accidents, injuries and poisoning (Rehm et al. 2010). Drinking during pregnancy can also have an adverse effect on the developing foetus. The resulting problems can include lower birth weight and slow growth, learning and behavioural difficulties and facial abnormalities (British Medical Association Board of Science 2007). In 2005 it has been estimated that 14,982 deaths were attributable to alcohol consumption (Jones et al. 2008). Alcohol is also linked to a number of social problems. In 2006/07, it was associated with over 500,000 recorded crimes in England (North West Public Health Observatory 2007). It may also be a contributory factor in up to 1 million assaults and is associated with 125,000 instances of domestic violence (DH 2009). Up to 17 million working days are lost annually through absences caused by drinking – and up to 20 million are lost through loss of employment or reduced employment opportunities (Prime Minister's Strategy Unit 2003). The impact on other family members can be profound, leading to feelings of anxiety, worry, depression, helplessness, anger and guilt. For example, it can lead to financial worries and concern about the user's state of physical and mental health, as well as their behaviour. It can also affect the family's social life and make it difficult for family members to communicate. (Orford et al. 2005). Alcohol-use disorders are associated with relationship breakdown, domestic abuse, poor parenting, unsafe and regretted sex, truancy, delinquency, antisocial behaviour and homelessness (Prime Minister's Strategy Unit 2003). # Cost of alcohol-use disorders Alcohol-related harm is estimated to cost society between £17.7 billion and £25.1 billion per year (DH 2008a). It costs the NHS in England up to £2.7 billion a year to treat the chronic and acute effects of drinking (DH 2008b). It is also estimated that up to 35% of all emergency department attendances and ambulance costs are alcohol-related (Prime Minister's Strategy Unit 2003). In 2007/08 there were 863,300 alcohol-related admissions, a 69% increase since 2002/03 (The NHS Information Centre 2009). # Socioeconomic factors The interaction between social class and alcohol is complex. Managers and other professionals self-report that they consume the most alcohol (an average of 19.9 units a week compared with 16.7 units a week for people in routine and manual groups). The difference is even more marked when the figures are broken down by gender: female managers and professionals drink an average of 10.7 units (86 g) a week, compared with 7.1 units (57 g) a week for women in routine and manual groups (Goddard 2008). However, the adverse effects of alcohol are exacerbated among those from lower socioeconomic groups, as they are more likely to experience its negative consequences. (This is not necessarily as a result of drinking themselves, but can be due to other people's drinking.) In addition, factors such as a poor diet and a general lack of money mean that people in lower socioeconomic groups who do drink heavily cannot protect themselves as well as those in more affluent groups against the negative health and social consequences. Compared with those living in more affluent areas, people in the most deprived fifth of the country are: two to 3 times more likely to die of causes influenced, in part, by alcohol three to 5 times more likely to die of an alcohol-specific cause two to 5 times more likely to be admitted to hospital because of an alcohol-use disorder (North West Public Health Observatory 2007). # Government policy Since 2004, the detrimental effects of alcohol-use disorders has resulted in several government policy initiatives. In addition, the need to prevent and reduce alcohol-use disorders has been incorporated into several public service agreements (PSAs). For examples, see the list below. 'Alcohol harm reduction strategy for England' (Prime Minister's Strategy Unit 2004). 'Choosing health: making healthy choices easier' (DH 2004). 'PSA 14: increase the number of children and young people on the path to success' (HM Treasury 2007a). 'PSA 23: make communities safer' (HM Treasury 2007b). 'PSA 25: reduce the harm caused by alcohol and drugs' (HM Treasury 2007c). 'Safe. Sensible. Social. The next steps in the national alcohol strategy' (DH 2007). 'Youth alcohol action plan' (Department for Children, Schools and Families 2008).# Considerations The Programme Development Group (PDG) took account of a number of factors and issues when developing the recommendations. # General The PDG agreed that the state has a duty to look after the welfare of the population as a whole (Nuffield Council on Bioethics 2007). This includes protecting it from the range of problems that may be caused by alcohol. The PDG believes interventions to prevent alcohol-related harm are likely to improve the population's overall wellbeing and productivity. It also believes they will help reduce health inequalities, as alcohol-related problems have a disproprotionate effect on disadvantaged groups. The PDG believes both population-wide and individual interventions are needed as part of a combined approach to reducing alcohol-related harm that will benefit society as a whole. Population-level approaches are very important because they can help reduce the aggregate level of alcohol consumed and therefore lower the whole population's risk of alcohol-related harm. They can help those not in regular contact with relevant services. They can also help reduce the number of people who start drinking harmful or hazardous amounts in the first place. In addition, they may help those who have been specifically advised to reduce their alcohol intake, by creating an environment that supports lower risk drinking. The PDG acknowledges that some people drink alcohol as a result of underlying problems. Clearly, these need to be addressed along with any alcohol-related issues. # Risks and benefits The PDG recognises that a large percentage (76%) of the population drinks alcohol at a level that is unlikely to cause risk to themselves or others. However, for others, alcohol is associated with many detrimental outcomes. In his 2008 annual report, the Chief Medical Officer highlighted that alcohol can affect not only the person drinking but those around them, including their families and the wider population. For example, each year, drinking adversely affects up to 1.3 million children and leads to over 7,000 road accident injuries and 17 million lost working days. It may also be a contributory factor in up to 1 million assaults and is associated with 125,000 instances of domestic violence (DH 2009). The PDG therefore believes that interventions to address alcohol-related harm should take these wider consequences into account. Although there is evidence that alcohol may reduce the risk of certain cardiovascular diseases, these effects are limited to men over the age of 40 and postmenopausal women who drink small amounts. Overall, the evidence suggests that drinking alcohol is never without risk and that, as consumption increases so does the risk of developing an alcohol-related problem. An increase in per capita alcohol consumption is associated with an increase in related deaths. # Population-wide interventions The PDG believes that most of the recommendations will have a greater impact on those who drink irresponsibly. However, taken together, they are very likely to improve the health of the population as a whole. As indicated by the Rose hypothesis, a small reduction in risk among a large number of people may prevent many more cases, rather than treating a small number at higher risk. A whole-population approach explicitly focuses on changing everyone's exposure to risk (Rose 2008). In this instance, the number of people who drink a heavy or excessive amount in a given population is related to how much the whole population drinks on average. Thus, reducing the average drinking level, via population interventions, is likely to reduce the number of people with severe problems due to alcohol. The PDG felt that a population-level approach to preventing alcohol-related harm could be as effective as legislation to address drink-driving had been. The latter was based on a much more limited evidence base than the proposals in these recommendations. In this case, there is extensive and consistent evidence in favour of a population-level approach on alcohol. The PDG has not been able to consider all the population-wide actions needed to reduce alcohol-related harm. For example, it did not consider the provision of information on product labels and at the point-of-sale on the alcoholic content of drinks and the risks related to different levels of consumption. (This is in line with a proposed amendment to the Food Safety Act 1990 ). Other issues that have not been considered include: wider dissemination of information on alcohol units and related health information (for example, within the workplace); the provision of non-alcohol related activities for young people; and the introduction of mandatory conditions for the responsible sale of alcohol. The PDG feels that these are all important areas that need to be tackled, in conjunction with the recommendations made in this guidance. # Minimum price Making alcohol less affordable is the most effective way of reducing the harm it causes among a population where hazardous drinking is common – such as in the UK (Chisholm et al. 2004). There is extensive evidence (within the published literature and from the economic analysis undertaken to support this guidance) to justify the introduction of a minimum price per unit. For example, the evidence suggests that young people who drink and people (including young people) who drink harmful amounts tend to choose cheaper alcoholic products. Establishing a minimum price per unit would limit the ability of these groups to 'trade down' to cheaper products. The same effect would be more difficult to achieve through alcohol duties, as retailers or producers may absorb the cost of any extra duty levied. Prohibiting 'below cost' selling would ensure any price increases (for example, through taxation) are passed on in full. However, a large increase in duty would be needed to raise the price of the cheapest products to a level that would reduce alcohol harm. Unlike a minimum price per unit, this would affect all products equally rather than focusing on cheaper and stronger goods. A minimum price per unit (unlike a tax increase) would prevent retailers from passing on any increase to producers, or absorbing it themselves. It would also encourage producers to reduce the strength of products. As an example of the effect of minimum pricing, over a 10-year period it is estimated that a 50p minimum price per unit would reduce the cost of alcohol-related problems by £9.7 bn. The PDG is aware of concerns that introducing a minimum price per unit for alcohol would have an unfair impact on people who are from disadvantaged groups. The reality is, however, that alcohol problems are not evenly distributed throughout society. Evidence shows that people from disadvantaged groups experience more health problems than others as a result of their alcohol use. They are also affected more when others around them consume excessive amounts. The PDG concluded that the overall benefits of introducing and maintaining a minimum price for alcohol would far outweigh any perceived disadvantage to lower income groups. Although the introduction of a minimum price per unit of alcohol would prevent low cost promotions, it would not affect other types of alcohol promotion. The PDG, therefore, strongly supported the government's mandatory code on retailing which included a ban on irresponsible promotions. Introducing a minimum price per unit of alcohol might lead to price promotions on other products that could, in turn, offset the impact of any alcohol price increases for many consumers. The PDG also noted that alcohol price increases are factored into the 'Retail prices index' which, in turn, influences the index-linked increases in state benefits and allowances for lower income groups. # Availability International evidence suggests that making it less easy to buy alcohol, by reducing the number of outlets selling it in a given area and the days and hours when it can be sold, is an effective way of reducing alcohol-related harm. Changes to the current licensing provisions will enable members of licensing authorities to be an interested party. However, the Licensing Act does not, as it stands, cover public health considerations. Making this kind of change to the current licensing provisions may result in some initial implementation difficulties. However, the PDG believes that the long-term benefits would outweigh any immediate difficulties. The PDG noted the recent legislative changes in Scotland, where the protection and improvement of the public's health has been included within the licensing objectives. Increasing the price of alcohol, or reducing its accessibility, may lead to an increase in the amount of alcohol imported from abroad (both legal and illegal imports). The PDG considered that the current personal alcohol import allowance could undermine the introduction of a minimum price per unit for alcohol. # Advertising Evidence from a systematic review of 132 studies finds a clear and consistent relationship between advertising expenditure and alcohol consumption, across the whole population. However, the median effect is very small, possibly due to the limited variation in advertising expenditure, which restricts the range of effects that are available for analysis. A greater variation might have produced larger effects. There is limited evidence relating to a complete ban on advertising. However, there is evidence that bans on tobacco have had an impact on tobacco consumption and the PDG considered that this issue merited further consideration. There is strong evidence that alcohol advertising affects children and young people. The data show that exposure to alcohol advertising is associated with the onset of drinking and increased consumption among young people who already drink. The PDG is aware of the role of the Advertising Standards Authority (ASA) in monitoring the self-regulation code for alcohol advertising within the UK. It noted recent positive changes to the advertising code. It also noted the findings from a recent Ofcom and ASA report which assessed the impact of these changes. The report found that young people recalled fewer advertisements and were less likely to say that they were aimed at them. However, they were also more likely to say that the adverts made alcohol look appealing and would encourage people to drink. The PDG recognised that a complete ban would be needed to fully protect children and young people from alcohol advertising. However, this strategy would also affect adults, for whom there is less evidence of an adverse impact. Hence the PDG concluded that there should be a cost-benefit assessment of the impact of an advertising ban. In the meantime, it felt there was potential for the appropriate bodies to strengthen current regulations. The Group believes that a balanced, realistic portrayal of alcohol by the media (illustrating the negative consequences of excessive alcohol consumption) would be a helpful move. The PDG noted that product placement (a form of advertisement, where branded goods are placed within television programmes) may soon be allowed on commercial television. In view of the increase in health-related harms from alcohol in recent years, and the need to protect children from alcohol advertising, the PDG did not think it appropriate for alcohol to be included in this. # Commissioning The PDG acknowledges the importance of 'World class commissioning', 'Vital signs operating frameworks' (VSOF) and commissioning strategic plans (CSP) when developing services. 'World class commissioning' emphasises the importance of ensuring patients' views are taken into account when making commissioing decisions. Many people attending health and other public and voluntary sector services will benefit from the recommendations on screening and brief alcohol interventions –not just those who are seeking treatment for alcohol-related problems. The benefits of using a brief intervention are most clearly seen when it is used with people who are unaware that alcohol is compromising their mental or physical wellbeing. This approach may also help those people who may be aware that their drinking is harming either themselves or others, but are ambivalent about cutting down. NICE is producing 2 complementary pieces of guidance which, in conjunction with this publication, will provide advice on how to support these groups. Healthcare professionals are well placed to identify and help people with alcohol-related problems. There is strong evidence to show that many people benefit from brief advice provided by healthcare professionals who are not alcohol specialists. The PDG noted the benefits of local area agreements that identify and tackle the wider determinants of health within local communities. The PDG acknowledges the important role of the voluntary sector in helping to deliver the recommendations made in this NICE guidance. Research on alcohol screening and brief interventions in primary healthcare and emergency departments has not been widely replicated in other health or social care settings. Nevertheless, the PDG believes evidence from other areas (such as educational settings) clearly shows that it is worthwhile for healthcare professionals outside primary care – and non-healthcare professionals – to carry out these interventions. Many of those working in public services (such as social care, criminal justice, higher education, occupational health and children's services) have contact with people who are drinking a hazardous or harmful amount. The PDG believes these professionals are well-placed to help – and that many of their clients would benefit. The PDG is aware of the importance of ensuring service delivery is coordinated (for screening, brief interventions and referrals) so that people can receive the appropriate level of care. Where possible, the recommendations for practice refer to explicit and easily available intervention protocols. The aim has been to maintain standards by encouraging the use of interventions that have been evaluated and have been shown to be effective. A number of intervention packages offer a coordinated collection of evidence-based materials for use when screening and carrying out a brief intervention. They usually consist of: a short guide on delivery a screening questionnaire visual material (clarifying the risks or harm caused by alcohol consumption and showing people how their drinking compares with the rest of the population) practical suggestions on how to reduce alcohol consumption a self-help leaflet an optional poster for display in waiting rooms. An example is the 'Drink-less pack', which was used and evaluated in the WHO series of studies on brief interventions (Centre for Drug and Alcohol Studies 1993). Another is the 'How much is too much?' pack, which was based on the Drink-less pack but is specifically tailored for the UK (Institute of Health and Society 2006), and has been used by the DH for training. The PDG acknowledges that public finances, especially NHS and local authority funding, may be subject to constraints. However, it concluded that the public sector savings realised in the long term by investing in alcohol misuse prevention and intervention will be significant. # Working with children and young people The PDG noted that the Chief Medical Officer has called for an alcohol-free childhood up to the age of 15. Young people are particularly vulnerable to alcohol and the harm it causes, because they are still developing both physically and emotionally. They may also be drinking in unsupervised situations and in 'unsafe' environments (parks and street corners) where problems are more likely to occur. The PDG noted that young people may have underlying problems which may cause them to drink alcohol and that these need to be addressed. For example, their behaviour in relation to alcohol may be indicative of underlying difficulties within the family, school or elsewhere. Inevitably some children and young people will drink alcohol and the PDG felt it was necessary to provide guidance on how to help this group. While developing the recommendations, the PDG took into account other NICE guidance that addresses alcohol use among this age group. The problems young people aged under 16 may face and their susceptibility to alcohol will vary greatly. For example, a young person aged 10 is different, both physically and emotionally, to someone aged 15. In addition, young girls and boys develop at a different rate (girls often experience puberty earlier than boys). Girls who drink at an earlier age may be more likely to take risks with their sexual health, while boys may be more likely to have accidents or experience a trauma. Thus, it takes professional judgement to decide how to deal with children and young people who drink early in life. The PDG noted that, in keeping with Gillick and Fraser principles (see below) it is important for professionals to encourage vulnerable young people to include their parents or guardians in any professional intervention. It is also important that professionals are aware of child safeguarding, consent and confidentiality issues. It is likely that a proportion of young people will have intellectual or other developmental difficulties that will require parental or carer involvement. The Gillick principle is: "As a matter of law the parental right to determine whether or not their minor child below the age of 16 will have medical treatment terminates if and when the child achieves sufficient understanding and intelligence to understand fully what is proposed" per Lord Scarman. In terms of determining the competence of a young person to consent to treatment, a clinician needs to apply the Fraser guidelines. These were laid down by Lord Fraser and require the professional to be satisfied that: the young person will understand the professional's advice the young person cannot be persuaded to inform their parents the young person is likely to begin, or to continue having, sexual intercourse with or without contraceptive treatment unless the young person receives contraceptive treatment, their physical or mental health, or both, are likely to suffer the young person's best interests require them to receive contraceptive advice or treatment with or without parental consent. Although the Fraser guidelines specifically refer to contraception, the principles are deemed to apply to other treatments. In addition, although the judgment in the House of Lords referred specifically to medical practitioners, it is considered to apply to other health professionals, including nurses. The Advisory Council on the Misuse of Drugs (ACMD) 'Hidden harm' report provides strong evidence of the impact of parental drug misuse on children and the steps required to address this. There has been no equivalent study of the impact of parental alcohol misuse on children (ACMD 2003). # Screening Screening is a systematic process of identifying people whose alcohol consumption places them at increased risk of physical, psychological or social problems and who would benefit from a preventive intervention. Questionnaire-based screening is accurate, minimally intrusive and has been found to be acceptable to recipients. It is also considerably cheaper than using physiological tests to detect alcohol-related problems (Wallace 2001). The 'Alcohol-use disorders identification test' (AUDIT) was the first screening tool designed specifically to detect hazardous and harmful drinking (Saunders et al. 1993). It has been validated in a number of health and social care settings and across a range of drinking cultures (Reinert and Allen 2007). This 10-question screening tool asks about drinking frequency and intensity and covers experience of alcohol-related problems and signs of possible dependence. AUDIT can detect 92% of genuinely hazardous and harmful drinkers and excludes 93% of those who are not. It is regarded as the 'gold standard' screening questionnaire for detecting hazardous and harmful drinking. 'Hazardous' and 'harmful' drinking are medically defined terms that have been used extensively in the scientific literature and in many recommended tools. 'Harmful use of a psychoactive substance' is an official term in the World Health Organization's (WHO) 'International classification of diseases' (10th revision). 'Hazardous use of a psychoactive substance', while not an alcohol-use disorder in itself, is included in WHO's 'Lexicon of alcohol and drug terms' (1994). It is also useful to define drinking behaviour in terms of the types of risk associated with it. The DH has recently used the terms lower risk, increasing risk and higher risk drinking. This unit-based approach complements the medically-defined terms described above. For the purposes of this guidance, 'increasing risk' equates with 'hazardous drinking' and 'higher risk' equates with 'harmful drinking'. In addition, categories of risk in relation to alcohol consumption may be defined by scores used in the 'Alcohol use disorders identification test' (AUDIT). These are as follows: 1–7: low-risk drinking; 8–15: hazardous drinking; 16–19: harmful drinking; 20+: possible dependence. For simplicity and convenience, the terms 'hazardous' and 'harmful' are used in this guidance (Room et al. 2005). Even with just 10 questions, the full AUDIT questionnaire has been considered too lengthy for use in routine practice. Thus several shorter versions of AUDIT have been developed. These comprise between 1 and 4 questions. Generally, they are less accurate than the full AUDIT and do not clearly differentiate between hazardous, harmful and possibly dependent drinking. Different factors may make some people more vulnerable to alcohol than others and this can affect the precision of some screening tools. These factors can include lower body weight, inexperience in handling the psychological effects of alcohol being less able to metabolise it or being more susceptible to its adverse effects. Women are more vulnerable to the effects of alcohol than men and younger and older people tend to be more vulnerable than those who are middle-aged. In addition, some black and minority ethnic groups are less able to metabolise alcohol than caucasians. In such cases, lower cut-off points on screening tools may need to be applied. Reducing the cut-off point on a screening tool will increase its sensitivity (that is, the ability to identify truly positive cases of hazardous or harmful drinking). However, this can be at the expense of specificity (the ability to accurately exclude those who are not drinking a hazardous or harmful amount). Thus, professional judgement may be needed before screening cut-off points can be altered. It is for this reason that the PDG has not recommended specific (lowered) cut-off points on various screening tools. Professional judgement is needed to decide on any additional support that should be offered to vulnerable groups who are identified as being hazardous or harmful drinkers. This includes: women (in particular those who are, or are thinking of becoming, pregnant) younger people people aged 65 and over people from some black and minority ethnic groups. The PDG recognises that a language-based screening questionnaire may not be the most appropriate tool for certain groups. This includes those whose first language is not English and people with learning disabilities or cognitive impairment. How best to establish whether people in these groups are at risk from alcohol or are experiencing alcohol-related harm will be a matter of professional judgement. # Brief interventions There are 2 main types of brief intervention: structured brief advice or extended brief intervention. Nearly all of the latter are based on the principles and practice of 'motivational interviewing' (Miller and Rollnick 2002). Evidence shows that brief advice is effective where time is tight – even when there is only 5 minutes available. The evidence is mixed on the additional benefit of providing extended brief interventions in healthcare settings. Thus brief advice is recommended as a first step for adults (aged 18 and over) who have been identified as drinking at hazardous or harmful levels. If brief advice does not lead to a reduction in hazardous or harmful drinking (or if an individuals wishes further input) then an extended brief intervention, including motivational interviewing, has been recommended (see recommendations 8 and 11). Most extended brief interventions that have been evaluated in research are short versions of motivational interviewing. Examples include the 'Drinker's check-up' (Miller et al. 1988), consisting of 1 assessment session and 1 feedback and counselling session. Another example is 'motivational enhancement therapy', which was developed as a four-session intervention in 'Project MATCH' in the USA (Miller et al. 1992). It was then adapted as a three-session intervention in the 'United Kingdom alcohol treatment trial' (UKATT Research Team 2005). Some extended brief interventions, perhaps consisting of a single session lasting 30–40 minutes, are based on motivational interviewing principles but would not qualify as full motivational interviewing. While the distinctions between motivationally-based interventions should be borne in mind, for the purposes of this guidance, all motivationally-based interventions are referred to as extended brief interventions. There is limited evidence on the effectiveness of brief interventions for young people under the age of 16, with some data suggesting there could be adverse outcomes. Most of the research has been carried out among adults in healthcare settings. However, there is broadly positive evidence from educational settings (such as colleges and universities). Generally, the interventions have taken the form of motivational interviews with young people aged over 16. As a result, the PDG has recommended the use of extended brief interventions for people aged 16–17. However, it is not clear from current evidence if this type of brief intervention can be adapted for younger people. In motivational interviewing, the practitioner establishes the client's readiness to change and it helps them to make their own decisions with regard to their alcohol use. Some young people may not have the language skills to partake in a motivational interview. In addition, it may not be appropriate to emphasise to those who may need external direction and indeed, safeguarding, that they have a choice. For more mature young people (that is, those who are 'Gillick-competent'), however, the PDG judges that it is appropriate to extrapolate the evidence from educational settings to health and social care settings, especially as part of a response to meeting their identified needs. But as noted elsewhere, intervening with those below 16 years generally requires efforts to include parents or carers. # Referral A brief intervention will address many people's alcohol-related problems. However, those who are moderately or severely alcohol-dependent are likely to need specialist help. This is also true of people who experience physical harm, such as liver damage or mental health problems, as a result of drinking alcohol. In such cases, the recommendations in this guidance should be read in conjunction with 2 complementary pieces of NICE guidance: 'Alcohol use disorders in adults and young people: clinical management' and 'Alcohol-use disorders: diagnosis, assessment and management in young people and adults'. # Evaluation The PDG recognises that its recommendation to carry out formal evaluations (see recommendation 5) and routine follow-ups of alcohol interventions will change established commissioning practice. Commissioning bodies may seek partnerships with academic institutions to help design evaluation protocols. It may also be that government will provide guidance on minimum standards for comprehensive, routine evaluation and research into local alcohol treatment systems. Although some aspects of evaluation may be cost neutral, robust evaluation and research will need specified resources. However, the PDG takes the view that evaluation will be essential in ensuring value for money in reconfigured local alcohol treatment systems. # Interpreting the evidence The PDG recognised that empirical data alone, even from the best conducted investigation, seldom provides a sufficient basis for making recommendations. This data requires interpretation and analysis, using prior knowledge and understanding and existing models and theories. Therefore, the PDG developed its recommendations using the best available empirical data and inductive and deductive reasoning. The PDG acknowledged that the traditional hierarchy of evidence does not resolve all the problems associated with empirical data. For example, while it explicates the degree of bias attributable to poor internal validity, it does not answer it completely. Nor does it deal with external validity, that is, the degree to which findings are transferable to other experimental settings or to practice. The PDG therefore looked at a broad range of evidence.# Recommendations for research The PDG recommends that the following research questions should be addressed. It notes that 'effectiveness' in this context relates not only to the size of the effect, but also to cost effectiveness and duration of effect. It also takes into account any harmful or negative side effects. How does advertising by industry and health agencies affect the drinking behaviour of the population as whole? (This includes the use of new media.) . What is the effect on alcohol consumption of combining different policies on price, promotion and availability? . Which screening tool should be considered as the 'gold standard' for assessing the drinking behaviour of those under the age of 18? . Are brief interventions effective and cost effective in reducing alcohol use among various subgroups of the population, such as: those under 16 and over 65 people from some black and minority ethnic groups pregnant women attending antenatal care? . Are screening and brief alcohol interventions effective and cost-effective in: medical settings outside primary care and emergency departments (for example, in district hospitals or mental health settings) non-medical settings (for example, on criminal justice or social services premises, in pharmacies or in the workplace) voluntary sector organisations? . What factors (conditions and components) ensure a brief intervention is effective in promoting low-risk alcohol consumption? . To what extent are local services responding to the needs of children affected either by parental alcohol misuse or their own drinking – and which interventions are effective in helping these families? . More detail on the gaps in the evidence identified during development of this guidance is provided in appendix D.# Glossary # Alcohol dependence A cluster of behavioural, cognitive and physiological factors that typically include a strong desire to drink alcohol and difficulties in controlling its use. Someone who is alcohol-dependent may persist in drinking, despite harmful consequences. They will also give alcohol a higher priority than other activities and obligations. For further information, please refer to: 'Diagnostic and statistical manual of mental disorders' (DSM-IV) (American Psychiatric Association 2000) and 'International statistical classification of diseases and related health problems – 10th revision' (ICD-10) (World Health Organization 2007). # Alcohol-related harm Physical or mental harm caused either entirely or partly by alcohol. If it is entirely as a result of alcohol, it is known as 'alcohol-specific'. If it is only partly caused by alcohol it is described as 'alcohol-attributable'. # Alcohol-use disorders Alcohol-use disorders cover a wide range of mental health problems as recognised within the international disease classification systems (ICD-10, DSM-IV). These include hazardous and harmful drinking and alcohol dependence. See 'Harmful' and 'Hazardous' drinking and 'Alcohol dependence'. # Alcohol-use disorders identification test (AUDIT) AUDIT is an alcohol screening test designed to see if people are drinking harmful or hazardous amounts of alcohol. It can also be used to identify people who warrant further diagnostic tests for alcohol dependence. # Binge drinking A heavy drinking session in which someone drinks a lot of alcohol in a short period of time raising their risk of harm on that occasion. The Chief Medical Officer recommends lowering the level of alcohol consumption on a single occasion to avoid short-term risks (risk of injuries, losing control or misjudging risky situations). The risks increase in people who drink within recommended levels of regular drinking (less than 14 units/week for men and women) but drink in a single occasion or too quickly or with higher levels of alcohol consumption (Alcohol Guidelines Review – Report from the Guidelines Development Group to the UK Chief Medical Officers and Health Survey for England 2015: adult alcohol consumption. # Brief intervention This can comprise either a short session of structured brief advice or a longer, more motivationally-based session (that is, an extended brief intervention – see also below). Both aim to help someone reduce their alcohol consumption (sometimes even to abstain) and can be carried out by non-alcohol specialists. # Clinical management of people with alcohol-related disorders Any pharmacological or psychosocial intervention carried out by a clinician to manage the clinical problems caused by alcohol or any related medical or psychiatric complications. For example, support to help with withdrawal, managing liver damage and treating conditions such as Wernicke's encephalopathy. # Commissioning Primary care trusts (PCTs) and drug and alcohol action teams (DAATs) may commission alcohol support services from a range of 'providers'. This includes GPs, hospitals, mental health trusts and voluntary and private organisations. # Dependence See alcohol dependence. # Extended brief intervention This is motivationally-based and can take the form of motivational-enhancement therapy or motivational interviewing. The aim is to motivate people to change their behaviour by exploring with them why they behave the way they do and identifying positive reasons for making change. In this guidance, all motivationally-based interventions are referred to as 'extended brief interventions'. # FRAMES FRAMES is an acronym summarising the components of a brief intervention. Feedback (on the client's risk of having alcohol problems), responsibility (change is the client's responsibility), advice (provision of clear advice when requested), menu (what are the options for change?), empathy (an approach that is warm, reflective and understanding) and self-efficacy (optimism about the behaviour change). # Harmful drinking (high-risk drinking) A pattern of alcohol consumption that is causing mental or physical damage (ICD-10, DSM-V). Consumption (units per week): Drinking 35 units a week or more for women. Drinking 50 units a week or more for men. # Hazardous drinking (increasing risk drinking) A pattern of alcohol consumption that increases someone's risk of harm. Some would limit this definition to the physical or mental health consequences (as in harmful use). Others would include the social consequences. The term is currently used by the World Health Organization to describe this pattern of alcohol consumption. It is not a diagnostic term. Consumption (units per week): Drinking more than 14 units a week, but less than 35 units a week for women. Drinking more than 14 units a week, but less than 50 units for men (Health Survey for England 2015: adult alcohol consumption). # Higher-risk drinking Regularly consuming over 50 alcohol units per week (adult men) or over 35 units per week (adult women). # Looked after children The term 'looked after' has a specific legal meaning. It refers to children and young people who are provided with accommodation on a voluntary basis for more than 24 hours. This compares with the term 'in care' which refers to those who are compulsorily removed from home and placed in care under a court order. # Lower-risk drinking To keep the risk of harm from alcohol low, the UK Chief Medical Officer advises that men and women should not regularly drink more than 14 units of alcohol per week. It is also recommended that if the alcohol consumption is as much as 14 units per week, it should be spread evenly over 3 or more days (Alcohol Guidelines Review – Report from the Guidelines Development Group to the UK Chief Medical Officers ). See 'Unit'. # Responsible authority Responsible authorities have to be notified of all licence variations and new applications and can make representations regarding them. The Licensing Act 2003 lists responsible authorities. They include the police, environmental health and child protection services, fire and rescue and trading standards. # Saturated (in relation to licensed premises) Describes a specific geographical area where there are already a lot of premises selling alcohol – and where the awarding of any new licences to sell alcohol may contribute to an increase in alcohol-related disorder. # Screening For the purposes of this guidance, screening involves identifying people who are not seeking treatment for alcohol problems but who may have an alcohol-use disorder. Practitioners may use any contact with clients to carry out this type of screening. The term is not used here to refer to national screening programmes such as those recommended by the UK National Screening Committee (UK NSC). # Structured brief advice A brief intervention that takes only a few minutes to deliver. # Treatment A programme designed to reduce alcohol consumption or any related problems. It could involve a combination of counselling and medicinal solutions. # UK government drinking guidelines Guidelines set by the UK government on how much alcohol may be consumed without a serious impact on health. To keep the risk of harm from alcohol low, the UK Chief Medical Officer advises that men and women should not regularly drink more than 14 units of alcohol per week. It is also recommended that if the alcohol consumption is as much as 14 units per week, to spread it evenly over 3 or more days. See 'Unit'. # Unit In the UK, alcoholic drinks are measured in units. Each unit corresponds to approximately 8 g or 10 ml of ethanol. The same volume of similar types of alcohol (for example, 2 pints of lager) can comprise a different number of units depending on the drink's strength (that is, its percentage concentration of alcohol).# References Advisory Council on the Misuse of Drugs (2003) Hidden harm – responding to the needs of children of problem drug users. 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British Journal of General Practice 51: 172–3 World Health Organization (1994) Lexicon of alcohol and drug terms# Appendix B Summary of the methods used to develop this guidance # Introduction The reviews and economic analysis include full details of the methods used to select the evidence (including search strategies), assess its quality and summarise it. The minutes of the PDG meetings provide further detail about the Group's interpretation of the evidence and development of the recommendations. All supporting documents are listed in appendix E. # Key questions The key questions were established as part of the scope. They formed the starting point for the reviews of evidence and were used by the PDG to help develop the recommendations. The primary questions were: Question 1: What type of price controls are effective and cost effective in reducing alcohol consumption, alcohol misuse, alcohol-related harm or alcohol-related social problems among adults and young people? Question 2: Which interventions are effective and cost effective at managing alcohol availability to reduce levels of consumption, alcohol misuse, alcohol-related harm or alcohol-related social problems among adults and young people? Question 3: Is the control of alcohol promotion (for example, advertising) effective and cost effective in reducing levels of consumption, alcohol misuse, alcohol-related harm or alcohol-related social problems among adults and young people? Question 4: What are the key factors that increase the risk of an individual misusing alcohol? When are individuals most vulnerable to alcohol misuse? Question 5: Are alcohol screening questionnaires, biochemical markers or clinical indicators (for example, hypertension, dilated facial capillaries) an effective and cost effective way of identifying adults and young people who currently misuse – or are at risk of misusing – alcohol? Question 6: Are brief interventions effective and cost effective in managing hazardous and harmful drinking among adults and young people? Question 7: What are the key barriers to helping adults and young people manage their drinking behaviour (for example, is access to services a problem)? What are the key facilitators? These questions were made more specific for each review (see reviews for further details). # Reviewing the evidence of effectiveness Two reviews of effectiveness were conducted. ## Identifying the evidence Relevant literature was identified using an iterative search process. Study types and years were not predefined. The following databases were searched. ASSIA (Applied Social Science Index and Abstracts) Cochrane Library (Cochrane database of systematic reviews, Database of abstracts of reviews of effects, Health technology assessment and Cochrane-controlled trials register) EconLit MEDLINE (including MEDLINE in process) NHS Economic Evaluation Database (NHS EED) Social Science Citation Index Additional searches (non-systematic) were carried out on the following websites: Alcohol and Education Research Council Alcohol Concern Association of Public Health Observatories Department for Digital, Culture, Media and Sport Department of Health and Social Care Home Office NICE National Treatment Agency Portman Group ## Selection criteria Studies were included in the effectiveness reviews if: people of a range of ages were involved interventions were relevant to the key questions set out in the reviews -utcomes such as alcohol consumption, alcohol misuse, alcohol-related harm, social problems, costs and economic impact were reported. Studies were excluded if: they were not published in English the study population was below the age of 10 years the evidence did not originate in economically developed countries (that is, if it did not come from countries that are members of the Organisation for Economic Cooperation and Development ). ## Quality appraisal Included papers were assessed for methodological rigour and quality using the NICE methodology checklist, as set out in the NICE technical manual 'Methods for the development of NICE public health guidance' (see appendix E). Each study was graded (++, +, –) to reflect the risk of potential bias arising from its design and execution. ++ All or most of the methodology checklist criteria have been fulfilled. Where they have not been fulfilled, the conclusions are thought very unlikely to alter. - Some of the methodology checklist criteria have been fulfilled. Those criteria that have not been fulfilled or not adequately described are thought unlikely to alter the conclusions. – Few or no methodology checklist criteria have been fulfilled. The conclusions of the study are thought likely or very likely to alter. ## Summarising the evidence and making evidence statements The review data was summarised in evidence tables (see full reviews). The findings from the reviews were synthesised and used as the basis for a number of evidence statements relating to each key question. The evidence statements were prepared by the public health collaborating centre (see appendix A). The statements reflect the collaborating centre's judgement of the strength (quantity, type and quality) of evidence and its applicability to the populations and settings in the scope. # Economic analysis The economic analysis consisted of 2 cost effectiveness reviews and an economic modelling report . ## Review of economic evaluations The following databases were searched for economic literature, in addition to the searches carried out for the effectiveness reviews: EconLIT NHS Economic Evaluation Database (NHS EED). Studies were included if: they addressed key questions 1, 2, 3, 5 and 6 they were from peer-reviewed journals published in English the study population involved a range of ages (10+ years) they were carried out in OECD countries. ## Economic modelling report A number of assumptions were made which could underestimate or overestimate the cost effectiveness of the interventions (see review modelling report for further details). An economic model was constructed to incorporate data from the reviews of effectiveness and cost effectiveness. The results are reported in the economic modelling report – Modelling to assess the effectiveness and cost-effectiveness of public health-related strategies and interventions to reduce alcohol attributable harm in England using the Sheffield alcohol policy model version 2.0. # Fieldwork Fieldwork was carried out to evaluate how relevant and useful NICE's recommendations are and how feasible it would be to put them into practice. It was conducted with commissioners, practitioners and other interested parties who are involved in alcohol services in the NHS, local authorities and the private, voluntary and community sectors. They included: policy makers, applied researchers, economists, trading standards, representatives of licensing boards, retailers and the alcohol industry, and representatives from criminal justice and social welfare. The fieldwork comprised: five meetings in Birmingham, Bristol, Leicester, Liverpool and London conducted by Liverpool John Moores University with policy makers, commissioners, industry representatives and practitioners an online survey of professionals (14) who could not attend the fieldwork meetings. The fieldwork meetings and online survey were commissioned to ensure there was ample geographical coverage. The main issues arising are set out in appendix C under fieldwork findings. Also see the fieldwork report – Alcohol-use disorders: preventing the development of hazardous or harmful drinking. # How the PDG formulated the recommendations At its meeting in July 2009, the PDG considered the evidence of effectiveness and cost effectiveness to determine: whether there was sufficient evidence (in terms of quantity, quality and applicability) to form a judgement whether, on balance, the evidence demonstrates that the intervention is effective, ineffective or equivocal where there is an effect, the typical size of effect. The PDG developed draft recommendations through informal consensus, based on the following criteria: Strength (quality and quantity) of evidence of effectiveness and its applicability to the populations/settings referred to in the scope. Effect size and potential impact on the target population's health. Impact on inequalities in health between different groups of the population. Cost effectiveness (for the NHS and other public sector organisations). Balance of risks and benefits. Ease of implementation and any anticipated changes in practice. The PDG noted that effectiveness can vary according to the context. For example, it depends on the enforcement of different regulatory regimes. Where possible, recommendations were linked to an evidence statement(s) (see appendix C for details). Where a recommendation was inferred from the evidence, this was indicated by the reference 'IDE' (inference derived from the evidence). The draft guidance, including the recommendations, was released for consultation in September 2009. At its meeting in December 2009, the PDG amended the guidance in light of comments from stakeholders and experts and the fieldwork. The guidance was signed off by the NICE Guidance Executive in March 2009.# Appendix C: The evidence This appendix lists the evidence statements from 4 reviews (2 effectiveness reviews and 2 cost-effectiveness reviews) and the economic modelling report provided by the public health collaborating centre (see appendix A). (See appendix B for the key to quality assessments.) The evidence statements are presented here without references – these can be found in the full reviews (see appendix E for details). It also sets out a brief summary of findings from the economic analysis. The 2 effectiveness reviews, 2 cost-effectiveness reviews and economic modelling report are: Effectiveness reviews: Review 1: 'Interventions on control of alcohol price, promotion and availability for prevention of alcohol-use disorders in adults and young people' Review 2: 'Screening and brief interventions for prevention and early identification of alcohol-use disorders in adults and young people'. Economic analysis: Review 3: 'Prevention and early identification of alcohol-use disorders in adults and young people. Macro-level interventions for alcohol-use disorders: cost-effectiveness review' Review 4: 'Prevention and early identification of alcohol-use disorders in adults and young people. Screening and brief interventions: Cost-effectiveness review' Economic modelling report: 'Modelling to assess the effectiveness and cost effectiveness of public health-related strategies and interventions to reduce alcohol attributable harm in England using the Sheffield alcohol policy model version 2.0'. Evidence statements numbered 1.1 to 3.8 are from review 1. Evidence statements numbered 5.1 to 7.7 are from review 2. Evidence statements numbered e1.1 to e2.3 are from review 3. Evidence statements numbered e5.1 to e6.2 are from review 4. Modelling statements numbered M1 to M50 are from the economic modelling report. Where a recommendation is not directly taken from the evidence statements, but is inferred from the evidence, this is indicated by IDE (inference derived from the evidence). Recommendation 1: evidence statements 1.1, 1.2, 1.3, 1.4, 2.27, 2.30, e1.1; modelling statements M12, M21, M22, M23, M24, M26, M27, M29, M34, M35, M36, M37 Recommendation 2: evidence statements 2.19, 2.20, 2.21, 2.22, 2.24, 2.25, e.2.3; modelling statements M51, M55, IDE Recommendation 3: evidence statements 3.1, 3.2, 3.3, 3.4, 3.6, 3.7, 3.8 Recommendation 4: evidence statements 2.4, 2.5, 2.8, 2.9, 2.19, 2.20, 2.21, 2.22, 2.24, 2.25 Recommendation 5: evidence statements 7.1, 7.2, 7.6 Recommendation 6: IDE Recommendation 7: evidence statements 5.7, 5.9; IDE Recommendation 8: evidence statements 5.1, 5.2, 5.5, 5.6, 5.7, 5.9, 5.10, 5.11, 7.3, 7.4, 7.5, 7.7, e5.1; modelling statements M2, M3 Recommendation 9: evidence statements 6.1, 6.2, 6.3, 6.4, 6.10, 7.3, e6.1, e6.2; modelling statement M6; IDE Recommendation 10: evidence statement 6.11; modelling statement M6 Recommendation 11: IDE # Evidence statements Please note that the wording of some evidence statements has been altered slightly from those in the review team's report to make them more consistent with each other and NICE's standard house style. ## Evidence statement 1.1 A comprehensive systematic review was identified that demonstrated a clear association between price/tax increases and reductions in consumer demand for alcohol (++). These conclusions were based on 2 rigorous meta-analyses of price elasticities. Further evidence was supportive of a negative relationship between the price of alcohol and alcohol consumption among young people (1 UK and 1 USA ). A positive relationship between alcohol affordability and alcohol consumption operating across the European Union was identified (1 EU). ## Evidence statement 1.2 A systematic review reported that there is some evidence that young people, binge drinkers and harmful drinkers tend to show a preference for cheaper drinks (++). ## Evidence statement 1.3 A limited evidence base was identified that indicated that minimum pricing may be effective in reducing alcohol consumption (1 and 1 UK ). Consulted members of the community were supportive of such measures (1 ). ## Evidence statement 1.4 An evidence base comprising a large number of primary studies was identified that demonstrated a relationship between price/tax increases and reductions in harms (1 systematic review). Additional evidence indicates that decreases in the price of alcohol contribute towards increases in alcohol-related deaths, particularly in deaths attributable to chronic causes such as alcoholic liver disease (1 Finland). Population groups specifically affected included the older population, the unemployed and individuals with lower levels of education, social class and income (1 Finland). However, the same authors observed no increase in interpersonal violence rates following the decrease in alcohol prices (1 Finland). A time series analysis demonstrated that increases in tax were associated with decreases in alcohol-related disease mortality (1 USA). ## Evidence statement 2.4 Evidence was identified demonstrating that serving staff in alcohol outlets were disapproving of under-age sales (1 USA) and generally positive of implementing under-age checks, including electronic age-verification devices (1 USA). ## Evidence statement 2.5 The commitment of managers and licensees towards their legal responsibilities relating to under-age sales was variable (1 UK and 1 USA). ## Evidence statement 2.8 The effectiveness of enforcement checks in reducing alcohol sales to under-age young people was variable (1 systematic review). Compliance checks conducted by local police were not effective in reducing arrests in those aged under 18 years or reducing under-age sales (1 and 1 ) in the UK. Other studies showed favourable outcomes of compliance checks by local authorities in reducing under-age alcohol sales (2 USA, 1 USA and 1 USA ). Checks enforced with a 30-day licence suspension or a fine were effective in reducing sales (1 USA). However, the deterrent effect of enforcement was found to decay over time (1 USA and 1 USA ). Additional UK-specific evidence demonstrated that enforcement of laws relating to under-age sales supported by a local multi-agency community alcohol partnership, helped reduce possession of alcohol and antisocial behaviour and improved the relationship between enforcers and retailers. ## Evidence statement 2.9 A study based in Fife, Scotland indicated that on- and off-licensees perceived the most effective approach to preventing under-age sales to be test purchasing carried out in conjunction with a new, nationally-accepted proof-of-age card. ## Evidence statement 2.19 Other UK-specific studies of the effects of changes in licensing hours presented mixed findings, with some studies reporting no apparent effects on alcohol-related outcomes (2 UK). However, following the extension of licensing hours, 1 (+) UK study reported an increase in admissions for self-poisoning by overdose in which alcohol was also involved. Another UK study found increases in the occurrence of slight accidents in the workplace. ## Evidence statement 2.20 Extensions in trading hours in Australia were typically associated with increased violence (1 ), motor vehicle crash rates (1 ) and an increase in the apprehension of impaired male drivers aged 18 to 25 years (1 ). Local community restrictions on alcohol availability were found to have modestly favourable outcomes, including reductions in alcohol consumption and violence. However, in 1 evaluation of the restriction of take-away trading hours and volumes for alcohol sales in Australia, many customers shifted their purchases to cheap cask port, providing an illustration of the ways in which consumers may respond to limitations in alcohol availability. An increase in alcohol-related road traffic accidents followed the removal of the ban on Sunday sales of packaged alcohol in New Mexico (1 USA ). The introduction of unrestricted serving hours in Reykjavik, Iceland resulted in increased police work episodes, more emergency ward admissions for weekend nights, increased suspected drink-driving incidents, and more people circulating in the city centre at 6am (1 ). The Saturday opening of alcohol retail outlets in Sweden also led to an increase in sales (2 ++) but no apparent change in alcohol-related harms (1 ). A range of evidence from Scandinavia, based on largely small-scale, local natural experiments, showed the variable impact of changes in alcohol licensing, with decreased alcohol consumption typically observed as a result of restrictions. However, a USA-based study suggested that restrictions on Sunday alcohol sales had no apparent impact on consumption, whilst earlier closing hours in bars appeared to result in increased alcohol sales. ## Evidence statement 2.21 A clear positive relationship between increased outlet density and alcohol consumption among adults was demonstrated in a range of association studies (3 USA , 1 USA, 2 Canada and 1 Canada ). However, 1 USA study (not graded) found no significant association between alcohol outlet density and heavy drinking. ## Evidence statement 2.22 A positive relationship between alcohol outlet density and alcohol consumption was also observed in studies focusing on young people (1 USA, 1 Australia, 2 Switzerland and 2 New Zealand ). ## Evidence statement 2.24 A number of natural experiments demonstrated the effects of changes in alcohol outlet density on alcohol consumption and alcohol-related outcomes. Increases in alcohol outlet density tended to be associated with increases in alcohol consumption and alcohol-related morbidity and mortality in Scandinavia. A literature review found that the privatisation of alcohol retail monopolies in the USA, Canada and Scandinavia (not graded) was linked with higher outlet densities, longer hours or more days of sale and changes in price and promotion, typically resulting in increased alcohol consumption (international). A positive association between alcohol outlet density and gonorrhoea (1 USA ) was also observed following the civil unrest in Los Angeles. ## Evidence statement 2.25 An evidence base, within 1 literature review, was described demonstrating positive relationships between outlet density and a range of outcomes including rates of violence, drink-driving, pedestrian injury, and child maltreatment. ## Evidence statement 2.27 Evidence was identified that pre-drinking is a prevalent activity, both in the UK (1 UK and 1 UK ) and within 1 international literature review. ## Evidence statement 2.30 Evidence was identified that demonstrated that pre-drinking is associated with heavy alcohol consumption (1 UK and 1 international ) and increased risk of alcohol-related harm (1 UK). ## Evidence statement 3.1 One systematic review (++) demonstrated a small but consistent relationship between advertising and alcohol consumption at a population level. ## Evidence statement 3.2 A systematic review of longitudinal studies found that exposure to alcohol advertising and promotion was associated with the onset of adolescent alcohol consumption and with increased consumption among adolescents who were already drinking at baseline assessment (++). Another systematic review presented evidence of a small but consistent relationship between advertising and alcohol consumption among young people at an individual level (++). Another review concluded that the evidence base suggested the existence of an association between exposure to alcohol advertising and promotion and alcohol consumption among young people (++). Further literature reviews were also indicative of alcohol advertising having an impact on young people. There was evidence of awareness, familiarity and appreciation of alcohol advertisements among this age group. ## Evidence statement 3.3 One systematic review presented evidence of a moderate but consistent association between point of purchase promotions and effects on alcohol consumption among under-age drinkers, binge drinkers and regular drinkers (++). ## Evidence statement 3.4 A systematic review reported that outdoor and print advertising media may increase the probability of onset of adolescent alcohol consumption and also influence quantity and frequency of alcohol consumption among young people (++). Another review included 1 USA-based study that reported that outdoor advertising media did not have any effect on alcohol behaviour, but was a predictor of intention to use alcohol among adolescents (++). ## Evidence statement 3.6 One systematic review reported that evidence from longitudinal studies consistently demonstrated that exposure to television and other broadcast media was linked with the onset of and levels of alcohol consumption (++). Further evidence was included in a review that indicated that exposure to alcohol portrayals via television (including advertisements aired during sports programmes) and other broadcast media may be linked with alcohol use among adolescents (++). ## Evidence statement 3.7 The content of alcohol advertising was reported to be attractive to young people, conveying desirable lifestyles and images of alcohol consumption. Younger age groups and girls aged15 to 17 years were reported to be potentially experiencing the greatest impact of alcohol advertising (++). A further UK-specific report showed that, despite changes to the Advertising Code, while advertising recall fell (potentially due to reduced television advertising expenditure over the study period), there was an increased perception among young people that television alcohol advertisements were appealing and would encourage people to drink. However, there was a decrease in the proportion of young people who considered alcohol commercials to be aimed at them. A literature review stated that there was no scientific evidence available to describe the effectiveness of self-regulation in alcohol advertising. ## Evidence statement 3.8 Inconclusive evidence was identified, within 1 systematic review (++) and 1 literature review (not graded), of the impact of advertising bans on alcohol consumption . ## Evidence statement 5.1 The Alcohol-use disorders identification test (AUDIT) is effective in the identification of hazardous and harmful drinking in adults in primary care (3 systematic reviews, 1 Finland, 1 UK and 1 literature review ). The use of lower thresholds in conjunction with alcohol screening questionnaires was recommended for women (1 Finland, 1 Belgium, 1 systematic review and 1 literature review ). Optimal screening thresholds for the detection of hazardous or harmful drinking using AUDIT appeared to be greater than or equal to 7 or 8 among men (2 systematic reviews) and greater than or equal to 6 to 8 among women (1 systematic review, 1 Finland and 1 literature review ). Optimal screening thresholds for identifying binge drinking using AUDIT were greater than or equal to 7 or 8 for adult males (no data available for females) (1 Finland). Primary studies included in a systematic review (++) recommended higher AUDIT thresholds for males (5 to 8) than females (2 to 6). ## Evidence statement 5.2 The evidence for the effectiveness of shorter versions of AUDIT in adults in primary care was variable. Some authors of cross-sectional diagnostic evaluations observed comparable performance between the full AUDIT and shorter versions (2 Finland, 1 Belgium and 1 USA). Other findings drawn from primary care were more cautious of the utility of the shorter forms of this questionnaire (1 systematic review). The optimal screening threshold for the detection of hazardous drinking using AUDIT-C was greater than or equal to 3 among men and women (1 systematic review and 1 USA). However, thresholds of greater than or equal to 5 for the detection of heavy drinking among females and greater than or equal to 6 for identifying bingeing moderate and heavy drinking men were also recommended (1 Finland). Primary studies included in a systematic review recommended higher AUDIT-C thresholds for males (3 to 6) than females (2 to 5) (1 ). FAST was described, within a literature review (not graded), as being effective in the detection of alcohol problems at a cut-off point of greater than or equal to 1 in males and females in a primary care setting in the UK. ## Evidence statement 5.5 Only a limited amount of evidence could be identified relating to the performance of alcohol screening questionnaires in hospital settings. The 'Five-shot questionnaire' was shown to detect alcohol misuse in adult male inpatients at a cut-off of greater than or equal to 2.5 (1 Belgium). AUDIT was effective in screening UK male and female adult general medical admissions for hazardous and harmful alcohol consumption (1 UK). AUDIT was also reported to perform effectively among general hospital inpatients (1 systematic review). ## Evidence statement 5.6 Evidence was identified for the use of alcohol screening questionnaires among adults in emergency care settings. One study found that the CAGE questionnaire was effective in screening for a lifetime diagnosis of alcohol dependence in trauma centre patients ( USA). AUDIT-C was shown to effectively identify hazardous drinking among male and female adult traffic casualties in an emergency department (1 Spain). One literature review indicated that FAST displayed good screening properties in the identification of alcohol problems among males and females presenting to an A&E setting in the UK. The 'Paddington alcohol test' has been shown to be rapid, feasible to use, be UK-specific and to have reasonably good screening properties for the detection of alcohol misuse when implemented in response to clinical 'trigger' conditions in A&E care. These are listed as follows: fall; collapse; head injury; assault; accident; unwell; non-specific gastrointestinal conditions; psychiatric; cardiac; repeat attender (3 UK). ## Evidence statement 5.7 AUDIT was shown to perform more effectively in the identification of alcohol abuse or dependence (when used at a cut-off of greater than or equal to 10) than CAGE, CRAFFT (car, relax, alone, forget, friends, trouble) or RAPS-QF (rapid alcohol problems screen) questionnaires among young people (median age of 19 years) (1 USA). AUDIT was also demonstrated to have higher sensitivity (when used at an optimal cut-off of greater than or equal to 3) than CAGE, CRAFFT or POSIT (problem oriented screening instrument for teenagers) in the detection of problem use (that is, hazardous or harmful consumption not reaching the diagnostic threshold for an alcohol-related disorder, abuse and dependence) in a sample aged between 14 and 18 years (1 USA). The identified evidence for the effectiveness of SASSI (substance abuse subtle screening inventory) in screening for alcohol misuse was limited and inconclusive (2 USA and 1 USA). AUDIT was found to perform reasonably well in elderly populations (1 systematic review), while AUDIT-5 was described as showing potential as an appropriate tool for use among older people (1 systematic review). ## Evidence statement 5.9 The screening properties of questionnaires were influenced by the ethnicity of recipients and authors suggested that the use of appropriate cut-off scores should be considered (1 USA and 1 literature review ). ## Evidence statement 5.10 Laboratory markers are of limited value in the detection of alcohol misuse when compared with alcohol screening questionnaires (2 UK, 1 Belgium and 1 Germany). However, the use of blood-alcohol concentration testing may complement the use of later questionnaire screening in the identification of alcohol misuse among patients treated in the emergency department resuscitation room (1 UK). ## Evidence statement 5.11 A number of clinical indicators were described, within a cross-sectional study, a literature review and a case study, as being associated with excessive alcohol consumption (1 Spain, 1 literature reivew and 1 UK ). Awareness of such indicators may be useful in alerting health professionals to alcohol-related physical problems. ## Evidence statement 6.1 Twenty seven systematic reviews provided a considerable body of evidence supportive of the effectiveness of brief interventions for alcohol misuse. Brief interventions were found to reduce alcohol consumption, alcohol-related mortality, morbidity, injuries, social consequences and the consequent use of healthcare resources and laboratory indicators of alcohol misuse. ## Evidence statement 6.2 Six systematic reviews (all ) demonstrated that interventions delivered in primary care are effective in reducing alcohol-related negative outcomes. Three systematic reviews specifically focusing on the use of brief interventions in emergency care (1 and 2 ) found limited evidence of effectiveness. A further review (++) presented inconclusive evidence of the effectiveness of brief interventions in inpatient and outpatient settings. A systematic review of brief interventions for alcohol misuse in the workplace presented limited and inconclusive findings for the effectiveness of interventions in this setting (++). ## Evidence statement 6.3 Brief interventions are effective in reducing alcohol consumption in both men and women (7 ). ## Evidence statement 6.4 Most of the primary evidence was drawn from populations with an age range of 12 to 70 years. Therefore, brief interventions for adults have been shown to be effective among adult populations. ## Evidence statement 6.10 Extensive heterogeneity was evident in the characteristics of evaluated brief interventions. However, limited evidence would suggest that even very brief interventions may be effective in reducing alcohol-related negative outcomes, (1 systematic review) with inconclusive evidence for an additional positive impact resulting from increased dose (3 systematic reviews). Evidence from an additional review (++) suggests that brief interventions are effectivebut the impact of including motivational interviewing principles was unclear. ## Evidence statement 6.11 Extended brief interventions were demonstrated to be effective in the reduction of alcohol consumption (evaluated interventions consisted of two to 7 sessions with a duration of initial and booster sessions of 15 to 50 minutes (1 systematic review) or 10 to 15 minutes in 1 session with a number of specific booster sessions of 10 to 15 minutes duration (1 systematic review)). ## Evidence statement 7.1 Organisational factors such as adequate support and resources can influence the acceptability and implementation of screening and brief intervention for alcohol misuse. Implementation of screening and brief interventions is influenced by factors other than effectiveness. Positive support from the government, management and involvement of non-clinical members of staff are more likely to result in successful implementation. There is also evidence from a range of studies in primary care settings that adequate practitioner training and support in alcohol misuse screening and use of brief intervention materials facilitates – or would facilitate – effective implementation rates and appropriate detection of 'at risk' drinkers. Evidence suggests that the extent of training and support available to practitioners is variable. One RCT ( USA) showed more successful implementation of screening and brief intervention where there was prior experience of this type of work, management stability and positive support in terms of coordination of programmes. Financial incentives and successful management of staff changes, as well as assistance from receptionists, were also important. However, barriers to success included competing priorities and lack of time. The importance of financial and other incentives for GPs along with readily available materials and training was also highlighted in 1 survey in New Zealand (+). Evidence from RCTs (1 USA, 1 USA and 1 UK) suggests that the extent to which brief interventions are implemented, though not necessarily the appropriateness of implementation, is increased with use of a training and support intervention for GPs and nurses. One cross-sectional study ( Germany) provides evidence that GPs holding a qualification in addiction medicine are more likely to detect problem drinkers. However, a cross-national survey (++) found that training did not improve baseline role insecurity for GPs. One cross-sectional study ( Finland) and 1 qualitative study ( Finland) found that practitioner training rates and ratings of their own familiarity with screening tools and knowledge of brief intervention content was low. The importance of training to practitioners in this survey was evident, as were practitioner views that they lacked training to carry out counselling ( UK). The latter point was also evidenced in 1 cross-sectional study ( UK). A Delphi survey ( UK) provides evidence in the form of expert opinion that practitioner training should help raise awareness of risk factors and typical presentations of individuals with potential drinking problems. Evidence from qualitative studies show that some nurses in the UK (1 ) see training as an incentive to carrying out alcohol-related work. A sample of GPs in Finland perceived that they lacked training in identifying the early stages of alcohol misuse; and GPs in a Danish focus group study (+) felt they lacked training in counselling skills. In a probationary setting, forensic medical examiners in a UK qualitative study set in custody suites (-) felt they lacked the required training to carry out assessments of drinking behaviour. ## Evidence statement 7.2 Extending the current practitioner workload is a potential barrier to implementing screening and brief interventions on a large scale, particularly if all young people and adults are screened as routine practice. The extra time that implementation demands can be a barrier to acceptability and therefore a willingness to deliver such a programme. Implementation of routine screening and brief intervention programmes requires team-working between physicians, nurses and non-clinical personnel, with consideration required regarding the extent of involvement and specific roles of team members. Evidence from 1 systematic review ( Denmark) challenges the model of universal screening. The study concluded that implementation of universal screening does not benefit sufficient numbers of individuals to warrant the extra workload required. Nurses in 1 qualitative study ( UK) felt 'overloaded' with preventative work generally, with resources such as space, staff and sufficient time in short supply. In another qualitative study ( Denmark), the additional workload of screening and brief interventions was found to be creating stress among practitioners in primary care. In terms of time available, a Canadian qualitative study (++) found that time was constrained in terms of assessing each patient. A qualitative study of Finnish GPs (++) showed that they felt they lacked time to carry out a drinking assessment in the context of other consultation demands and weak evidence. One (-) study in Sweden found that nurses regarded time constraints as a barrier to engaging in alcohol prevention. There is mixed evidence from 1 RCT ( USA) for the utilisation of non-clinical staff in implementation in order to delegate work and thus to decrease the workload of clinicians. Another RCT found that receptionists did not have a particularly positive attitude to being involved in this type of work without adequate reimbursement ( UK), or to changing their perceived role ( USA). In an emergency care setting, 1 cross-sectional study ( USA) provides weak evidence (from a survey of physicians) that, despite support for brief interventions in theory, lack of time is a barrier to implementation. A further UK-based study set in an emergency department also reported that lack of time was viewed as a limiting factor in delivering screening (++). In a briefly reported UK qualitative study set in custody suites (-), forensic medical examiners felt they lacked the required time to carry out assessments of drinking behaviour. ## Evidence statement 7.3 There is evidence that implementation of screening and brief interventions would be facilitated by use of environments where alcohol can be discussed in a non-threatening way. Integrating screening and advice into general lifestyle discussions might increase the acceptability of screening and brief intervention for users. In a range of studies, providers and experts emphasise the importance of appropriate contexts for discussion of alcohol use with users in order to increase acceptability. Clinical consultations for non-alcohol-related medical problems can be an inappropriate time to discuss alcohol use, given that users are focused on the condition for which they are seeking advice. Instead, sessions such as new patient registrations and well-person clinics, where health promotion is often discussed, provide a less threatening opportunity to discuss drinking, as part of a general discussion on lifestyle issues such as diet, exercise and smoking. Evidence was found from a cross-sectional study ( Sweden) that primary care users attending for scheduled appointments are more likely to be asked about their drinking behaviour. This suggests that practitioners deem certain contexts as more appropriate or more convenient in some way for carrying out screening and a brief intervention. A Delphi survey ( UK) also provides expert-view evidence that clinics and new registration sessions are an appropriate context for assessing drinking behaviour (in terms of user acceptability). This study also suggests that interventions might be more acceptable to users if they are tailormade to the individual rather than global in design. There is further evidence from 5 UK qualitative studies (4 and 1 ) that practitioners and users regard clinics, registration sessions and routine consultations as opportunities for discussions in a less-threatening environment and context. That is, they provide an opportunity to discuss drinking in a context that is related to the purpose of the visit (such as lifestyle assessment or chronic condition monitoring). Emergency care and probation settings are regarded as 2 contexts that provide a potential opportunity to carry out alcohol screening and give advice. However, there is scarce evidence available. One survey of Scottish emergency care units (++) and 1 qualitative study ( UK) set in custody suites found that staff thought the location unsuitable for alcohol screening and intervention. However, 2 surveys from the US (both ) reported that both patients and surgeons found the emergency care setting acceptable and appropriate. One US evaluation (+) provided evidence that emergency care staff may not feel adequately supported either by management or financially, with training and workload as 2 particular concerns. One UK survey (+) provided mixed views, with some nurses preferring an holistic approach, and others prioritising care of injuries over health promotion. A further UK-based (++) study found that the majority of consulted professionals judged the emergency department to be an appropriate place to perform alcohol screening but that implementation rates were low, potentially due to clinical inertia. The importance of having resources in place to rapidly refer positively screened patients from the emergency department for a brief intervention was emphasised, because the rate of attendance for brief interventions dropped off markedly 2 days following referral (1 UK). Implementation of alcohol screening and brief interventions in emergency care settings is not as consistent as in primary care. The setting differs from primary care in terms of patient population and types of presenting cases, and as such, account needs to be taken of barriers and facilitators to implementation that are specific to the emergency care context, where attendance is brief and often traumatic, patients are more likely to be injured, traumatised, or intoxicated, and staff may feel less prepared to give advice. ## Evidence statement 7.4 There is evidence that service users have preferences regarding the status of the person dealing with their alcohol issues. Although experts consider alcohol and counselling specialists to be better qualified to carry out interventions, service users might feel stigmatised or rejected should their needs be referred on to such practitioners. Evidence from 1 RCT ( USA) carried out in a general medicine setting showed that service users are no more likely to attend for counselling with an alcohol specialist than with a physician or nurse. In addition, qualitative evidence from the UK (1 ) focusing on user views shows that counselling with alcohol specialists can sometimes be perceived as stigmatising. These views contrast with expert views (1 UK) that alcohol workers and counsellors might be best placed to deliver a brief intervention. There are mixed views from 3 UK studies (all ) in that professionals and some users perceive the nurse as having more time for discussing drinking with users, whereas other users report that they are more likely to discuss alcohol-related issues with their GP. ## Evidence statement 7.5 There is some evidence that service users are generally positive about screening and intervention. There is also evidence for general under-activity in discussing drinking with service users. Negative service user behaviour, such as aggression at being asked about their drinking, while rare, may serve as deterrents to practitioners approaching the topic of drinking with users. Actual drunkenness at consultations limits the likelihood that users will appreciate or remember the advice given. Practitioners may benefit from training in dealing with such situations, and in approaching the topic with individuals that they perceive as 'low risk' in appropriate contexts. Two studies (1 USA and 1 UK) provide evidence that the majority of service users are positive about screening, and another ( Finland) that they are positive about discussing drinking. However, 2 qualitative studies (1 UK and 1 Denmark) found that some professionals had encountered negative reactions from users in terms of embarrassment and unease, and that this led some to change their GP practice. Evidence from 2 UK cross-sectional studies (both ++) shows under-activity in terms of practitioner management of hazardous drinking, with a majority of GPs in the first study only intervening in between 1 and 6 cases of hazardous drinking per year. Even in cases of heavy drinking, service users are not being asked about their consumption ( Finland). Another cross-sectional study ( Sweden) found that advice on drinking behaviour is provided less often than for other lifestyle behaviours, such as exercise, diet, and smoking, and less often than service users expect. One cross-sectional study ( Finland) found that the time being spent on asking users about their drinking was typically less than 4 minutes, and another recent cross-sectional study ( Germany) found that detection rates of problem drinkers are low, at 1 in 3. Possible reasons are found in a Finnish qualitative study (++) of GPs, who reported their reluctance to ask users about their drinking unless they saw clear signs of risky drinking behaviour. ## Evidence statement 7.6 Evidence was found that provider attitudes, knowledge, skills and behaviour can influence the implementation of screening and brief interventions for alcohol misuse. There is evidence from primary care practitioner views of a shortfall in perceived knowledge in terms of detecting 'at-risk' individuals. There is also evidence of confusion regarding current guidelines around drinking behaviour, and the known benefits of drinking in moderation. This can affect practitioner confidence in, and motivation towards, implementing screening and brief intervention programmes effectively. In addition, the practitioner's own drinking behaviour and the user-practitioner relationship may affect the way that alcohol-related interventions are implemented. One UK qualitative study (++) provides evidence that GPs found difficulty in identifying early-stage heavy drinkers. The study also reports difficulty working with multiple definitions of problematic drinking. One qualitative study ( Finland) found that GPs and nurses saw the lack of clear guidance as a barrier to carrying out brief interventions. Utilising the skills of receptionists can be useful, but there is evidence from 1 RCT ( UK) that receptionist attitudes toward the work may be less positive than that of clinicians, and that this might have an impact upon implementation. There is weak evidence ( UK) that forensic medical examiners perceive that they lack the knowledge to carry out an assessment in custody suites in the UK. Two UK qualitative studies (1 and 1 ) found that nurses saw alcohol as a difficult and emotive topic to broach with users. In addition, nurses reported confusion for themselves and service users around the issue of standard drink units, and the potential benefits of alcohol that create ambiguity in discussing drinking from a health promotion perspective. Other studies (1 UK and 1 Finland) found that GPs relationship with alcohol could affect their behaviour in terms of addressing service user drinking, with feelings of guilt and hypocrisy potential barriers to open discussion, or facilitators to empathy. There is qualitative evidence from 3 studies focusing on user views (2 UK and 1 USA) that discussing drinking is facilitated by a good relationship with the health professional. In addition, there is evidence (1 Denmark) that practitioners are concerned not to offend users by discussing alcohol for fear of disturbing the therapeutic relationship. ## Evidence statement 7.7 Evidence was identified that shows disparities in the way screening and brief interventions for alcohol misuse are implemented in realtion to certain groups within the population. While certain groups, such as males and high earners, are more 'at-risk' than others from alcohol misuse, individuals from groups that are 'low-risk' – such as females, younger and older people – may be missed. Conversely, over-targeting can also occur due to misconceptions of the populations most at-risk of alcohol misuse. One systematic review (+) provides inconclusive evidence that socioeconomic status affects the uptake of brief interventions. However, 1 cross-sectional study ( UK) found that unemployed individuals were more likely to receive a brief intervention than those in employment. In terms of ethnicity, there is evidence from 1 cross-sectional study ( USA) that minorty ethnic groups, in this instance black and Hispanic, and particularly Hispanic people, were more likely to be approached by practitioners regarding their alcohol consumption. Four cross-sectional studies (1 UK, 1 Sweden, 1 Germany and 1 Finland) provide evidence that primary care users most likely to be given advice on drinking are males. Another cross-sectional study ( Finland) suggests that males, as well as heavy drinkers, are also more likely to adhere to the advice provided in a brief intervention. One qualitative study ( Denmark) found that GPs were reluctant to address drinking with young people as they felt that they would be likely to grow out of the habit of hazardous drinking. ## Evidence statement e1.1 There is limited evidence of the cost effectiveness of price controls in a UK setting. One systematic review (+) suggests that the available evidence is limited to 2 studies, 1 which takes an international perspective, and 1 set in Estonia. The review reports that the evidence is suggestive that in areas with a high prevalence (greater than 5%) of hazardous drinkers, as is the case in the UK, taxation will be more cost effective than other alcohol misuse macro interventions, but that the evidence base for this is not strong. ## Evidence statement e2.3 There is limited evidence of the cost effectiveness of opening hours interventions in a UK setting. One study of moderate quality that takes an international perspective (+) provides evidence that reducing licensing hours provides relatively small quality of life benefits compared to other alcohol misuse interventions. ## Evidence statement e5.1 One study shows that the AUDIT test is a more cost effective screening tool than measures of y-glutamyltransferase, aspartate aminotransferase, per cent carbohydrate deficient transferrin, and ethrocyte mean cell volume. This is because AUDIT is both cheaper and more effective than these other tests ( UK). The evidence does not allow a ranking of the cost effectiveness of these other screening methods. ## Evidence statement e6.1 Cost effectiveness evidence for screening and brief interventions in the emergency care setting is scarce. The available evidence does not allow firm conclusions regarding the long-term cost effectiveness of these interventions in a UK setting. However, the evidence does suggest that brief interventions in the emergency care setting may be cost effective in the UK. One study suggests that screening plus a brief intervention may produce long-term cost savings ( USA), but the applicability of this evidence to the UK is uncertain. One UK study suggests that a brief intervention administered by alcohol health workers in a hospital setting will reduce consumption in the short term without significantly increasing costs, but long-term evidence is lacking (++). ## Evidence statement e6.2 Cost effectiveness evidence for screening and brief interventions in the hospital setting is scarce. The available evidence does not allow conclusions regarding the cost effectiveness of these interventions in a UK setting to be made. A UK study presents evidence for screening by doctors and nurses in a general hospital setting (+), but this does not allow a conclusion to be reached regarding the most cost-effective screening method. One study suggests that screening plus a brief intervention may produce long-term cost savings ( Australia), but the reliability of this evidence is low due to the uncertainty in resource use estimates. ## Modelling statement M2 A policy of screening and brief intervention at next GP registration is a more phased approach over time than screening at next GP consultation. The former approach would screen an estimated 39% of the population, with 36% of hazardous and harmful drinkers receiving a brief intervention over the modelled 10-year screening programme. A policy of screening and brief intervention at next GP consultation is a very large-scale implementation, with an estimated 96% of the population screened after 10 years (of whom the majority would be screened in the first year of implementation), and 79% of hazardous and harmful drinkers receiving a brief intervention. ## Modelling statement M3 Screening and brief intervention in an A&E setting is estimated to screen 78% of the population within 10 years, but because the estimated uptake of brief interventions is just 30%, only 18% of hazardous and harmful drinkers are estimated to receive the brief intervention. ## Modelling statement M6 Sensitivity analysis shows that even fairly long brief interventions (for example, 25 minutes) would appear cost effective versus a 'do nothing' policy. There is currently no conclusive evidence of the differential effectiveness of delivery by different types of staff. On this basis, decision makers might consider the less costly staffing options that were modelled for screening and the brief intervention to be attractive. Evidence around the differential effectiveness of interventions of different duration is also inconclusive. Sensitivity analyses show that shorter duration interventions remain cost effective when using the best available evidence on the relationship between duration and effectiveness. ## Modelling statement M12 Increasing levels of minimum pricing show very steep increases in effectiveness. Overall changes in consumption for 20p, 25p, 30p, 35p, 40p, 45p, 50p, 60p, 70p are: 0.0%, -0.1%, -0.4%, -1.1%, -2.4%, -4.3%, -6.7%, -11.9% and -17.7%. Higher minimum prices reduce switching effects. Note that estimates for lower minimum prices are subject to less modelling uncertainty than those for higher minimum prices. This is because the consideration of supply-side responses and, in particular, a possible restructuring of the market following large mandated price increases in sections of the market, was outside the scope of the model. As an example, a minimum price of 40p per unit has the following estimated effects: % change in consumption: -2.4% Deaths p.a. (full effect): -1,190 Hospital admissions p.a.: -39,000 Crimes pa: -10,000 Work absences (days p.a.): -134,000 Unemployment (persons p.a.): -11,500 ## Modelling statement M21 As prices increase, alcohol-attributable hospital admissions and deaths are estimated to reduce. Prevented deaths occur disproportionately in harmful drinkers. On balance, the health-harm reductions mostly relate to chronic diseases rather than acute conditions such as injuries. This is because much of the alcohol-attributable health harm occurs in middle or older age groups at significant risk of developing and potentially dying from chronic disease. ## Modelling statement M22 For chronic diseases, the time for a change in consumption to achieve the full effect in changing the prevalence of disease is important in the modelling. The reductions in health-harms, for chronic disease, observed 1-year following implementation are estimated to be around one tenth of the level that will accrue when the full effect of consumption changes occurs. ## Modelling statement M23 Crime harms are estimated to reduce as prices are increased. The crime reductions observed for policies take place across the spectrum of violent crime, criminal damage and theft, robbery and other crimes. A minimum price of 40p is estimated to reduce total crimes by 9,000 per annum. ## Modelling statement M24 The evidence base for under-age purchasing is limited (because the youngest ages for which purchasing data exists in the 'Expenditure and food survey' are 16 and 17, and there are concerns on reliability even for this). Given this caveat, crime harms are estimated to reduce particularly for young people aged 11 to 18 years because they are disproportionately involved in alcohol-related crime and are affected significantly by targeting price rises at low-priced products. ## Modelling statement M26 Unemployment harm estimates (that is, estimated unemployment due to alcohol consumption), reduce proportionately more than health or crime harms. Generally, all policy options that target harmful and hazardous drinkers are effective in reducing alcohol-related harm in the workplace. The size of the effect is dependent on the extent of price increases. ## Modelling statement M27 Unemployment due to alcohol problems among harmful drinkers is estimated to reduce as prices increase: for example, a 40p minimum price is estimated to result in 11,500 avoided unemployment cases, while a 50p minimum price is estimated to result in 25,900 avoided unemployment cases. Absence reductions are particularly focused on hazardous and harmful drinkers: for example, for 40p, the 134,000 estimated reduction in days absence is made up of 38,000 days for hazardous and 78,000 days for harmful drinkers. ## Modelling statement M29 The societal value of harm reduction for many of the potential policies can be substantial. When accumulated over the 10-year time horizon of the model, many policies have estimated reductions in harm valued over £500m. For example, a 40p minimum price is valued at £4bn over the 10-year period. The financial value of harm reductions becomes larger as prices are increased. ## Modelling statement M34 Moderate drinkers are affected in only very small ways by the policy options examined, both in terms of their consumption of alcohol and their spending. ## Modelling statement M35 In terms of the differential effectiveness for priority groups, harmful drinkers are expected to reduce their absolute consumption the most, but in the more effective policy options, they also spend significantly more on their purchases. ## Modelling statement M36 Policies which target low-priced alcohol affect harmful drinkers disproportionately. This is because moderate drinkers tend to drink a smaller proportion of the very low priced products available. ## Modelling statement M37 There are significant effects on harmful drinkers, but important health gains also occur in hazardous and moderate drinkers. Even though moderate drinkers are at a lower risk of health-related harms, small changes in the consumption of the large number of moderate drinkers feed through in the model to small changes in risk and appreciable changes in population health. ## Modelling statement M51 Though smaller than price effects, outlet density reductions have been proven to reduce both consumption and harm. As an example, the 10% reduction in outlet density has the following estimated effects: % change in consumption: -2.3% Deaths per annum (full effect): -710 Hospital admissions per annum: -25,000 Crimes per annum: -61,000 Work absences (days per annum): -284,000 Unemployment (persons per annum): -8100 ## Modelling statement M55 Modelling a 10% change in licensing hours produces changes in alcohol consumption based on 3 studies of -1.2% (Canadian), +0.2% (US), and -3.5% (Swedish). As an example, the 10% reduction in licensing hours has the following estimated effects: % change in consumption: -1.2% Deaths per annum (full effect): -420 Hospital admissions per annum: -14,000 Crimes per annum: -27,000 Work absences (days per annum): -138,000 Unemployment (persons per annum): -3400 # Economic analysis The cost-effectiveness reviews and economic modelling showed that increasing the price of alcohol is likely to be a cost effective way of reducing consumption and alcohol-related harm. This could involve a general price increase, imposing a minimum price per unit or placing restrictions on discounting. There was limited evidence on the effectiveness of reducing the availability of alcohol and restricting or banning advertising. Exploratory analyses suggested that policies to address these issues would probably have a smaller positive effect than that expected by a price increase. The cost-effectiveness reviews and economic modelling suggested that screening plus a brief intervention at the next GP consultation, the next registration with a new GP, or the next A&E visit would be cost effective when compared against 'doing nothing'. # Fieldwork findings Fieldwork aimed to test the relevance, usefulness and feasibility of putting the recommendations into practice. The PDG considered the findings when developing the final recommendations. For details, go to the fieldwork section in appendix B and 'Alcohol-use disorders: preventing the development of hazardous or harmful drinking'. Fieldwork participants who work within the alcohol field were positive about the recommendations and their potential to help prevent alcohol-use disorders. However, they felt that a number of areas should be given further consideration as follows. A treatment pathway should be provided which not only illustrates the stages of care that the recommendations cover, but also outlines the roles and responsibilities of different professional groups. Good communication is needed between NICE and organisations in non-healthcare settings to ensure alcohol is tackled as part of partnership working. NICE should work closely with the National Treatment Agency (NTA) to ensure commissioners' concerns about the relative lack of investment in alcohol services (compared with drug services) is considered. The term 'motivational counselling' should be reconsidered or clearly differentiated from other motivational approaches. The presentation of the guidance will contribute to its impact and likely adoption. A standard approach should be used whereby each recommendation is preceded by a short statement of the evidence and a discussion of the likely outcomes of implementing the proposed actions. The contribution that community and voluntary groups make to reducing alcohol-related harm should be acknowledged and organisations working in these sectors should be mentioned throughout the guidance.# Appendix D: Gaps in the evidence The PDG identified a number of gaps in the evidence related to the programmes under examination, based on an assessment of the evidence. These gaps are set out below. . There is only limited evidence on how alcohol advertising affects consumption among the adult population. . There is only limited evidence on the effectiveness of brief alcohol-related interventions aimed at those under the age of 18 and those from black and minority ethnic groups within the UK. . Little is known about how brief interventions work and which elements are particularly effective. For example, there is only limited evidence on the settings and populations where brief advice or motivational interviewing will be more effective or cost effective. . There is variable evidence on the effectiveness of using brief interventions outside primary care and emergency departments. . There is little UK-based evidence on the cost effectiveness of different types of brief intervention. . There is a lack of good quality evaluations of UK community-based programmes to prevent alcohol problems. Source: Review 1, review 2 and review 4 (see appendix E for details). The Group made 7 recommendations for research.# Appendix E: supporting documents Supporting documents include the following: Effectiveness reviews: Review 1: 'Interventions on control of alcohol price, promotion and availability for prevention of alcohol-use disorders in adults and young people' Review 2: 'Screening and brief interventions for prevention and early identification of alcohol-use disorders in adults and young people'. Economic analysis: Review 3: 'Prevention and early identification of alcohol-use disorders in adults and young people. Macro-level interventions for alcohol use-disorders: cost-effectiveness review' Review 4: 'Prevention and early identification of alcohol-use disorders in adults and young people. Screening and brief interventions: cost-effectiveness review' Economic modelling report: 'Modelling to assess the effectiveness and cost effectiveness of public health-related strategies and interventions to reduce alcohol attributable harm in England using the Sheffield alcohol policy model version 2.0'. Fieldwork report: Alcohol-use disorders: preventing the development of hazardous or harmful drinking'.	{'Introduction': "The Department of Health asked NICE to produce public health guidance on the prevention and early identification of alcohol-use disorders among adults and adolescents.\n\nThe guidance is for government, industry and commerce, the NHS and all those whose actions affect the population's attitude to – and use of – alcohol. This includes commissioners, managers and practitioners working in local authorities, education and the wider public, private, voluntary and community sectors. In addition, it may be of interest to members of the public.\n\nThis is 1 of 3 pieces of NICE guidance addressing alcohol-related problems among people aged 10 years and older. The others are:\n\nNICE's guideline on alcohol-use disorders: diagnosis and management of physical complications (2010). A clinical guideline covering acute alcohol withdrawal including delirium tremens, alcohol-related liver damage, alcohol-related pancreatitis and management of Wernicke's encephalopathy.\n\nNICE's guideline on alcohol-use disorders: diagnosis, assessment and management of harmful drinking and alcohol dependence (2011). A clinical guideline covering identification, assessment, pharmacological and psychological/psychosocial interventions, and the prevention and management of neuropsychiatric complications.\n\nThe guidance complements, but does not replace, NICE guidance on school-based interventions on alcohol. It will also complement NICE guidance on: personal, social and health education; prevention of cardiovascular disease; antenatal care; and associated guidance on alcohol-use disorders (management and dependence).\n\nThe Programme Development Group (PDG) developed these recommendations on the basis of reviews of the evidence, an economic analysis, expert advice, stakeholder comments and fieldwork.\n\nMembers of the PDG are listed in appendix A. The methods used to develop the guidance are summarised in appendix B. Supporting documents used to prepare this document are listed in appendix E.\n\nFor more information see full details of the evidence collated, including fieldwork data and activities and stakeholder comments, along with a list of the stakeholders involved and NICE's supporting process and methods manuals.", 'Recommendations': "People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.\n\nMaking decisions using NICE guidelines has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.\n\nThis is NICE's formal guidance on the prefvention and early identification of alcohol-use disorders among adults and adolescents. When writing the recommendations, the Programme Development Group (PDG) (see appendix A) considered the evidence of effectiveness (including cost effectiveness), fieldwork data and comments from stakeholders and experts.\n\nThe evidence statements underpinning the recommendations are listed in appendix C.\n\nThe evidence reviews, supporting evidence statements and economic analysis are available.\n\n# Population versus individual approach\n\nA combination of interventions are needed to reduce alcohol-related harm – to the benefit of society as a whole.\n\nPopulation-level approaches are important because they can help reduce the aggregate level of alcohol consumed and therefore lower the whole population's risk of alcohol-related harm. They can help:\n\nthose who are not in regular contact with the relevant services\n\nthose who have been specifically advised to reduce their alcohol intake, by creating an environment that supports lower-risk drinking.\n\nThey can also help prevent people from drinking harmful or hazardous amounts in the first place.\n\nInterventions aimed at individuals can help make people aware of the potential risks they are taking (or harm they may be doing) at an early stage. This is important, as they are most likely to change their behaviour if it is tackled early. In addition, an early intervention could prevent extensive damage.\n\nThe government continues to use both individual and population approaches to address the harm caused by alcohol (for example, in its strategy 'Safe. Sensible. Social.' [Department of Health's Safe. Sensible. Social. The next steps in the national alcohol strategy (2007)]).\n\nThis NICE guidance provides authoritative recommendations, based on a robust analysis of the evidence, which support current government activities. The recommendations could form part of a national framework for action.\n\nAs highlighted by the House of Commons Public Accounts Committee, national-level action to reduce the population's alcohol consumption requires coordinated government policy. It also needs government, industry and key non-governmental organisations to work together (House of Commons Public Accounts Committee – Reducing alcohol harm: health services in England for alcohol misuse).\n\n# Policy and practice\n\nThis guidance makes the case that alcohol-related harm is a major public health problem. On the basis of the best available evidence, it also identifies the policy options that are most likely to be successful in combating such harm. The final decision on whether these policies are adopted – and how they are prioritised – will be determined by government and the normal political processes.\n\nThe policy recommendations (recommendations 1 to 3) are based on extensive and consistent evidence which suggests that the issues identified deserve close attention. This evidence also suggests that policy change is likely to be a more effective – and more cost-effective – way of reducing alcohol-related harm among the population than actions undertaken by local health professionals. Many of the policy changes considered in this guidance are similar to those proposed by the House of Commons Health Select Committee (House of Commons Health Select Committee – Alcohol first report of session 2009–10).\n\nThe recommendations for practice (recommendations 4 to 12) support, complement – and are reinforced by – these policy options. They include the use of screening and brief interventions. The latter includes structured brief advice and extended brief interventions.\n\nFor the purposes of this guidance, screening involves identifying people who are not seeking treatment for alcohol problems but who, in the view of the professional, may have an alcohol-use disorder. Practitioners may use any contact with clients to carry out this type of screening. The term is not used here to refer to national screening programmes such as those recommended by the UK National Screening Committee (UK NSC).\n\n# Recommendations for policy\n\n## Who should take action?\n\nThe Chief Medical Officer should coordinate the alcohol harm-reduction strategy for England across government, supported by the Department of Health.\n\nThe following departments and national agencies should also be involved:\n\nAdvertising Standards Authority\n\nDepartment for Business, Innovation and Skills\n\nDepartment for Culture, Media and Sport\n\nDepartment for Education\n\nDepartment for Environment, Food and Rural Affairs\n\nDepartment of Communities and Local Government\n\nHM Treasury\n\nHome Office\n\nMinistry of Justice\n\nNational Treatment Agency\n\nOfcom\n\nOffice of Fair Trading\n\nOrganisations that should be consulted include:\n\nadvertisers\n\nalcohol producers\n\nnational non-governmental organisations (for example, Alcohol Concern and the Royal Medical Colleges)\n\noff- and on-sale retailers.\n\n## Recommendation 1: price\n\nMaking alcohol less affordable is the most effective way of reducing alcohol-related harm. The current excise duty varies for different alcoholic products (for historical reasons and under EU legislation). This means that the duty does not always relate directly to the amount of alcohol in the product. In addition, an increase in the duty levied does not necessarily translate into a price increase as retailers or producers may absorb the cost. There is extensive international and national evidence (within the published literature and from economic analyses) to justify reviewing policies on pricing to reduce the affordability of alcohol.\n\nConsider introducing a minimum price per unit. Set the level by taking into account the health and social costs of alcohol-related harm and its impact on alcohol consumption. Consider initiating a review of the excise duty regime with fellow EU member states. The aim would be to obtain a pan-EU agreement on harmonisation which links alcohol duty to the strength of each product.\n\nRegularly review the minimum price per unit to ensure alcohol does not become more affordable over time.\n\nRegularly review alcohol duties to make sure alcohol does not become more affordable over time.\n\n## Recommendation 2: availability\n\nInternational evidence suggests that making it less easy to buy alcohol, by reducing the number of outlets selling it in a given area and the days and hours when it can be sold, is another effective way of reducing alcohol-related harm. In Scotland, protection of the public's health is part of the licensing objectives.\n\nConsider revising legislation on licensing to ensure:\n\n\n\nprotection of the public's health is 1 of its objectives\n\nhealth bodies are responsible authorities\n\nlicensing departments can take into account the links between the availability of alcohol and alcohol-related harm when considering a licence application (that is, they can take into account the number of alcohol outlets in a given area and times when it is on sale and the potential links to local crime and disorder and alcohol-related illnesses and deaths)\n\nimmediate sanctions can be imposed on any premises in breach of their licence, following review proceedings.\n\n\n\nConsider reducing personal import allowances to support the introduction of a minimum price per unit of alcohol.\n\n## Recommendation 3: marketing\n\nThere is evidence that alcohol advertising does affect children and young people. It shows that exposure to alcohol advertising is associated with the onset of drinking among young people and increased consumption among those who already drink. All of the evidence suggests that children and young people should be protected as much as is possible by strengthening the current regulations.\n\nEnsure children and young people's exposure to alcohol advertising is as low as possible by considering a review of the current advertising codes. This review would ensure:\n\n\n\nthe limits set by the Advertising Standards Authority (ASA) for the proportion of the audience under age 18 are appropriate\n\nwhere alcohol advertising is permitted there is adequate protection for children and young people\n\nall alcohol marketing, particularly when it involves new media (for example, web-based channels and mobile phones) and product placement, is covered by a stringent regulatory system which includes ongoing monitoring of practice.\n\n\n\nOfcom, the ASA and the government should keep the current regulatory structure under review.\n\nAssess the potential costs and benefits of a complete alcohol advertising ban to protect children and young people from exposure to alcohol marketing.\n\n# Recommendations for practice\n\n## Recommendation 4: licensing\n\nAlcohol licence-holders and designated supervisors of licensed premises.\n\nLocal authorities.\n\nTrading standards officers.\n\nThe police.\n\nMagistrates.\n\nRevenue and customs.\n\nUse local crime and related trauma data to map the extent of alcohol-related problems before developing or reviewing a licensing policy. If an area is saturated with licensed premises and the evidence suggests that additional premises may affect the licensing objectives, adopt a 'cumulative impact' policy. If necessary, limit the number of new licensed premises in a given area.\n\nEnsure sufficient resources are available to prevent under-age sales, sales to people who are intoxicated, proxy sales (that is, illegal purchases for someone who is under-age or intoxicated), non-compliance with any other alcohol licence condition and illegal imports of alcohol.\n\nWork in partnership with the appropriate authorities to identify and take action against premises that regularly sell alcohol to people who are under-age, intoxicated or making illegal purchases for others.\n\nUndertake test purchases (using 'mystery' shoppers) to ensure compliance with the law on under-age sales. Test purchases should also be used to identify and take action against premises where sales are made to people who are intoxicated or to those illegally purchasing alcohol for others.\n\nEnsure sanctions are fully applied to businesses that break the law on under-age sales, sales to those who are intoxicated and proxy purchases. This includes fixed penalty and closure notices (the latter should be applied to establishments that persistently sell alcohol to children and young people).\n\n## Recommendation 5: resources for screening and brief interventions\n\nProfessionals who have contact with those aged 16 and over.\n\nChief executives of NHS and local authorities.\n\nCommissioners of NHS healthcare services.\n\nCommissioners from multi-agency joint commissioning groups.\n\nManagers of NHS-commissioned services.\n\nChief executives of NHS and local authorities should prioritise alcohol-use disorder prevention as an 'invest to save' measure.\n\nCommissioners should ensure a local joint alcohol needs assessment is carried out in accordance with Public Health England's alcohol, drugs and tobacco: commissioning support pack and local alcohol services and systems improvement tool. They should also ensure locally defined integrated care pathways for alcohol treatment are reviewed.\n\nCommissioners should ensure their plans include screening and brief interventions for people at risk of an alcohol-related problem (hazardous drinkers) and those whose health is being damaged by alcohol (harmful drinkers). This includes people from disadvantaged groups.\n\nCommissioners should make provision for the likely increase in the number of referrals to services providing tier 2, 3 and 4 structured alcohol treatments as a result of screening. These services should be properly resourced to support the stepped care approach recommended in the Department of Health's Models of care for alcohol misusers.\n\nCommissioners should ensure at least 1 in 7 dependent drinkers can get treatment locally, in line with Signs for improvement.\n\nCommissioners should include formal evaluation within the commissioning framework so that alcohol interventions and treatment are routinely evaluated and followed up. The aim is to ensure adherence to evidence-based practice and to ensure interventions are cost effective.\n\nManagers of NHS-commissioned services must ensure an appropriately trained nurse or medical consultant, with dedicated time, is available to provide strategic direction, governance structures and clinical supervision to alcohol specialist nurses and care givers.\n\nManagers of NHS-commissioned services must ensure community and voluntary sector providers have an appropriately trained professional who can provide strategic direction, governance structures and supervision to those providing screening and brief interventions.\n\nManagers of NHS-commissioned services must ensure staff have enough time and resources to carry out screening and brief intervention work effectively. Staff should have access to recognised, evidence-based packs. These should include: a short guide on how to deliver a brief intervention, a validated screening questionnaire, a visual presentation (to compare the person's drinking levels with the average), practical advice on how to reduce alcohol consumption, a self-help leaflet and possibly a poster for display in waiting rooms.\n\nManagers of NHS-commissioned services must ensure staff are trained to provide alcohol screening and structured brief advice. If there is local demand, staff should also be trained to deliver extended brief interventions.\n\n## Recommendation 6: supporting children and young people aged 10 to 15 years\n\nChildren and young people aged 10 to 15 years who are thought to be at risk from their use of alcohol.\n\nAny professional with a safeguarding responsibility for children and young people and who regularly comes into contact with this age group.\n\nUse professional judgement to routinely assess the ability of these children and young people to consent to alcohol-related interventions and treatment. Some will require parental or carer involvement.\n\nObtain a detailed history of their alcohol use (for example, using the Common Assessment Framework as a guide). Include background factors such as family problems and instances of child abuse or under-achievement at school.\n\nUse professional judgement to decide on the appropriate course of action. In some cases, it may be sufficient to empathise and give an opinion about the significance of their drinking and other related issues that may arise. In other cases, more intensive counselling and support may be needed.\n\nIf there is a reason to believe that there is a significant risk of alcohol-related harm, consider referral to child and adolescent mental health services, social care or to young people's alcohol services for treatment, as appropriate and available.\n\nEnsure discussions are sensitive to the child or young person's age and their ability to understand what is involved, their emotional maturity, culture, faith and beliefs. The discussions (and tools used) should also take into account their particular needs (health and social) and be appropriate to the setting.\n\n## Recommendation 7: screening young people aged 16 and 17 years\n\nYoung people aged 16 and 17 years who are thought to be at risk from their use of alcohol.\n\nHealth and social care, criminal justice and community and voluntary professionals in both NHS and non-NHS settings who regularly come into contact with this group.\n\nComplete a validated alcohol screening questionnaire with these young people. Alternatively, if they are judged to be competent enough, ask them to fill 1 in themselves. In most cases, AUDIT (alcohol use disorders identification test) should be used. If time is limited, use an abbreviated version (such as AUDIT-C, AUDIT-PC, CRAFFT, SASQ or FAST). Screening tools should be appropriate to the setting. For instance, in an emergency department, FAST or the Paddington Alcohol Test (PAT) would be most appropriate. Use professional judgement as to whether to revise the AUDIT scores downwards when screening people under 18.\n\nFocus on key groups that may be at an increased risk of alcohol-related harm. This includes those:\n\n\n\nwho have had an accident or a minor injury\n\nwho regularly attend genito-urinary medicine (GUM) clinics or repeatedly seek emergency contraception\n\ninvolved in crime or other antisocial behaviour\n\nwho truant on a regular basis\n\nat risk of self-harm\n\nwho are looked after\n\ninvolved with child safeguarding agencies.\n\n\n\nWhen broaching the subject of alcohol and screening, ensure discussions are sensitive to the young person's age and their ability to understand what is involved, their emotional maturity, culture, faith and beliefs. The discussions should also take into account their particular needs (health and social) and be appropriate to the setting.\n\nRoutinely assess the young person's ability to consent to alcohol-related interventions and treatment. If there is doubt, encourage them to consider involving their parents in any alcohol counselling they receive.\n\n## Recommendation 8: extended brief interventions with young people aged 16 and 17 years\n\nYoung people aged 16 and 17 years who have been identified via screening as drinking hazardously or harmfully.\n\nHealth and social care, criminal justice and community and voluntary sector professionals in both NHS and non-NHS settings who regularly come into contact with this group.\n\nAsk the young person's permission to arrange an extended brief intervention for them.\n\nAppropriately trained staff should offer the young person an extended brief intervention.\n\nProvide information on local specialist addiction services to those who do not respond well to discussion but who want further help. Refer them to these services if this is what they want. Referral must be made to services that deal with young people.\n\nGive those who are actively seeking treatment for an alcohol problem a physical and mental assessment and offer, or refer them for, appropriate treatment and care.\n\n## Recommendation 9: screening adults\n\nAdults.\n\nHealth and social care, criminal justice and community and voluntary sector professionals in both NHS and non-NHS settings who regularly come into contact with people who may be at risk of harm from the amount of alcohol they drink.\n\nNHS professionals should routinely carry out alcohol screening as an integral part of practice. For instance, discussions should take place during new patient registrations, when screening for other conditions and when managing chronic disease or carrying out a medicine review. These discussions should also take place when promoting sexual health, when seeing someone for an antenatal appointment and when treating minor injuries.\n\nWhere screening everyone is not feasible or practicable, NHS professionals should focus on groups that may be at an increased risk of harm from alcohol and those with an alcohol-related condition. This includes people:\n\n\n\nwith relevant physical conditions (such as hypertension and gastrointestinal or liver disorders)\n\nwith relevant mental health problems (such as anxiety, depression or other mood disorders)\n\nwho have been assaulted\n\nat risk of self-harm\n\nwho regularly experience accidents or minor traumas\n\nwho regularly attend GUM clinics or repeatedly seek emergency contraception.\n\n\n\nNon-NHS professionals should focus on groups that may be at an increased risk of harm from alcohol and people who have alcohol-related problems. For example, this could include those:\n\n\n\nat risk of self-harm\n\ninvolved in crime or other antisocial behaviour\n\nwho have been assaulted\n\nat risk of domestic abuse\n\nwhose children are involved with child safeguarding agencies\n\nwith drug problems.\n\n\n\nWhen broaching the subject of alcohol and screening, ensure the discussions are sensitive to people's culture and faith and tailored to their needs.\n\nComplete a validated alcohol questionnaire with the adults being screened. Alternatively, if they are competent enough, ask them to fill 1 in themselves. Use AUDIT to decide whether to offer them a brief intervention (and, if so, what type) or whether to make a referral. If time is limited, use an abbreviated version (such as AUDIT-C, AUDIT-PC, SASQ or FAST). Screening tools should be appropriate to the setting. For instance, in an emergency department FAST or PAT would be most appropriate.\n\nDo not offer simple brief advice to anyone who may be dependent on alcohol. Instead, refer them for specialist treatment (see recommendation 12). If someone is reluctant to accept a referral, offer an extended brief intervention (see recommendation 11).\n\nUse professional judgement as to whether to revise the AUDIT scores downwards when screening:\n\n\n\nwomen, including those who are, or are planning to become, pregnant\n\npeople aged 65 and over\n\npeople from some black and minority ethnic groups.If in doubt, consult relevant specialists. Work on the basis that offering an intervention is less likely to cause harm than failing to act where there are concerns.\n\n\n\nConsult relevant specialists when it is not appropriate to use an English language-based screening questionnaire. (For example, when dealing with people whose first language is not English or who have a learning disability.)\n\nBiochemical measures should not be used as a matter of routine to screen someone to see if they are drinking hazardously or harmfully. (This includes measures of blood alcohol concentration [BAC].) Biochemical measures may be used to assess the severity and progress of an established alcohol-related problem, or as part of a hospital assessment (including assessments carried out in emergency departments).\n\n## Recommendation 10: brief advice for adults\n\nAdults who have been identified via screening as drinking a hazardous or harmful amount of alcohol and who are attending NHS or NHS-commissioned services or services offered by other public institutions.\n\nProfessionals who have received the necessary training and work in:\n\nprimary healthcare\n\nemergency departments\n\nother healthcare services (hospital wards, outpatient departments, occupational health, sexual health, needle and syringe exchange programmes, pharmacies, dental surgeries, antenatal clinics and those commissioned from the voluntary, community and private sector)\n\nthe criminal justice system\n\nsocial services\n\nhigher education\n\nother public services.\n\nOffer a session of structured brief advice on alcohol. If this cannot be offered immediately, offer an appointment as soon as possible thereafter.\n\nUse a recognised, evidence-based resource that is based on FRAMES principles (feedback, responsibility, advice, menu, empathy, self-efficacy). It should take 5–15 minutes and should:\n\n\n\ncover the potential harm caused by their level of drinking and reasons for changing the behaviour, including the health and wellbeing benefits\n\ncover the barriers to change\n\noutline practical strategies to help reduce alcohol consumption (to address the 'menu' component of FRAMES)\n\nlead to a set of goals.\n\n\n\nWhere there is an ongoing relationship with the patient or client, routinely monitor their progress in reducing their alcohol consumption to a low-risk level. Where required, offer an additional session of structured brief advice or, if there has been no response, offer an extended brief intervention.\n\n## Recommendation 11: extended brief interventions for adults\n\nAdults who have not responded to brief structured advice on alcohol and require an extended brief intervention or would benefit from an extended brief intervention for other reasons.\n\nNHS and other professionals in the public, private, community and voluntary sector who are in contact with adults and have received training in extended brief intervention techniques.\n\nOffer an extended brief intervention to help people address their alcohol use. This could take the form of motivational interviewing or motivational-enhancement therapy. Sessions should last from 20 to 30 minutes. They should aim to help people to reduce the amount they drink to low risk levels, reduce risk-taking behaviour as a result of drinking alcohol or to consider abstinence.\n\nFollow up and assess people who have received an extended brief intervention. Where necessary, offer up to 4 additional sessions or referral to a specialist alcohol treatment service (see recommendation 12).\n\n## Recommendation 12: referral\n\nThose aged 16 years and over who attend NHS or other public services and may be alcohol-dependent. (For those under 16 see recommendation 6.)\n\nNHS and other professionals in the public, private, community and voluntary sector who have contact with anyone aged 16 and over.\n\nConsider making a referral for specialist treatment if 1 or more of the following has occurred. They:\n\nshow signs of moderate or severe alcohol dependence\n\nhave failed to benefit from structured brief advice and an extended brief intervention and wish to receive further help for an alcohol problem\n\nshow signs of severe alcohol-related impairment or have a related co-morbid condition (for example, liver disease or alcohol-related mental health problems).", 'Public health need and practice': "In Britain, the amount of pure alcohol sold per adult rose from 9.53 litres in 1986/87 to a peak of 11.78 litres in 2004/05, before dropping to 11.53 litres in 2007/08 (HM Revenue and Customs 2008). This approximates to 22 units (176\xa0g) per week for each person aged over 15 years.\n\nLevels of self-reported hazardous and harmful drinking are lowest in the central and eastern regions of England (21–24% of men and 10–14% of women). They are highest in the North East, North West and Yorkshire and Humber (26–28% of men, 16–18% of women) (North West Public Health Observatory 2007).\n\nA recent paper has also indicated that alcohol-related mortality within the UK varies according to a person's country of birth. For example, there is a higher alcohol-related mortality rate among those born in Ireland, Scotland and India compared to those born in Bangladesh, China, Hong Kong, Pakistan, the Middle East, West Africa and the West Indies (Bhala et al. 2009).\n\nAlthough the amount most people drink poses a relatively low risk to their health, an estimated 24% of adults drink a hazardous or harmful amount (The NHS Information Centre 2009). For definitions of harmful and hazardous drinking see the glossary.\n\nIn 2007, 72% of men and 57% of women in England had an alcoholic drink on at least 1 day during the previous week (Robinson and Lader 2009). In addition, 41% of men and 35% of women exceeded the daily recommended limits on at least 1 day in the previous week (Robinson and Lader 2009).\n\nAmong those aged 15 and under, 18% had drunk alcohol in the previous week (Diment et al. 2009). Although the proportion of schoolchildren who have never had an alcoholic drink has risen (from 39% in 2003 to 48% in 2008), those who do drink are consuming more.\n\nBetween 2007 and 2008, mean alcohol consumption among young people aged 11 to 15 (specifically, those who had drunk alcohol in the previous week) increased from 12.7 units (102\xa0g) to 14.6 units (117\xa0g) (Diment et al. 2009). Regional analysis shows that consumption is highest among those living in the North East (17.7 units) and the North West (16.3 units). It is lowest in London (11.3 units) (The NHS Information Centre 2010).\n\nIn addition, nearly 10,000 children and young people (under the age of 18) are admitted to hospital each year as a result of their drinking (Department for Children, Schools and Families 2009).\n\n# Trends in alcohol pricing and consumption\n\nIn the past 20 years, the price of alcohol has been rising at around the same rate as for other consumer products. However, incomes have risen much faster. As a result, between 1980 and 2008 alcohol became 75% more affordable (The NHS Information Centre 2009). Since 1987, for example, beer and wine have become 139% and 124% more affordable respectively when bought from an off license (Booth et al. 2008).\n\nOverall, 80% of alcohol is purchased by 30% of the population (Booth et al. 2008). This suggests that the current low pricing policy in supermarkets mainly benefits those drinking at hazardous and harmful levels. In some cases, alcohol products are sold below cost. It is not possible to say exactly who pays for this subsidy, but it may be that moderate drinkers pay higher prices for other goods as a result.\n\n# Health and social problems\n\nAlcohol consumption is associated with many chronic health problems including psychiatric, liver, neurological, gastrointestinal and cardiovascular conditions and several types of cancer. It is also linked to accidents, injuries and poisoning (Rehm et al. 2010). Drinking during pregnancy can also have an adverse effect on the developing foetus. The resulting problems can include lower birth weight and slow growth, learning and behavioural difficulties and facial abnormalities (British Medical Association Board of Science 2007).\n\nIn 2005 it has been estimated that 14,982 deaths were attributable to alcohol consumption (Jones et al. 2008).\n\nAlcohol is also linked to a number of social problems. In 2006/07, it was associated with over 500,000 recorded crimes in England (North West Public Health Observatory 2007). It may also be a contributory factor in up to 1 million assaults and is associated with 125,000 instances of domestic violence (DH 2009). Up to 17 million working days are lost annually through absences caused by drinking – and up to 20 million are lost through loss of employment or reduced employment opportunities (Prime Minister's Strategy Unit 2003).\n\nThe impact on other family members can be profound, leading to feelings of anxiety, worry, depression, helplessness, anger and guilt. For example, it can lead to financial worries and concern about the user's state of physical and mental health, as well as their behaviour. It can also affect the family's social life and make it difficult for family members to communicate. (Orford et al. 2005).\n\nAlcohol-use disorders are associated with relationship breakdown, domestic abuse, poor parenting, unsafe and regretted sex, truancy, delinquency, antisocial behaviour and homelessness (Prime Minister's Strategy Unit 2003).\n\n# Cost of alcohol-use disorders\n\nAlcohol-related harm is estimated to cost society between £17.7 billion and £25.1 billion per year (DH 2008a).\n\nIt costs the NHS in England up to £2.7 billion a year to treat the chronic and acute effects of drinking (DH 2008b). It is also estimated that up to 35% of all emergency department attendances and ambulance costs are alcohol-related (Prime Minister's Strategy Unit 2003). In 2007/08 there were 863,300 alcohol-related admissions, a 69% increase since 2002/03 (The NHS Information Centre 2009).\n\n# Socioeconomic factors\n\nThe interaction between social class and alcohol is complex.\n\nManagers and other professionals self-report that they consume the most alcohol (an average of 19.9 units [160\xa0g] a week compared with 16.7 units [134\xa0g] a week for people in routine and manual groups). The difference is even more marked when the figures are broken down by gender: female managers and professionals drink an average of 10.7 units (86\xa0g) a week, compared with 7.1 units (57\xa0g) a week for women in routine and manual groups (Goddard 2008).\n\nHowever, the adverse effects of alcohol are exacerbated among those from lower socioeconomic groups, as they are more likely to experience its negative consequences. (This is not necessarily as a result of drinking themselves, but can be due to other people's drinking.) In addition, factors such as a poor diet and a general lack of money mean that people in lower socioeconomic groups who do drink heavily cannot protect themselves as well as those in more affluent groups against the negative health and social consequences.\n\nCompared with those living in more affluent areas, people in the most deprived fifth of the country are:\n\ntwo to 3 times more likely to die of causes influenced, in part, by alcohol\n\nthree to 5 times more likely to die of an alcohol-specific cause\n\ntwo to 5 times more likely to be admitted to hospital because of an alcohol-use disorder (North West Public Health Observatory 2007).\n\n# Government policy\n\nSince 2004, the detrimental effects of alcohol-use disorders has resulted in several government policy initiatives. In addition, the need to prevent and reduce alcohol-use disorders has been incorporated into several public service agreements (PSAs). For examples, see the list below.\n\n'Alcohol harm reduction strategy for England' (Prime Minister's Strategy Unit 2004).\n\n'Choosing health: making healthy choices easier' (DH 2004).\n\n'PSA 14: increase the number of children and young people on the path to success' (HM Treasury 2007a).\n\n'PSA 23: make communities safer' (HM Treasury 2007b).\n\n'PSA 25: reduce the harm caused by alcohol and drugs' (HM Treasury 2007c).\n\n'Safe. Sensible. Social. The next steps in the national alcohol strategy' (DH 2007).\n\n'Youth alcohol action plan' (Department for Children, Schools and Families 2008).", 'Considerations': 'The Programme Development Group (PDG) took account of a number of factors and issues when developing the recommendations.\n\n# General\n\nThe PDG agreed that the state has a duty to look after the welfare of the population as a whole (Nuffield Council on Bioethics 2007). This includes protecting it from the range of problems that may be caused by alcohol. The PDG believes interventions to prevent alcohol-related harm are likely to improve the population\'s overall wellbeing and productivity. It also believes they will help reduce health inequalities, as alcohol-related problems have a disproprotionate effect on disadvantaged groups.\n\nThe PDG believes both population-wide and individual interventions are needed as part of a combined approach to reducing alcohol-related harm that will benefit society as a whole. Population-level approaches are very important because they can help reduce the aggregate level of alcohol consumed and therefore lower the whole population\'s risk of alcohol-related harm. They can help those not in regular contact with relevant services. They can also help reduce the number of people who start drinking harmful or hazardous amounts in the first place. In addition, they may help those who have been specifically advised to reduce their alcohol intake, by creating an environment that supports lower risk drinking.\n\nThe PDG acknowledges that some people drink alcohol as a result of underlying problems. Clearly, these need to be addressed along with any alcohol-related issues.\n\n# Risks and benefits\n\nThe PDG recognises that a large percentage (76%) of the population drinks alcohol at a level that is unlikely to cause risk to themselves or others. However, for others, alcohol is associated with many detrimental outcomes. In his 2008 annual report, the Chief Medical Officer highlighted that alcohol can affect not only the person drinking but those around them, including their families and the wider population. For example, each year, drinking adversely affects up to 1.3\xa0million children and leads to over 7,000 road accident injuries and 17\xa0million lost working days. It may also be a contributory factor in up to 1 million assaults and is associated with 125,000 instances of domestic violence (DH 2009). The PDG therefore believes that interventions to address alcohol-related harm should take these wider consequences into account.\n\nAlthough there is evidence that alcohol may reduce the risk of certain cardiovascular diseases, these effects are limited to men over the age of 40 and postmenopausal women who drink small amounts. Overall, the evidence suggests that drinking alcohol is never without risk and that, as consumption increases so does the risk of developing an alcohol-related problem. An increase in per capita alcohol consumption is associated with an increase in related deaths.\n\n# Population-wide interventions\n\nThe PDG believes that most of the recommendations will have a greater impact on those who drink irresponsibly. However, taken together, they are very likely to improve the health of the population as a whole. As indicated by the Rose hypothesis, a small reduction in risk among a large number of people may prevent many more cases, rather than treating a small number at higher risk. A whole-population approach explicitly focuses on changing everyone\'s exposure to risk (Rose 2008). In this instance, the number of people who drink a heavy or excessive amount in a given population is related to how much the whole population drinks on average. Thus, reducing the average drinking level, via population interventions, is likely to reduce the number of people with severe problems due to alcohol.\n\nThe PDG felt that a population-level approach to preventing alcohol-related harm could be as effective as legislation to address drink-driving had been. The latter was based on a much more limited evidence base than the proposals in these recommendations. In this case, there is extensive and consistent evidence in favour of a population-level approach on alcohol.\n\nThe PDG has not been able to consider all the population-wide actions needed to reduce alcohol-related harm. For example, it did not consider the provision of information on product labels and at the point-of-sale on the alcoholic content of drinks and the risks related to different levels of consumption. (This is in line with a proposed amendment to the Food Safety Act 1990 [Home Office 2009]). Other issues that have not been considered include: wider dissemination of information on alcohol units and related health information (for example, within the workplace); the provision of non-alcohol related activities for young people; and the introduction of mandatory conditions for the responsible sale of alcohol. The PDG feels that these are all important areas that need to be tackled, in conjunction with the recommendations made in this guidance.\n\n# Minimum price\n\nMaking alcohol less affordable is the most effective way of reducing the harm it causes among a population where hazardous drinking is common – such as in the UK (Chisholm et al. 2004). There is extensive evidence (within the published literature and from the economic analysis undertaken to support this guidance) to justify the introduction of a minimum price per unit. For example, the evidence suggests that young people who drink and people (including young people) who drink harmful amounts tend to choose cheaper alcoholic products. Establishing a minimum price per unit would limit the ability of these groups to \'trade down\' to cheaper products. The same effect would be more difficult to achieve through alcohol duties, as retailers or producers may absorb the cost of any extra duty levied.\n\nProhibiting \'below cost\' selling would ensure any price increases (for example, through taxation) are passed on in full. However, a large increase in duty would be needed to raise the price of the cheapest products to a level that would reduce alcohol harm. Unlike a minimum price per unit, this would affect all products equally rather than focusing on cheaper and stronger goods.\n\nA minimum price per unit (unlike a tax increase) would prevent retailers from passing on any increase to producers, or absorbing it themselves. It would also encourage producers to reduce the strength of products. As an example of the effect of minimum pricing, over a 10-year period it is estimated that a 50p minimum price per unit would reduce the cost of alcohol-related problems by £9.7\xa0bn.\n\nThe PDG is aware of concerns that introducing a minimum price per unit for alcohol would have an unfair impact on people who are from disadvantaged groups. The reality is, however, that alcohol problems are not evenly distributed throughout society. Evidence shows that people from disadvantaged groups experience more health problems than others as a result of their alcohol use. They are also affected more when others around them consume excessive amounts. The PDG concluded that the overall benefits of introducing and maintaining a minimum price for alcohol would far outweigh any perceived disadvantage to lower income groups.\n\nAlthough the introduction of a minimum price per unit of alcohol would prevent low cost promotions, it would not affect other types of alcohol promotion. The PDG, therefore, strongly supported the government\'s mandatory code on retailing which included a ban on irresponsible promotions.\n\nIntroducing a minimum price per unit of alcohol might lead to price promotions on other products that could, in turn, offset the impact of any alcohol price increases for many consumers. The PDG also noted that alcohol price increases are factored into the \'Retail prices index\' which, in turn, influences the index-linked increases in state benefits and allowances for lower income groups.\n\n# Availability\n\nInternational evidence suggests that making it less easy to buy alcohol, by reducing the number of outlets selling it in a given area and the days and hours when it can be sold, is an effective way of reducing alcohol-related harm. Changes to the current licensing provisions will enable members of licensing authorities to be an interested party. However, the Licensing Act does not, as it stands, cover public health considerations. Making this kind of change to the current licensing provisions may result in some initial implementation difficulties. However, the PDG believes that the long-term benefits would outweigh any immediate difficulties.\n\nThe PDG noted the recent legislative changes in Scotland, where the protection and improvement of the public\'s health has been included within the licensing objectives.\n\nIncreasing the price of alcohol, or reducing its accessibility, may lead to an increase in the amount of alcohol imported from abroad (both legal and illegal imports). The PDG considered that the current personal alcohol import allowance could undermine the introduction of a minimum price per unit for alcohol.\n\n# Advertising\n\nEvidence from a systematic review of 132 studies finds a clear and consistent relationship between advertising expenditure and alcohol consumption, across the whole population. However, the median effect is very small, possibly due to the limited variation in advertising expenditure, which restricts the range of effects that are available for analysis. A greater variation might have produced larger effects. There is limited evidence relating to a complete ban on advertising. However, there is evidence that bans on tobacco have had an impact on tobacco consumption and the PDG considered that this issue merited further consideration.\n\nThere is strong evidence that alcohol advertising affects children and young people. The data show that exposure to alcohol advertising is associated with the onset of drinking and increased consumption among young people who already drink.\n\nThe PDG is aware of the role of the Advertising Standards Authority (ASA) in monitoring the self-regulation code for alcohol advertising within the UK. It noted recent positive changes to the advertising code. It also noted the findings from a recent Ofcom and ASA report which assessed the impact of these changes. The report found that young people recalled fewer advertisements and were less likely to say that they were aimed at them. However, they were also more likely to say that the adverts made alcohol look appealing and would encourage people to drink.\n\nThe PDG recognised that a complete ban would be needed to fully protect children and young people from alcohol advertising. However, this strategy would also affect adults, for whom there is less evidence of an adverse impact. Hence the PDG concluded that there should be a cost-benefit assessment of the impact of an advertising ban. In the meantime, it felt there was potential for the appropriate bodies to strengthen current regulations. The Group believes that a balanced, realistic portrayal of alcohol by the media (illustrating the negative consequences of excessive alcohol consumption) would be a helpful move.\n\nThe PDG noted that product placement (a form of advertisement, where branded goods are placed within television programmes) may soon be allowed on commercial television. In view of the increase in health-related harms from alcohol in recent years, and the need to protect children from alcohol advertising, the PDG did not think it appropriate for alcohol to be included in this.\n\n# Commissioning\n\nThe PDG acknowledges the importance of \'World class commissioning\', \'Vital signs operating frameworks\' (VSOF) and commissioning strategic plans (CSP) when developing services. \'World class commissioning\' emphasises the importance of ensuring patients\' views are taken into account when making commissioing decisions.\n\nMany people attending health and other public and voluntary sector services will benefit from the recommendations on screening and brief alcohol interventions –not just those who are seeking treatment for alcohol-related problems. The benefits of using a brief intervention are most clearly seen when it is used with people who are unaware that alcohol is compromising their mental or physical wellbeing. This approach may also help those people who may be aware that their drinking is harming either themselves or others, but are ambivalent about cutting down. NICE is producing 2 complementary pieces of guidance which, in conjunction with this publication, will provide advice on how to support these groups.\n\nHealthcare professionals are well placed to identify and help people with alcohol-related problems. There is strong evidence to show that many people benefit from brief advice provided by healthcare professionals who are not alcohol specialists.\n\nThe PDG noted the benefits of local area agreements that identify and tackle the wider determinants of health within local communities.\n\nThe PDG acknowledges the important role of the voluntary sector in helping to deliver the recommendations made in this NICE guidance.\n\nResearch on alcohol screening and brief interventions in primary healthcare and emergency departments has not been widely replicated in other health or social care settings. Nevertheless, the PDG believes evidence from other areas (such as educational settings) clearly shows that it is worthwhile for healthcare professionals outside primary care – and non-healthcare professionals – to carry out these interventions. Many of those working in public services (such as social care, criminal justice, higher education, occupational health and children\'s services) have contact with people who are drinking a hazardous or harmful amount. The PDG believes these professionals are well-placed to help – and that many of their clients would benefit.\n\nThe PDG is aware of the importance of ensuring service delivery is coordinated (for screening, brief interventions and referrals) so that people can receive the appropriate level of care.\n\nWhere possible, the recommendations for practice refer to explicit and easily available intervention protocols. The aim has been to maintain standards by encouraging the use of interventions that have been evaluated and have been shown to be effective.\n\nA number of intervention packages offer a coordinated collection of evidence-based materials for use when screening and carrying out a brief intervention. They usually consist of:\n\na short guide on delivery\n\na screening questionnaire\n\nvisual material (clarifying the risks or harm caused by alcohol consumption and showing people how their drinking compares with the rest of the population)\n\npractical suggestions on how to reduce alcohol consumption\n\na self-help leaflet\n\nan optional poster for display in waiting rooms. An example is the \'Drink-less pack\', which was used and evaluated in the WHO series of studies on brief interventions (Centre for Drug and Alcohol Studies 1993). Another is the \'How much is too much?\' pack, which was based on the Drink-less pack but is specifically tailored for the UK (Institute of Health and Society 2006), and has been used by the DH for training.\n\nThe PDG acknowledges that public finances, especially NHS and local authority funding, may be subject to constraints. However, it concluded that the public sector savings realised in the long term by investing in alcohol misuse prevention and intervention will be significant.\n\n# Working with children and young people\n\nThe PDG noted that the Chief Medical Officer has called for an alcohol-free childhood up to the age of 15. Young people are particularly vulnerable to alcohol and the harm it causes, because they are still developing both physically and emotionally. They may also be drinking in unsupervised situations and in \'unsafe\' environments (parks and street corners) where problems are more likely to occur. The PDG noted that young people may have underlying problems which may cause them to drink alcohol and that these need to be addressed. For example, their behaviour in relation to alcohol may be indicative of underlying difficulties within the family, school or elsewhere.\n\nInevitably some children and young people will drink alcohol and the PDG felt it was necessary to provide guidance on how to help this group. While developing the recommendations, the PDG took into account other NICE guidance that addresses alcohol use among this age group.\n\nThe problems young people aged under 16 may face and their susceptibility to alcohol will vary greatly. For example, a young person aged 10 is different, both physically and emotionally, to someone aged 15. In addition, young girls and boys develop at a different rate (girls often experience puberty earlier than boys). Girls who drink at an earlier age may be more likely to take risks with their sexual health, while boys may be more likely to have accidents or experience a trauma. Thus, it takes professional judgement to decide how to deal with children and young people who drink early in life.\n\nThe PDG noted that, in keeping with Gillick and Fraser principles (see below) it is important for professionals to encourage vulnerable young people to include their parents or guardians in any professional intervention. It is also important that professionals are aware of child safeguarding, consent and confidentiality issues. It is likely that a proportion of young people will have intellectual or other developmental difficulties that will require parental or carer involvement.\n\nThe Gillick principle is: "As a matter of law the parental right to determine whether or not their minor child below the age of 16 will have medical treatment terminates if and when the child achieves sufficient understanding and intelligence to understand fully what is proposed" per Lord Scarman. In terms of determining the competence of a young person to consent to treatment, a clinician needs to apply the Fraser guidelines. These were laid down by Lord Fraser and require the professional to be satisfied that:\n\nthe young person will understand the professional\'s advice\n\nthe young person cannot be persuaded to inform their parents\n\nthe young person is likely to begin, or to continue having, sexual intercourse with or without contraceptive treatment\n\nunless the young person receives contraceptive treatment, their physical or mental health, or both, are likely to suffer\n\nthe young person\'s best interests require them to receive contraceptive advice or treatment with or without parental consent.\n\nAlthough the Fraser guidelines specifically refer to contraception, the principles are deemed to apply to other treatments. In addition, although the judgment in the House of Lords referred specifically to medical practitioners, it is considered to apply to other health professionals, including nurses.\n\nThe Advisory Council on the Misuse of Drugs (ACMD) \'Hidden harm\' report provides strong evidence of the impact of parental drug misuse on children and the steps required to address this. There has been no equivalent study of the impact of parental alcohol misuse on children (ACMD 2003).\n\n# Screening\n\nScreening is a systematic process of identifying people whose alcohol consumption places them at increased risk of physical, psychological or social problems and who would benefit from a preventive intervention. Questionnaire-based screening is accurate, minimally intrusive and has been found to be acceptable to recipients. It is also considerably cheaper than using physiological tests to detect alcohol-related problems (Wallace 2001).\n\nThe \'Alcohol-use disorders identification test\' (AUDIT) was the first screening tool designed specifically to detect hazardous and harmful drinking (Saunders et al. 1993). It has been validated in a number of health and social care settings and across a range of drinking cultures (Reinert and Allen 2007). This 10-question screening tool asks about drinking frequency and intensity and covers experience of alcohol-related problems and signs of possible dependence. AUDIT can detect 92% of genuinely hazardous and harmful drinkers and excludes 93% of those who are not. It is regarded as the \'gold standard\' screening questionnaire for detecting hazardous and harmful drinking.\n\n\'Hazardous\' and \'harmful\' drinking are medically defined terms that have been used extensively in the scientific literature and in many recommended tools. \'Harmful use of a psychoactive substance\' is an official term in the World Health Organization\'s (WHO) \'International classification of diseases\' (10th revision). \'Hazardous use of a psychoactive substance\', while not an alcohol-use disorder in itself, is included in WHO\'s \'Lexicon of alcohol and drug terms\' (1994). It is also useful to define drinking behaviour in terms of the types of risk associated with it. The DH has recently used the terms lower risk, increasing risk and higher risk drinking. This unit-based approach complements the medically-defined terms described above. For the purposes of this guidance, \'increasing risk\' equates with \'hazardous drinking\' and \'higher risk\' equates with \'harmful drinking\'. In addition, categories of risk in relation to alcohol consumption may be defined by scores used in the \'Alcohol use disorders identification test\' (AUDIT). These are as follows: 1–7: low-risk drinking; 8–15: hazardous drinking; 16–19: harmful drinking; 20+: possible dependence. For simplicity and convenience, the terms \'hazardous\' and \'harmful\' are used in this guidance (Room et al. 2005).\n\nEven with just 10 questions, the full AUDIT questionnaire has been considered too lengthy for use in routine practice. Thus several shorter versions of AUDIT have been developed. These comprise between 1 and 4 questions. Generally, they are less accurate than the full AUDIT and do not clearly differentiate between hazardous, harmful and possibly dependent drinking.\n\nDifferent factors may make some people more vulnerable to alcohol than others and this can affect the precision of some screening tools. These factors can include lower body weight, inexperience in handling the psychological effects of alcohol being less able to metabolise it or being more susceptible to its adverse effects.\n\nWomen are more vulnerable to the effects of alcohol than men and younger and older people tend to be more vulnerable than those who are middle-aged. In addition, some black and minority ethnic groups are less able to metabolise alcohol than caucasians. In such cases, lower cut-off points on screening tools may need to be applied.\n\nReducing the cut-off point on a screening tool will increase its sensitivity (that is, the ability to identify truly positive cases of hazardous or harmful drinking). However, this can be at the expense of specificity (the ability to accurately exclude those who are not drinking a hazardous or harmful amount). Thus, professional judgement may be needed before screening cut-off points can be altered. It is for this reason that the PDG has not recommended specific (lowered) cut-off points on various screening tools.\n\nProfessional judgement is needed to decide on any additional support that should be offered to vulnerable groups who are identified as being hazardous or harmful drinkers. This includes:\n\nwomen (in particular those who are, or are thinking of becoming, pregnant)\n\nyounger people\n\npeople aged 65 and over\n\npeople from some black and minority ethnic groups.\n\nThe PDG recognises that a language-based screening questionnaire may not be the most appropriate tool for certain groups. This includes those whose first language is not English and people with learning disabilities or cognitive impairment. How best to establish whether people in these groups are at risk from alcohol or are experiencing alcohol-related harm will be a matter of professional judgement.\n\n# Brief interventions\n\nThere are 2 main types of brief intervention: structured brief advice or extended brief intervention. Nearly all of the latter are based on the principles and practice of \'motivational interviewing\' (Miller and Rollnick 2002).\n\nEvidence shows that brief advice is effective where time is tight – even when there is only 5 minutes available. The evidence is mixed on the additional benefit of providing extended brief interventions in healthcare settings. Thus brief advice is recommended as a first step for adults (aged 18 and over) who have been identified as drinking at hazardous or harmful levels. If brief advice does not lead to a reduction in hazardous or harmful drinking (or if an individuals wishes further input) then an extended brief intervention, including motivational interviewing, has been recommended (see recommendations 8 and 11).\n\nMost extended brief interventions that have been evaluated in research are short versions of motivational interviewing. Examples include the \'Drinker\'s check-up\' (Miller et al. 1988), consisting of 1 assessment session and 1 feedback and counselling session. Another example is \'motivational enhancement therapy\', which was developed as a four-session intervention in \'Project MATCH\' in the USA (Miller et al. 1992). It was then adapted as a three-session intervention in the \'United Kingdom alcohol treatment trial\' (UKATT Research Team 2005).\n\nSome extended brief interventions, perhaps consisting of a single session lasting 30–40 minutes, are based on motivational interviewing principles but would not qualify as full motivational interviewing.\n\nWhile the distinctions between motivationally-based interventions should be borne in mind, for the purposes of this guidance, all motivationally-based interventions are referred to as extended brief interventions.\n\nThere is limited evidence on the effectiveness of brief interventions for young people under the age of 16, with some data suggesting there could be adverse outcomes. Most of the research has been carried out among adults in healthcare settings. However, there is broadly positive evidence from educational settings (such as colleges and universities). Generally, the interventions have taken the form of motivational interviews with young people aged over 16. As a result, the PDG has recommended the use of extended brief interventions for people aged 16–17. However, it is not clear from current evidence if this type of brief intervention can be adapted for younger people.\n\nIn motivational interviewing, the practitioner establishes the client\'s readiness to change and it helps them to make their own decisions with regard to their alcohol use. Some young people may not have the language skills to partake in a motivational interview. In addition, it may not be appropriate to emphasise to those who may need external direction and indeed, safeguarding, that they have a choice. For more mature young people (that is, those who are \'Gillick-competent\'), however, the PDG judges that it is appropriate to extrapolate the evidence from educational settings to health and social care settings, especially as part of a response to meeting their identified needs. But as noted elsewhere, intervening with those below 16 years generally requires efforts to include parents or carers.\n\n# Referral\n\nA brief intervention will address many people\'s alcohol-related problems. However, those who are moderately or severely alcohol-dependent are likely to need specialist help. This is also true of people who experience physical harm, such as liver damage or mental health problems, as a result of drinking alcohol. In such cases, the recommendations in this guidance should be read in conjunction with 2 complementary pieces of NICE guidance: \'Alcohol use disorders in adults and young people: clinical management\' and \'Alcohol-use disorders: diagnosis, assessment and management in young people and adults\'.\n\n# Evaluation\n\nThe PDG recognises that its recommendation to carry out formal evaluations (see recommendation 5) and routine follow-ups of alcohol interventions will change established commissioning practice. Commissioning bodies may seek partnerships with academic institutions to help design evaluation protocols. It may also be that government will provide guidance on minimum standards for comprehensive, routine evaluation and research into local alcohol treatment systems. Although some aspects of evaluation may be cost neutral, robust evaluation and research will need specified resources. However, the PDG takes the view that evaluation will be essential in ensuring value for money in reconfigured local alcohol treatment systems.\n\n# Interpreting the evidence\n\nThe PDG recognised that empirical data alone, even from the best conducted investigation, seldom provides a sufficient basis for making recommendations. This data requires interpretation and analysis, using prior knowledge and understanding and existing models and theories. Therefore, the PDG developed its recommendations using the best available empirical data and inductive and deductive reasoning.\n\nThe PDG acknowledged that the traditional hierarchy of evidence does not resolve all the problems associated with empirical data. For example, while it explicates the degree of bias attributable to poor internal validity, it does not answer it completely. Nor does it deal with external validity, that is, the degree to which findings are transferable to other experimental settings or to practice. The PDG therefore looked at a broad range of evidence.', 'Recommendations for research': "The PDG recommends that the following research questions should be addressed. It notes that 'effectiveness' in this context relates not only to the size of the effect, but also to cost effectiveness and duration of effect. It also takes into account any harmful or negative side effects.\n\nHow does advertising by industry and health agencies affect the drinking behaviour of the population as whole? (This includes the use of new media.)\n\n. What is the effect on alcohol consumption of combining different policies on price, promotion and availability?\n\n. Which screening tool should be considered as the 'gold standard' for assessing the drinking behaviour of those under the age of 18?\n\n. Are brief interventions effective and cost effective in reducing alcohol use among various subgroups of the population, such as:\n\nthose under 16 and over 65\n\npeople from some black and minority ethnic groups\n\npregnant women attending antenatal care?\n\n. Are screening and brief alcohol interventions effective and cost-effective in:\n\nmedical settings outside primary care and emergency departments (for example, in district hospitals or mental health settings)\n\nnon-medical settings (for example, on criminal justice or social services premises, in pharmacies or in the workplace)\n\nvoluntary sector organisations?\n\n. What factors (conditions and components) ensure a brief intervention is effective in promoting low-risk alcohol consumption?\n\n. To what extent are local services responding to the needs of children affected either by parental alcohol misuse or their own drinking – and which interventions are effective in helping these families?\n\n. More detail on the gaps in the evidence identified during development of this guidance is provided in appendix D.", 'Glossary': "# Alcohol dependence\n\nA cluster of behavioural, cognitive and physiological factors that typically include a strong desire to drink alcohol and difficulties in controlling its use. Someone who is alcohol-dependent may persist in drinking, despite harmful consequences. They will also give alcohol a higher priority than other activities and obligations. For further information, please refer to: 'Diagnostic and statistical manual of mental disorders' (DSM-IV) (American Psychiatric Association 2000) and 'International statistical classification of diseases and related health problems – 10th revision' (ICD-10) (World Health Organization 2007).\n\n# Alcohol-related harm\n\nPhysical or mental harm caused either entirely or partly by alcohol. If it is entirely as a result of alcohol, it is known as 'alcohol-specific'. If it is only partly caused by alcohol it is described as 'alcohol-attributable'.\n\n# Alcohol-use disorders\n\nAlcohol-use disorders cover a wide range of mental health problems as recognised within the international disease classification systems (ICD-10, DSM-IV). These include hazardous and harmful drinking and alcohol dependence. See 'Harmful' and 'Hazardous' drinking and 'Alcohol dependence'.\n\n# Alcohol-use disorders identification test (AUDIT)\n\nAUDIT is an alcohol screening test designed to see if people are drinking harmful or hazardous amounts of alcohol. It can also be used to identify people who warrant further diagnostic tests for alcohol dependence.\n\n# Binge drinking\n\nA heavy drinking session in which someone drinks a lot of alcohol in a short period of time raising their risk of harm on that occasion.\n\nThe Chief Medical Officer recommends lowering the level of alcohol consumption on a single occasion to avoid short-term risks (risk of injuries, losing control or misjudging risky situations).\n\nThe risks increase in people who drink within recommended levels of regular drinking (less than 14 units/week for men and women) but drink in a single occasion or too quickly or with higher levels of alcohol consumption (Alcohol Guidelines Review – Report from the Guidelines Development Group to the UK Chief Medical Officers and Health Survey for England 2015: adult alcohol consumption.\n\n# Brief intervention\n\nThis can comprise either a short session of structured brief advice or a longer, more motivationally-based session (that is, an extended brief intervention – see also below). Both aim to help someone reduce their alcohol consumption (sometimes even to abstain) and can be carried out by non-alcohol specialists.\n\n# Clinical management of people with alcohol-related disorders\n\nAny pharmacological or psychosocial intervention carried out by a clinician to manage the clinical problems caused by alcohol or any related medical or psychiatric complications. For example, support to help with withdrawal, managing liver damage and treating conditions such as Wernicke's encephalopathy.\n\n# Commissioning\n\nPrimary care trusts (PCTs) and drug and alcohol action teams (DAATs) may commission alcohol support services from a range of 'providers'. This includes GPs, hospitals, mental health trusts and voluntary and private organisations.\n\n# Dependence\n\nSee alcohol dependence.\n\n# Extended brief intervention\n\nThis is motivationally-based and can take the form of motivational-enhancement therapy or motivational interviewing. The aim is to motivate people to change their behaviour by exploring with them why they behave the way they do and identifying positive reasons for making change. In this guidance, all motivationally-based interventions are referred to as 'extended brief interventions'.\n\n# FRAMES\n\nFRAMES is an acronym summarising the components of a brief intervention. Feedback (on the client's risk of having alcohol problems), responsibility (change is the client's responsibility), advice (provision of clear advice when requested), menu (what are the options for change?), empathy (an approach that is warm, reflective and understanding) and self-efficacy (optimism about the behaviour change).\n\n# Harmful drinking (high-risk drinking)\n\nA pattern of alcohol consumption that is causing mental or physical damage (ICD-10, DSM-V).\n\nConsumption (units per week): Drinking 35 units a week or more for women. Drinking 50 units a week or more for men.\n\n# Hazardous drinking (increasing risk drinking)\n\nA pattern of alcohol consumption that increases someone's risk of harm. Some would limit this definition to the physical or mental health consequences (as in harmful use). Others would include the social consequences. The term is currently used by the World Health Organization to describe this pattern of alcohol consumption. It is not a diagnostic term.\n\nConsumption (units per week): Drinking more than 14 units a week, but less than 35 units a week for women. Drinking more than 14 units a week, but less than 50 units for men (Health Survey for England 2015: adult alcohol consumption).\n\n# Higher-risk drinking\n\nRegularly consuming over 50 alcohol units per week (adult men) or over 35 units per week (adult women).\n\n# Looked after children\n\nThe term 'looked after' has a specific legal meaning. It refers to children and young people who are provided with accommodation on a voluntary basis for more than 24 hours. This compares with the term 'in care' which refers to those who are compulsorily removed from home and placed in care under a court order.\n\n# Lower-risk drinking\n\nTo keep the risk of harm from alcohol low, the UK Chief Medical Officer advises that men and women should not regularly drink more than 14 units of alcohol per week. It is also recommended that if the alcohol consumption is as much as 14 units per week, it should be spread evenly over 3 or more days (Alcohol Guidelines Review – Report from the Guidelines Development Group to the UK Chief Medical Officers ). See 'Unit'.\n\n# Responsible authority\n\nResponsible authorities have to be notified of all licence variations and new applications and can make representations regarding them. The Licensing Act 2003 lists responsible authorities. They include the police, environmental health and child protection services, fire and rescue and trading standards.\n\n# Saturated (in relation to licensed premises)\n\nDescribes a specific geographical area where there are already a lot of premises selling alcohol – and where the awarding of any new licences to sell alcohol may contribute to an increase in alcohol-related disorder.\n\n# Screening\n\nFor the purposes of this guidance, screening involves identifying people who are not seeking treatment for alcohol problems but who may have an alcohol-use disorder. Practitioners may use any contact with clients to carry out this type of screening. The term is not used here to refer to national screening programmes such as those recommended by the UK National Screening Committee (UK NSC).\n\n# Structured brief advice\n\nA brief intervention that takes only a few minutes to deliver.\n\n# Treatment\n\nA programme designed to reduce alcohol consumption or any related problems. It could involve a combination of counselling and medicinal solutions.\n\n# UK government drinking guidelines\n\nGuidelines set by the UK government on how much alcohol may be consumed without a serious impact on health. To keep the risk of harm from alcohol low, the UK Chief Medical Officer advises that men and women should not regularly drink more than 14 units of alcohol per week. It is also recommended that if the alcohol consumption is as much as 14 units per week, to spread it evenly over 3 or more days. See 'Unit'.\n\n# Unit\n\nIn the UK, alcoholic drinks are measured in units. Each unit corresponds to approximately 8\xa0g or 10\xa0ml of ethanol. The same volume of similar types of alcohol (for example, 2 pints of lager) can comprise a different number of units depending on the drink's strength (that is, its percentage concentration of alcohol).", 'References': "Advisory Council on the Misuse of Drugs (2003) Hidden harm – responding to the needs of children of problem drug users. London: The Home Office\n\nBhala N, Bhopal R, Brock A et al. (2009) Alcohol-related and hepatocellular cancer deaths by country of birth in England and Wales: analysis of mortality and census data. Journal of Public Health 31: 250–7\n\nBooth A, Meier P, Stockwell T (2008) Independent review of the effects of alcohol pricing and promotion. Part A: systematic reviews. Sheffield: School of Health and Related Research\n\nBritish Medical Association Board of Science (2007) Fetal alcohol spectrum disorders – a guide for health professionals. London: British Medical Association\n\nCentre for Drug and Alcohol Studies (1993) The drink-less programme. Sydney: Sydney University\n\nChisholm D, Rehm J, Van Ommeren M et al. (2004) Reducing the global burden of hazardous alcohol use: a comparative cost-effectiveness analysis. Journal of Studies on Alcohol 65: 782–93\n\nDepartment for Children, Families and Schools; Home Office; Department of Health (2008) Youth alcohol action plan. London: The Stationery Office\n\nDepartment for Children, Families and Schools (2009) Consultation on children, young people and alcohol. London: Department for Children, Families and Schools\n\nDepartment of Health (2004) Choosing health: making healthy choices easier. London: Department of Health\n\nDepartment of Health (2007) Safe. Sensible. Social. The next steps in the national alcohol strategy. London: Department of Health\n\nDepartment of Health (2008a) Safe, sensible, social – consultation on further action. London: Department of Health\n\nDepartment of Health (2008b) The cost of alcohol harm to the NHS in England: An update to the Cabinet Office (2003) study. London: Department of Health\n\nDepartment of Health (2009) 150 years of the annual report of the Chief Medical Officer: on the state of public health 2008. London: Department of Health\n\nDiment E, Harris J, Jotangia D et al. (2009) Smoking, drinking and drug use among young people in England in 2008. London: The Health and Social Care Information Centre\n\nGoddard E (2008) General household survey 2006: smoking and drinking among adults. London: Office for National Statistics\n\nHM Revenue and Customs (2008) Alcohol factsheet\n\nHM Treasury (2007a) PSA delivery agreement 14: increase the number of children and young people on the path to success. London: The Stationery Office\n\nHM Treasury (2007b) PSA delivery agreement 23: make communities safer. London: The Stationery Office\n\nHM Treasury (2007c) PSA delivery agreement 25: reduce the harm caused by alcohol and drugs. London: The Stationery Office\n\nHome Office (2009) Safe. Sensible. Social. Selling alcohol responsibly: a consultation on the new code of practice for alcohol retailers. London: Home Office\n\nInstitute of Health and Society (2006) How much is too much? Newcastle: Newcastle University\n\nJones L, Bellis M, Dedham D et al. (2008) Alcohol attributable fractions for England: alcohol attributable mortality and hospital admissions. Liverpool: North West Public Health Observatory\n\nMiller WR, Rollnick S (2002) Motivational interviewing: preparing people to change addictive behaviour. New York: The Guilford Press\n\nMiller WR, Sovereign RG, Krege B (1988) Motivational interviewing with problem drinkers: II. The drinkers check-up as a preventive intervention. Behavioural Psychotherapy 16: 251–68\n\nMiller WR, Zweben A, DiClemente C et al. (1992) Motivational enhancement therapy: a clinical research guide for therapists treating individuals with alcohol abuse and dependence. Project MATCH monograph series 2: 92–1894\n\nNorth West Public Health Observatory (2007) Indications of public health in the English Regions 8: alcohol. Liverpool: Association of Public Health Observatories\n\nNuffield Council on Bioethics (2007) Public health: ethical issues. Cambridge: Cambridge Publishers Ltd\n\nOrford J, Natera G, Copello A et al. (2005) Coping with alcohol and drug problems: The experiences of family members in three contrasting cultures. London: Taylor and Francis\n\nPrime Minister's Strategy Unit (2003) Strategy unit alcohol harm reduction project: interim analytical report. London: Cabinet Office\n\nPrime Minister's Strategy Unit (2004) Alcohol harm reduction strategy for England. London: Cabinet Office\n\nRehm J, Baliunas D, Borges GLG et al. (2010) The relation between different dimensions of alcohol consumption and burden of disease – an overview. Addiction (in press)\n\nReinert D, Allen J (2007) The alcohol use disorders identification test: an update of research findings. Alcoholism: Clinical and Experimental Research 31 (2):185–99\n\nRobinson S, Lader D (2009) General household survey 2007: smoking and drinking among adults. London: Office for National Statistics\n\nRoom R, Babor T, Rehm J (2005) Alcohol and public health. Lancet 365: 519–30\n\nRose G (2008) Rose's strategy of preventive medicine. The complete original text. Commentary by Khaw KT, Marmot M. Oxford: Oxford University Press\n\nSaunders JB, Aasland OG, Babor TF et al. (1993) Development of the alcohol use disorders identification test (AUDIT): WHO collaborative project on early detection of persons with harmful alcohol consumption II. Addiction 88 (6): 791–804\n\nThe NHS Information Centre (2009) Statistics on alcohol: England. Leeds: The Health and Social Care Information Centre\n\nThe NHS Information Centre (2010) Smoking, drinking and drug use among young people in England. Findings by region, 2006 to 2008. Leeds: The Health and Social Care Information Centre\n\nUKATT Research Team (2005) Effectiveness of treatment for alcohol problems: findings of the randomised UK alcohol treatment trial (UKATT). British Medical Journal 311: 541–4\n\nWallace P (2001) Patients with alcohol problems – simple questioning is the key to effective identification and management. British Journal of General Practice 51: 172–3\n\nWorld Health Organization (1994) Lexicon of alcohol and drug terms", 'Appendix B Summary of the methods used to develop this guidance': "# Introduction\n\nThe reviews and economic analysis include full details of the methods used to select the evidence (including search strategies), assess its quality and summarise it.\n\nThe minutes of the PDG meetings provide further detail about the Group's interpretation of the evidence and development of the recommendations.\n\nAll supporting documents are listed in appendix E.\n\n# Key questions\n\nThe key questions were established as part of the scope. They formed the starting point for the reviews of evidence and were used by the PDG to help develop the recommendations. The primary questions were:\n\nQuestion 1: What type of price controls are effective and cost effective in reducing alcohol consumption, alcohol misuse, alcohol-related harm or alcohol-related social problems among adults and young people?\n\nQuestion 2: Which interventions are effective and cost effective at managing alcohol availability to reduce levels of consumption, alcohol misuse, alcohol-related harm or alcohol-related social problems among adults and young people?\n\nQuestion 3: Is the control of alcohol promotion (for example, advertising) effective and cost effective in reducing levels of consumption, alcohol misuse, alcohol-related harm or alcohol-related social problems among adults and young people?\n\nQuestion 4: What are the key factors that increase the risk of an individual misusing alcohol? When are individuals most vulnerable to alcohol misuse?\n\nQuestion 5: Are alcohol screening questionnaires, biochemical markers or clinical indicators (for example, hypertension, dilated facial capillaries) an effective and cost effective way of identifying adults and young people who currently misuse – or are at risk of misusing – alcohol?\n\nQuestion 6: Are brief interventions effective and cost effective in managing hazardous and harmful drinking among adults and young people?\n\nQuestion 7: What are the key barriers to helping adults and young people manage their drinking behaviour (for example, is access to services a problem)? What are the key facilitators?\n\nThese questions were made more specific for each review (see reviews for further details).\n\n# Reviewing the evidence of effectiveness\n\nTwo reviews of effectiveness were conducted.\n\n## Identifying the evidence\n\nRelevant literature was identified using an iterative search process. Study types and years were not predefined. The following databases were searched.\n\nASSIA (Applied Social Science Index and Abstracts)\n\nCochrane Library (Cochrane database of systematic reviews, Database of abstracts of reviews of effects, Health technology assessment and Cochrane-controlled trials register)\n\nEconLit\n\nMEDLINE (including MEDLINE in process)\n\nNHS Economic Evaluation Database (NHS EED)\n\nSocial Science Citation Index\n\nAdditional searches (non-systematic) were carried out on the following websites:\n\nAlcohol and Education Research Council\n\nAlcohol Concern\n\nAssociation of Public Health Observatories\n\nDepartment for Digital, Culture, Media and Sport\n\nDepartment of Health and Social Care\n\nHome Office\n\nNICE\n\nNational Treatment Agency\n\nPortman Group\n\n## Selection criteria\n\nStudies were included in the effectiveness reviews if:\n\npeople of a range of ages were involved\n\ninterventions were relevant to the key questions set out in the reviews\n\noutcomes such as alcohol consumption, alcohol misuse, alcohol-related harm, social problems, costs and economic impact were reported.\n\nStudies were excluded if:\n\nthey were not published in English\n\nthe study population was below the age of 10 years\n\nthe evidence did not originate in economically developed countries (that is, if it did not come from countries that are members of the Organisation for Economic Cooperation and Development [OECD]).\n\n## Quality appraisal\n\nIncluded papers were assessed for methodological rigour and quality using the NICE methodology checklist, as set out in the NICE technical manual 'Methods for the development of NICE public health guidance' (see appendix E). Each study was graded (++, +, –) to reflect the risk of potential bias arising from its design and execution.\n\n++ All or most of the methodology checklist criteria have been fulfilled. Where they have not been fulfilled, the conclusions are thought very unlikely to alter.\n\n+ Some of the methodology checklist criteria have been fulfilled. Those criteria that have not been fulfilled or not adequately described are thought unlikely to alter the conclusions.\n\n– Few or no methodology checklist criteria have been fulfilled. The conclusions of the study are thought likely or very likely to alter.\n\n## Summarising the evidence and making evidence statements\n\nThe review data was summarised in evidence tables (see full reviews).\n\nThe findings from the reviews were synthesised and used as the basis for a number of evidence statements relating to each key question. The evidence statements were prepared by the public health collaborating centre (see appendix A). The statements reflect the collaborating centre's judgement of the strength (quantity, type and quality) of evidence and its applicability to the populations and settings in the scope.\n\n# Economic analysis\n\nThe economic analysis consisted of 2 cost effectiveness reviews and an economic modelling report .\n\n## Review of economic evaluations\n\nThe following databases were searched for economic literature, in addition to the searches carried out for the effectiveness reviews:\n\nEconLIT\n\nNHS Economic Evaluation Database (NHS EED).\n\nStudies were included if:\n\nthey addressed key questions 1, 2, 3, 5 and 6\n\nthey were from peer-reviewed journals published in English\n\nthe study population involved a range of ages (10+ years)\n\nthey were carried out in OECD countries.\n\n## Economic modelling report\n\nA number of assumptions were made which could underestimate or overestimate the cost effectiveness of the interventions (see review modelling report for further details).\n\nAn economic model was constructed to incorporate data from the reviews of effectiveness and cost effectiveness. The results are reported in the economic modelling report – Modelling to assess the effectiveness and cost-effectiveness of public health-related strategies and interventions to reduce alcohol attributable harm in England using the Sheffield alcohol policy model version 2.0.\n\n# Fieldwork\n\nFieldwork was carried out to evaluate how relevant and useful NICE's recommendations are and how feasible it would be to put them into practice. It was conducted with commissioners, practitioners and other interested parties who are involved in alcohol services in the NHS, local authorities and the private, voluntary and community sectors. They included: policy makers, applied researchers, economists, trading standards, representatives of licensing boards, retailers and the alcohol industry, and representatives from criminal justice and social welfare.\n\nThe fieldwork comprised:\n\nfive meetings in Birmingham, Bristol, Leicester, Liverpool and London conducted by Liverpool John Moores University with policy makers, commissioners, industry representatives and practitioners\n\nan online survey of professionals (14) who could not attend the fieldwork meetings.\n\nThe fieldwork meetings and online survey were commissioned to ensure there was ample geographical coverage. The main issues arising are set out in appendix C under fieldwork findings. Also see the fieldwork report – Alcohol-use disorders: preventing the development of hazardous or harmful drinking.\n\n# How the PDG formulated the recommendations\n\nAt its meeting in July 2009, the PDG considered the evidence of effectiveness and cost effectiveness to determine:\n\nwhether there was sufficient evidence (in terms of quantity, quality and applicability) to form a judgement\n\nwhether, on balance, the evidence demonstrates that the intervention is effective, ineffective or equivocal\n\nwhere there is an effect, the typical size of effect.\n\nThe PDG developed draft recommendations through informal consensus, based on the following criteria:\n\nStrength (quality and quantity) of evidence of effectiveness and its applicability to the populations/settings referred to in the scope.\n\nEffect size and potential impact on the target population's health.\n\nImpact on inequalities in health between different groups of the population.\n\nCost effectiveness (for the NHS and other public sector organisations).\n\nBalance of risks and benefits.\n\nEase of implementation and any anticipated changes in practice.\n\nThe PDG noted that effectiveness can vary according to the context. For example, it depends on the enforcement of different regulatory regimes.\n\nWhere possible, recommendations were linked to an evidence statement(s) (see appendix C for details). Where a recommendation was inferred from the evidence, this was indicated by the reference 'IDE' (inference derived from the evidence).\n\nThe draft guidance, including the recommendations, was released for consultation in September 2009. At its meeting in December 2009, the PDG amended the guidance in light of comments from stakeholders and experts and the fieldwork. The guidance was signed off by the NICE Guidance Executive in March 2009.", 'Appendix C: The evidence': "This appendix lists the evidence statements from 4 reviews (2 effectiveness reviews and 2 cost-effectiveness reviews) and the economic modelling report provided by the public health collaborating centre (see appendix A). (See appendix B for the key to quality assessments.)\n\nThe evidence statements are presented here without references – these can be found in the full reviews (see appendix E for details). It also sets out a brief summary of findings from the economic analysis.\n\nThe 2 effectiveness reviews, 2 cost-effectiveness reviews and economic modelling report are:\n\nEffectiveness reviews:\n\n\n\nReview 1: 'Interventions on control of alcohol price, promotion and availability for prevention of alcohol-use disorders in adults and young people'\n\nReview 2: 'Screening and brief interventions for prevention and early identification of alcohol-use disorders in adults and young people'.\n\n\n\nEconomic analysis:\n\n\n\nReview 3: 'Prevention and early identification of alcohol-use disorders in adults and young people. Macro-level interventions for alcohol-use disorders: cost-effectiveness review'\n\nReview 4: 'Prevention and early identification of alcohol-use disorders in adults and young people. Screening and brief interventions: Cost-effectiveness review'\n\nEconomic modelling report: 'Modelling to assess the effectiveness and cost effectiveness of public health-related strategies and interventions to reduce alcohol attributable harm in England using the Sheffield alcohol policy model version 2.0'.\n\n\n\nEvidence statements numbered 1.1 to 3.8 are from review 1. Evidence statements numbered 5.1 to 7.7 are from review 2. Evidence statements numbered e1.1 to e2.3 are from review 3. Evidence statements numbered e5.1 to e6.2 are from review 4. Modelling statements numbered M1 to M50 are from the economic modelling report.\n\nWhere a recommendation is not directly taken from the evidence statements, but is inferred from the evidence, this is indicated by IDE (inference derived from the evidence).\n\nRecommendation 1: evidence statements 1.1, 1.2, 1.3, 1.4, 2.27, 2.30, e1.1; modelling statements M12, M21, M22, M23, M24, M26, M27, M29, M34, M35, M36, M37\n\nRecommendation 2: evidence statements 2.19, 2.20, 2.21, 2.22, 2.24, 2.25, e.2.3; modelling statements M51, M55, IDE\n\nRecommendation 3: evidence statements 3.1, 3.2, 3.3, 3.4, 3.6, 3.7, 3.8\n\nRecommendation 4: evidence statements 2.4, 2.5, 2.8, 2.9, 2.19, 2.20, 2.21, 2.22, 2.24, 2.25\n\nRecommendation 5: evidence statements 7.1, 7.2, 7.6\n\nRecommendation 6: IDE\n\nRecommendation 7: evidence statements 5.7, 5.9; IDE\n\nRecommendation 8: evidence statements 5.1, 5.2, 5.5, 5.6, 5.7, 5.9, 5.10, 5.11, 7.3, 7.4, 7.5, 7.7, e5.1; modelling statements M2, M3\n\nRecommendation 9: evidence statements 6.1, 6.2, 6.3, 6.4, 6.10, 7.3, e6.1, e6.2; modelling statement M6; IDE\n\nRecommendation 10: evidence statement 6.11; modelling statement M6\n\nRecommendation 11: IDE\n\n# Evidence statements\n\nPlease note that the wording of some evidence statements has been altered slightly from those in the review team's report to make them more consistent with each other and NICE's standard house style.\n\n## Evidence statement 1.1\n\nA comprehensive systematic review was identified that demonstrated a clear association between price/tax increases and reductions in consumer demand for alcohol (++). These conclusions were based on 2 rigorous meta-analyses of price elasticities. Further evidence was supportive of a negative relationship between the price of alcohol and alcohol consumption among young people (1 UK and 1 USA [not graded]). A positive relationship between alcohol affordability and alcohol consumption operating across the European Union was identified (1 EU).\n\n## Evidence statement 1.2\n\nA systematic review reported that there is some evidence that young people, binge drinkers and harmful drinkers tend to show a preference for cheaper drinks (++).\n\n## Evidence statement 1.3\n\nA limited evidence base was identified that indicated that minimum pricing may be effective in reducing alcohol consumption (1 [++] and 1 UK [not graded]). Consulted members of the community were supportive of such measures (1 [++]).\n\n## Evidence statement 1.4\n\nAn evidence base comprising a large number of primary studies was identified that demonstrated a relationship between price/tax increases and reductions in harms (1 [++] systematic review). Additional evidence indicates that decreases in the price of alcohol contribute towards increases in alcohol-related deaths, particularly in deaths attributable to chronic causes such as alcoholic liver disease (1 [++] Finland). Population groups specifically affected included the older population, the unemployed and individuals with lower levels of education, social class and income (1 [++] Finland). However, the same authors observed no increase in interpersonal violence rates following the decrease in alcohol prices (1 [++] Finland). A time series analysis demonstrated that increases in tax were associated with decreases in alcohol-related disease mortality (1 [++] USA).\n\n## Evidence statement 2.4\n\nEvidence was identified demonstrating that serving staff in alcohol outlets were disapproving of under-age sales (1 [+] USA) and generally positive of implementing under-age checks, including electronic age-verification devices (1 [++] USA).\n\n## Evidence statement 2.5\n\nThe commitment of managers and licensees towards their legal responsibilities relating to under-age sales was variable (1 [+] UK and 1 [+] USA).\n\n## Evidence statement 2.8\n\nThe effectiveness of enforcement checks in reducing alcohol sales to under-age young people was variable (1 [+] systematic review). Compliance checks conducted by local police were not effective in reducing arrests in those aged under 18 years or reducing under-age sales (1 [+] and 1 [++]) in the UK. Other studies showed favourable outcomes of compliance checks by local authorities in reducing under-age alcohol sales (2 [+] USA, 1 [++] USA and 1 USA [not graded]). Checks enforced with a 30-day licence suspension or a fine were effective in reducing sales (1 [+] USA). However, the deterrent effect of enforcement was found to decay over time (1 [+] USA and 1 USA [not graded]). Additional UK-specific evidence demonstrated that enforcement of laws relating to under-age sales supported by a local multi-agency community alcohol partnership, helped reduce possession of alcohol and antisocial behaviour and improved the relationship between enforcers and retailers.\n\n## Evidence statement 2.9\n\nA study based in Fife, Scotland indicated that on- and off-licensees perceived the most effective approach to preventing under-age sales to be test purchasing carried out in conjunction with a new, nationally-accepted proof-of-age card.\n\n## Evidence statement 2.19\n\nOther UK-specific studies of the effects of changes in licensing hours presented mixed findings, with some studies reporting no apparent effects on alcohol-related outcomes (2 [++] UK). However, following the extension of licensing hours, 1 (+) UK study reported an increase in admissions for self-poisoning by overdose in which alcohol was also involved. Another UK study found increases in the occurrence of slight accidents in the workplace.\n\n## Evidence statement 2.20\n\nExtensions in trading hours in Australia were typically associated with increased violence (1 [++]), motor vehicle crash rates (1 [++]) and an increase in the apprehension of impaired male drivers aged 18 to 25 years (1 [++]). Local community restrictions on alcohol availability were found to have modestly favourable outcomes, including reductions in alcohol consumption and violence. However, in 1 evaluation of the restriction of take-away trading hours and volumes for alcohol sales in Australia, many customers shifted their purchases to cheap cask port, providing an illustration of the ways in which consumers may respond to limitations in alcohol availability.\n\nAn increase in alcohol-related road traffic accidents followed the removal of the ban on Sunday sales of packaged alcohol in New Mexico (1 USA [not graded]).\n\nThe introduction of unrestricted serving hours in Reykjavik, Iceland resulted in increased police work episodes, more emergency ward admissions for weekend nights, increased suspected drink-driving incidents, and more people circulating in the city centre at 6am (1 [+]).\n\nThe Saturday opening of alcohol retail outlets in Sweden also led to an increase in sales (2 ++) but no apparent change in alcohol-related harms (1 [++]).\n\nA range of evidence from Scandinavia, based on largely small-scale, local natural experiments, showed the variable impact of changes in alcohol licensing, with decreased alcohol consumption typically observed as a result of restrictions. However, a USA-based study suggested that restrictions on Sunday alcohol sales had no apparent impact on consumption, whilst earlier closing hours in bars appeared to result in increased alcohol sales.\n\n## Evidence statement 2.21\n\nA clear positive relationship between increased outlet density and alcohol consumption among adults was demonstrated in a range of association studies (3 USA [not graded], 1 [++] USA, 2 [++] Canada and 1 Canada [not graded]). However, 1 USA study (not graded) found no significant association between alcohol outlet density and heavy drinking.\n\n## Evidence statement 2.22\n\nA positive relationship between alcohol outlet density and alcohol consumption was also observed in studies focusing on young people (1 USA, 1 Australia, 2 Switzerland and 2 New Zealand [not graded]).\n\n## Evidence statement 2.24\n\nA number of natural experiments demonstrated the effects of changes in alcohol outlet density on alcohol consumption and alcohol-related outcomes. Increases in alcohol outlet density tended to be associated with increases in alcohol consumption and alcohol-related morbidity and mortality in Scandinavia. A literature review found that the privatisation of alcohol retail monopolies in the USA, Canada and Scandinavia (not graded) was linked with higher outlet densities, longer hours or more days of sale and changes in price and promotion, typically resulting in increased alcohol consumption (international). A positive association between alcohol outlet density and gonorrhoea (1 USA [not graded]) was also observed following the civil unrest in Los Angeles.\n\n## Evidence statement 2.25\n\nAn evidence base, within 1 literature review, was described demonstrating positive relationships between outlet density and a range of outcomes including rates of violence, drink-driving, pedestrian injury, and child maltreatment.\n\n## Evidence statement 2.27\n\nEvidence was identified that pre-drinking [drinking before going out] is a prevalent activity, both in the UK (1 [++] UK and 1 UK [not graded]) and within 1 international literature review.\n\n## Evidence statement 2.30\n\nEvidence was identified that demonstrated that pre-drinking is associated with heavy alcohol consumption (1 [++] UK and 1 international [not graded]) and increased risk of alcohol-related harm (1 [++] UK).\n\n## Evidence statement 3.1\n\nOne systematic review (++) demonstrated a small but consistent relationship between advertising and alcohol consumption at a population level.\n\n## Evidence statement 3.2\n\nA systematic review of longitudinal studies found that exposure to alcohol advertising and promotion was associated with the onset of adolescent alcohol consumption and with increased consumption among adolescents who were already drinking at baseline assessment (++). Another systematic review presented evidence of a small but consistent relationship between advertising and alcohol consumption among young people at an individual level (++). Another review concluded that the evidence base suggested the existence of an association between exposure to alcohol advertising and promotion and alcohol consumption among young people (++). Further literature reviews were also indicative of alcohol advertising having an impact on young people. There was evidence of awareness, familiarity and appreciation of alcohol advertisements among this age group.\n\n## Evidence statement 3.3\n\nOne systematic review presented evidence of a moderate but consistent association between point of purchase promotions and effects on alcohol consumption among under-age drinkers, binge drinkers and regular drinkers (++).\n\n## Evidence statement 3.4\n\nA systematic review reported that outdoor and print advertising media may increase the probability of onset of adolescent alcohol consumption and also influence quantity and frequency of alcohol consumption among young people (++). Another review included 1 USA-based study that reported that outdoor advertising media did not have any effect on alcohol behaviour, but was a predictor of intention to use alcohol among adolescents (++).\n\n## Evidence statement 3.6\n\nOne systematic review reported that evidence from longitudinal studies consistently demonstrated that exposure to television and other broadcast media was linked with the onset of and levels of alcohol consumption (++). Further evidence was included in a review that indicated that exposure to alcohol portrayals via television (including advertisements aired during sports programmes) and other broadcast media may be linked with alcohol use among adolescents (++).\n\n## Evidence statement 3.7\n\nThe content of alcohol advertising was reported to be attractive to young people, conveying desirable lifestyles and images of alcohol consumption. Younger age groups and girls aged15 to 17 years were reported to be potentially experiencing the greatest impact of alcohol advertising (++). A further UK-specific report showed that, despite changes to the Advertising Code, while advertising recall fell (potentially due to reduced television advertising expenditure over the study period), there was an increased perception among young people that television alcohol advertisements were appealing and would encourage people to drink. However, there was a decrease in the proportion of young people who considered alcohol commercials to be aimed at them. A literature review stated that there was no scientific evidence available to describe the effectiveness of self-regulation in alcohol advertising.\n\n## Evidence statement 3.8\n\nInconclusive evidence was identified, within 1 systematic review (++) and 1 literature review (not graded), of the impact of advertising bans on alcohol consumption .\n\n## Evidence statement 5.1\n\nThe Alcohol-use disorders identification test (AUDIT) is effective in the identification of hazardous and harmful drinking in adults in primary care (3 [++] systematic reviews, 1 [++] Finland, 1 [++] UK and 1 literature review [not graded]). The use of lower thresholds in conjunction with alcohol screening questionnaires was recommended for women (1 [++] Finland, 1 [++] Belgium, 1 [++] systematic review and 1 literature review [not graded]). Optimal screening thresholds for the detection of hazardous or harmful drinking using AUDIT appeared to be greater than or equal to 7 or 8 among men (2 [++] systematic reviews) and greater than or equal to 6 to 8 among women (1 [++] systematic review, 1 [++] Finland and 1 literature review [not graded]). Optimal screening thresholds for identifying binge drinking using AUDIT were greater than or equal to 7 or 8 for adult males (no data available for females) (1 [++] Finland). Primary studies included in a systematic review (++) recommended higher AUDIT thresholds for males (5 to 8) than females (2 to 6).\n\n## Evidence statement 5.2\n\nThe evidence for the effectiveness of shorter versions of AUDIT in adults in primary care was variable. Some authors of cross-sectional diagnostic evaluations observed comparable performance between the full AUDIT and shorter versions (2 [++] Finland, 1 [++] Belgium and 1 [++] USA). Other findings drawn from primary care were more cautious of the utility of the shorter forms of this questionnaire (1 [++] systematic review). The optimal screening threshold for the detection of hazardous drinking using AUDIT-C was greater than or equal to 3 among men and women (1 [++] systematic review and 1[++] USA). However, thresholds of greater than or equal to 5 for the detection of heavy drinking among females and greater than or equal to 6 for identifying bingeing moderate and heavy drinking men were also recommended (1 [++] Finland). Primary studies included in a systematic review recommended higher AUDIT-C thresholds for males (3 to 6) than females (2 to 5) (1 [++]). FAST was described, within a literature review (not graded), as being effective in the detection of alcohol problems at a cut-off point of greater than or equal to 1 in males and females in a primary care setting in the UK.\n\n## Evidence statement 5.5\n\nOnly a limited amount of evidence could be identified relating to the performance of alcohol screening questionnaires in hospital settings. The 'Five-shot questionnaire' was shown to detect alcohol misuse in adult male inpatients at a cut-off of greater than or equal to 2.5 (1 [++] Belgium). AUDIT was effective in screening UK male and female adult general medical admissions for hazardous and harmful alcohol consumption (1 [+] UK). AUDIT was also reported to perform effectively among general hospital inpatients (1 [++] systematic review).\n\n## Evidence statement 5.6\n\nEvidence was identified for the use of alcohol screening questionnaires among adults in emergency care settings. One study found that the CAGE questionnaire was effective in screening for a lifetime diagnosis of alcohol dependence in trauma centre patients ([++] USA). AUDIT-C was shown to effectively identify hazardous drinking among male and female adult traffic casualties in an emergency department (1 [+] Spain). One literature review indicated that FAST displayed good screening properties in the identification of alcohol problems among males and females presenting to an A&E setting in the UK. The 'Paddington alcohol test' has been shown to be rapid, feasible to use, be UK-specific and to have reasonably good screening properties for the detection of alcohol misuse when implemented in response to clinical 'trigger' conditions in A&E care. These are listed as follows: fall; collapse; head injury; assault; accident; unwell; non-specific gastrointestinal conditions; psychiatric; cardiac; repeat attender (3 [++] UK).\n\n## Evidence statement 5.7\n\nAUDIT was shown to perform more effectively in the identification of alcohol abuse or dependence (when used at a cut-off of greater than or equal to 10) than CAGE, CRAFFT (car, relax, alone, forget, friends, trouble) or RAPS-QF (rapid alcohol problems screen) questionnaires among young people (median age of 19 years) (1 [++] USA). AUDIT was also demonstrated to have higher sensitivity (when used at an optimal cut-off of greater than or equal to 3) than CAGE, CRAFFT or POSIT (problem oriented screening instrument for teenagers) in the detection of problem use (that is, hazardous or harmful consumption not reaching the diagnostic threshold for an alcohol-related disorder, abuse and dependence) in a sample aged between 14 and 18 years (1 [++] USA). The identified evidence for the effectiveness of SASSI (substance abuse subtle screening inventory) in screening for alcohol misuse was limited and inconclusive (2 [++] USA and 1 [+] USA). AUDIT was found to perform reasonably well in elderly populations (1 [++] systematic review), while AUDIT-5 was described as showing potential as an appropriate tool for use among older people (1 [+] systematic review).\n\n## Evidence statement 5.9\n\nThe screening properties of questionnaires were influenced by the ethnicity of recipients and authors suggested that the use of appropriate cut-off scores should be considered (1 [++ systematic review, 1 [++] USA and 1 literature review [not graded]).\n\n## Evidence statement 5.10\n\nLaboratory markers are of limited value in the detection of alcohol misuse when compared with alcohol screening questionnaires (2 [++] UK, 1 [++] Belgium and 1 [+] Germany). However, the use of blood-alcohol concentration testing may complement the use of later questionnaire screening in the identification of alcohol misuse among patients treated in the emergency department resuscitation room (1 [++] UK).\n\n## Evidence statement 5.11\n\nA number of clinical indicators were described, within a cross-sectional study, a literature review and a case study, as being associated with excessive alcohol consumption (1 [++] Spain, 1 literature reivew and 1 UK [not graded]). Awareness of such indicators may be useful in alerting health professionals to alcohol-related physical problems.\n\n## Evidence statement 6.1\n\nTwenty seven systematic reviews provided a considerable body of evidence supportive of the effectiveness of brief interventions for alcohol misuse. Brief interventions were found to reduce alcohol consumption, alcohol-related mortality, morbidity, injuries, social consequences and the consequent use of healthcare resources and laboratory indicators of alcohol misuse.\n\n## Evidence statement 6.2\n\nSix systematic reviews (all [++]) demonstrated that interventions delivered in primary care are effective in reducing alcohol-related negative outcomes. Three systematic reviews specifically focusing on the use of brief interventions in emergency care (1 [+] and 2 [++]) found limited evidence of effectiveness. A further review (++) presented inconclusive evidence of the effectiveness of brief interventions in inpatient and outpatient settings. A systematic review of brief interventions for alcohol misuse in the workplace presented limited and inconclusive findings for the effectiveness of interventions in this setting (++).\n\n## Evidence statement 6.3\n\nBrief interventions are effective in reducing alcohol consumption in both men and women (7 [++]).\n\n## Evidence statement 6.4\n\nMost of the primary evidence was drawn from populations with an age range of 12 to 70 years. Therefore, brief interventions for adults have been shown to be effective among adult populations.\n\n## Evidence statement 6.10\n\nExtensive heterogeneity was evident in the characteristics of evaluated brief interventions. However, limited evidence would suggest that even very brief interventions may be effective in reducing alcohol-related negative outcomes, (1 [++] systematic review) with inconclusive evidence for an additional positive impact resulting from increased dose (3 [++] systematic reviews). Evidence from an additional review (++) suggests that brief interventions are effectivebut the impact of including motivational interviewing principles was unclear.\n\n## Evidence statement 6.11\n\nExtended brief interventions were demonstrated to be effective in the reduction of alcohol consumption (evaluated interventions consisted of two to 7 sessions with a duration of initial and booster sessions of 15 to 50 minutes (1 [++] systematic review) or 10 to 15 minutes in 1 session with a number of specific booster sessions of 10 to 15 minutes duration (1 [++] systematic review)).\n\n## Evidence statement 7.1\n\nOrganisational factors such as adequate support and resources can influence the acceptability and implementation of screening and brief intervention for alcohol misuse.\n\nImplementation of screening and brief interventions is influenced by factors other than effectiveness. Positive support from the government, management and involvement of non-clinical members of staff are more likely to result in successful implementation.\n\nThere is also evidence from a range of studies in primary care settings that adequate practitioner training and support in alcohol misuse screening and use of brief intervention materials facilitates – or would facilitate – effective implementation rates and appropriate detection of 'at risk' drinkers. Evidence suggests that the extent of training and support available to practitioners is variable.\n\nOne RCT ([++] USA) showed more successful implementation of screening and brief intervention where there was prior experience of this type of work, management stability and positive support in terms of coordination of programmes. Financial incentives and successful management of staff changes, as well as assistance from receptionists, were also important. However, barriers to success included competing priorities and lack of time. The importance of financial and other incentives for GPs along with readily available materials and training was also highlighted in 1 survey in New Zealand (+).\n\nEvidence from RCTs (1 [++] USA, 1 [+] USA and 1 [+] UK) suggests that the extent to which brief interventions are implemented, though not necessarily the appropriateness of implementation, is increased with use of a training and support intervention for GPs and nurses. One cross-sectional study ([++] Germany) provides evidence that GPs holding a qualification in addiction medicine are more likely to detect problem drinkers. However, a cross-national survey (++) found that training did not improve baseline role insecurity for GPs.\n\nOne cross-sectional study ([+] Finland) and 1 qualitative study ([++] Finland) found that practitioner training rates and ratings of their own familiarity with screening tools and knowledge of brief intervention content was low. The importance of training to practitioners in this survey was evident, as were practitioner views that they lacked training to carry out counselling ([++] UK). The latter point was also evidenced in 1 cross-sectional study ([++] UK). A Delphi survey ([++] UK) provides evidence in the form of expert opinion that practitioner training should help raise awareness of risk factors and typical presentations of individuals with potential drinking problems.\n\nEvidence from qualitative studies show that some nurses in the UK (1 [++]) see training as an incentive to carrying out alcohol-related work.\n\nA sample of GPs in Finland perceived that they lacked training in identifying the early stages of alcohol misuse; and GPs in a Danish focus group study (+) felt they lacked training in counselling skills.\n\nIn a probationary setting, forensic medical examiners in a UK qualitative study set in custody suites (-) felt they lacked the required training to carry out assessments of drinking behaviour.\n\n## Evidence statement 7.2\n\nExtending the current practitioner workload is a potential barrier to implementing screening and brief interventions on a large scale, particularly if all young people and adults are screened as routine practice. The extra time that implementation demands can be a barrier to acceptability and therefore a willingness to deliver such a programme.\n\nImplementation of routine screening and brief intervention programmes requires team-working between physicians, nurses and non-clinical personnel, with consideration required regarding the extent of involvement and specific roles of team members.\n\nEvidence from 1 systematic review ([++] Denmark) challenges the model of universal screening. The study concluded that implementation of universal screening does not benefit sufficient numbers of individuals to warrant the extra workload required. Nurses in 1 qualitative study ([++] UK) felt 'overloaded' with preventative work generally, with resources such as space, staff and sufficient time in short supply. In another qualitative study ([+] Denmark), the additional workload of screening and brief interventions was found to be creating stress among practitioners in primary care. In terms of time available, a Canadian qualitative study (++) found that time was constrained in terms of assessing each patient.\n\nA qualitative study of Finnish GPs (++) showed that they felt they lacked time to carry out a drinking assessment in the context of other consultation demands and weak evidence. One (-) study in Sweden found that nurses regarded time constraints as a barrier to engaging in alcohol prevention. There is mixed evidence from 1 RCT ([++] USA) for the utilisation of non-clinical staff in implementation in order to delegate work and thus to decrease the workload of clinicians. Another RCT found that receptionists did not have a particularly positive attitude to being involved in this type of work without adequate reimbursement ([++] UK), or to changing their perceived role ([++] USA).\n\nIn an emergency care setting, 1 cross-sectional study ([-] USA) provides weak evidence (from a survey of physicians) that, despite support for brief interventions in theory, lack of time is a barrier to implementation. A further UK-based study set in an emergency department also reported that lack of time was viewed as a limiting factor in delivering screening (++).\n\nIn a briefly reported UK qualitative study set in custody suites (-), forensic medical examiners felt they lacked the required time to carry out assessments of drinking behaviour.\n\n## Evidence statement 7.3\n\nThere is evidence that implementation of screening and brief interventions would be facilitated by use of environments where alcohol can be discussed in a non-threatening way. Integrating screening and advice into general lifestyle discussions might increase the acceptability of screening and brief intervention for users. In a range of studies, providers and experts emphasise the importance of appropriate contexts for discussion of alcohol use with users in order to increase acceptability.\n\nClinical consultations for non-alcohol-related medical problems can be an inappropriate time to discuss alcohol use, given that users are focused on the condition for which they are seeking advice. Instead, sessions such as new patient registrations and well-person clinics, where health promotion is often discussed, provide a less threatening opportunity to discuss drinking, as part of a general discussion on lifestyle issues such as diet, exercise and smoking.\n\nEvidence was found from a cross-sectional study ([+] Sweden) that primary care users attending for scheduled appointments are more likely to be asked about their drinking behaviour. This suggests that practitioners deem certain contexts as more appropriate or more convenient in some way for carrying out screening and a brief intervention. A Delphi survey ([++] UK) also provides expert-view evidence that clinics and new registration sessions are an appropriate context for assessing drinking behaviour (in terms of user acceptability). This study also suggests that interventions might be more acceptable to users if they are tailormade to the individual rather than global in design. There is further evidence from 5 UK qualitative studies (4 [++] and 1 [+]) that practitioners and users regard clinics, registration sessions and routine consultations as opportunities for discussions in a less-threatening environment and context. That is, they provide an opportunity to discuss drinking in a context that is related to the purpose of the visit (such as lifestyle assessment or chronic condition monitoring).\n\nEmergency care and probation settings are regarded as 2 contexts that provide a potential opportunity to carry out alcohol screening and give advice. However, there is scarce evidence available.\n\nOne survey of Scottish emergency care units (++) and 1 qualitative study ([-] UK) set in custody suites found that staff thought the location unsuitable for alcohol screening and intervention. However, 2 surveys from the US (both [+]) reported that both patients and surgeons found the emergency care setting acceptable and appropriate. One US evaluation (+) provided evidence that emergency care staff may not feel adequately supported either by management or financially, with training and workload as 2 particular concerns. One UK survey (+) provided mixed views, with some nurses preferring an holistic approach, and others prioritising care of injuries over health promotion. A further UK-based (++) study found that the majority of consulted professionals judged the emergency department to be an appropriate place to perform alcohol screening but that implementation rates were low, potentially due to clinical inertia.\n\nThe importance of having resources in place to rapidly refer positively screened patients from the emergency department for a brief intervention was emphasised, because the rate of attendance for brief interventions dropped off markedly 2 days following referral (1 [++] UK).\n\nImplementation of alcohol screening and brief interventions in emergency care settings is not as consistent as in primary care. The setting differs from primary care in terms of patient population and types of presenting cases, and as such, account needs to be taken of barriers and facilitators to implementation that are specific to the emergency care context, where attendance is brief and often traumatic, patients are more likely to be injured, traumatised, or intoxicated, and staff may feel less prepared to give advice.\n\n## Evidence statement 7.4\n\nThere is evidence that service users have preferences regarding the status of the person dealing with their alcohol issues. Although experts consider alcohol and counselling specialists to be better qualified to carry out interventions, service users might feel stigmatised or rejected should their needs be referred on to such practitioners.\n\nEvidence from 1 RCT ([+] USA) carried out in a general medicine setting showed that service users are no more likely to attend for counselling with an alcohol specialist than with a physician or nurse. In addition, qualitative evidence from the UK (1 [++]) focusing on user views shows that counselling with alcohol specialists can sometimes be perceived as stigmatising. These views contrast with expert views (1 [++] UK) that alcohol workers and counsellors might be best placed to deliver a brief intervention. There are mixed views from 3 UK studies (all [++]) in that professionals and some users perceive the nurse as having more time for discussing drinking with users, whereas other users report that they are more likely to discuss alcohol-related issues with their GP.\n\n## Evidence statement 7.5\n\nThere is some evidence that service users are generally positive about screening and intervention. There is also evidence for general under-activity in discussing drinking with service users.\n\nNegative service user behaviour, such as aggression at being asked about their drinking, while rare, may serve as deterrents to practitioners approaching the topic of drinking with users. Actual drunkenness at consultations limits the likelihood that users will appreciate or remember the advice given. Practitioners may benefit from training in dealing with such situations, and in approaching the topic with individuals that they perceive as 'low risk' in appropriate contexts.\n\nTwo studies (1 [+] USA and 1 [++] UK) provide evidence that the majority of service users are positive about screening, and another ([+] Finland) that they are positive about discussing drinking. However, 2 qualitative studies (1 [++] UK and 1 [+] Denmark) found that some professionals had encountered negative reactions from users in terms of embarrassment and unease, and that this led some to change their GP practice.\n\nEvidence from 2 UK cross-sectional studies (both ++) shows under-activity in terms of practitioner management of hazardous drinking, with a majority of GPs in the first study only intervening in between 1 and 6 cases of hazardous drinking per year. Even in cases of heavy drinking, service users are not being asked about their consumption ([+] Finland). Another cross-sectional study ([+] Sweden) found that advice on drinking behaviour is provided less often than for other lifestyle behaviours, such as exercise, diet, and smoking, and less often than service users expect. One cross-sectional study ([++] Finland) found that the time being spent on asking users about their drinking was typically less than 4 minutes, and another recent cross-sectional study ([+] Germany) found that detection rates of problem drinkers are low, at 1 in 3. Possible reasons are found in a Finnish qualitative study (++) of GPs, who reported their reluctance to ask users about their drinking unless they saw clear signs of risky drinking behaviour.\n\n## Evidence statement 7.6\n\nEvidence was found that provider attitudes, knowledge, skills and behaviour can influence the implementation of screening and brief interventions for alcohol misuse.\n\nThere is evidence from primary care practitioner views of a shortfall in perceived knowledge in terms of detecting 'at-risk' individuals. There is also evidence of confusion regarding current guidelines around drinking behaviour, and the known benefits of drinking in moderation. This can affect practitioner confidence in, and motivation towards, implementing screening and brief intervention programmes effectively. In addition, the practitioner's own drinking behaviour and the user-practitioner relationship may affect the way that alcohol-related interventions are implemented.\n\nOne UK qualitative study (++) provides evidence that GPs found difficulty in identifying early-stage heavy drinkers. The study also reports difficulty working with multiple definitions of problematic drinking. One qualitative study ([+] Finland) found that GPs and nurses saw the lack of clear guidance as a barrier to carrying out brief interventions. Utilising the skills of receptionists can be useful, but there is evidence from 1 RCT ([++] UK) that receptionist attitudes toward the work may be less positive than that of clinicians, and that this might have an impact upon implementation.\n\nThere is weak evidence ([-] UK) that forensic medical examiners perceive that they lack the knowledge to carry out an assessment in custody suites in the UK.\n\nTwo UK qualitative studies (1 [++] and 1 [+]) found that nurses saw alcohol as a difficult and emotive topic to broach with users. In addition, nurses reported confusion for themselves and service users around the issue of standard drink units, and the potential benefits of alcohol that create ambiguity in discussing drinking from a health promotion perspective. Other studies (1 [+] UK and 1 [+] Finland) found that GPs relationship with alcohol could affect their behaviour in terms of addressing service user drinking, with feelings of guilt and hypocrisy potential barriers to open discussion, or facilitators to empathy. There is qualitative evidence from 3 studies focusing on user views (2 [++] UK and 1 [+] USA) that discussing drinking is facilitated by a good relationship with the health professional. In addition, there is evidence (1 [+] Denmark) that practitioners are concerned not to offend users by discussing alcohol for fear of disturbing the therapeutic relationship.\n\n## Evidence statement 7.7\n\nEvidence was identified that shows disparities in the way screening and brief interventions for alcohol misuse are implemented in realtion to certain groups within the population. While certain groups, such as males and high earners, are more 'at-risk' than others from alcohol misuse, individuals from groups that are 'low-risk' – such as females, younger and older people – may be missed. Conversely, over-targeting can also occur due to misconceptions of the populations most at-risk of alcohol misuse.\n\nOne systematic review (+) provides inconclusive evidence that socioeconomic status affects the uptake of brief interventions. However, 1 cross-sectional study ([++] UK) found that unemployed individuals were more likely to receive a brief intervention than those in employment. In terms of ethnicity, there is evidence from 1 cross-sectional study ([+] USA) that minorty ethnic groups, in this instance black and Hispanic, and particularly Hispanic people, were more likely to be approached by practitioners regarding their alcohol consumption.\n\nFour cross-sectional studies (1 [++] UK, 1 [+] Sweden, 1 [++] Germany and 1 [+] Finland) provide evidence that primary care users most likely to be given advice on drinking are males. Another cross-sectional study ([+] Finland) suggests that males, as well as heavy drinkers, are also more likely to adhere to the advice provided in a brief intervention. One qualitative study ([+] Denmark) found that GPs were reluctant to address drinking with young people as they felt that they would be likely to grow out of the habit of hazardous drinking.\n\n## Evidence statement e1.1\n\nThere is limited evidence of the cost effectiveness of price controls in a UK setting. One systematic review (+) suggests that the available evidence is limited to 2 studies, 1 which takes an international perspective, and 1 set in Estonia. The review reports that the evidence is suggestive that in areas with a high prevalence (greater than 5%) of hazardous drinkers, as is the case in the UK, taxation will be more cost effective than other alcohol misuse macro interventions, but that the evidence base for this is not strong.\n\n## Evidence statement e2.3\n\nThere is limited evidence of the cost effectiveness of opening hours interventions in a UK setting. One study of moderate quality that takes an international perspective (+) provides evidence that reducing licensing hours provides relatively small quality of life benefits compared to other alcohol misuse interventions.\n\n## Evidence statement e5.1\n\nOne study shows that the AUDIT test is a more cost effective screening tool than measures of y-glutamyltransferase, aspartate aminotransferase, per cent carbohydrate deficient transferrin, and ethrocyte mean cell volume. This is because AUDIT is both cheaper and more effective than these other tests ([+] UK). The evidence does not allow a ranking of the cost effectiveness of these other screening methods.\n\n## Evidence statement e6.1\n\nCost effectiveness evidence for screening and brief interventions in the emergency care setting is scarce. The available evidence does not allow firm conclusions regarding the long-term cost effectiveness of these interventions in a UK setting. However, the evidence does suggest that brief interventions in the emergency care setting may be cost effective in the UK. One study suggests that screening plus a brief intervention may produce long-term cost savings ([+] USA), but the applicability of this evidence to the UK is uncertain. One UK study suggests that a brief intervention administered by alcohol health workers in a hospital setting will reduce consumption in the short term without significantly increasing costs, but long-term evidence is lacking (++).\n\n## Evidence statement e6.2\n\nCost effectiveness evidence for screening and brief interventions in the hospital setting is scarce. The available evidence does not allow conclusions regarding the cost effectiveness of these interventions in a UK setting to be made. A UK study presents evidence for screening by doctors and nurses in a general hospital setting (+), but this does not allow a conclusion to be reached regarding the most cost-effective screening method. One study suggests that screening plus a brief intervention may produce long-term cost savings ([-] Australia), but the reliability of this evidence is low due to the uncertainty in resource use estimates.\n\n## Modelling statement M2\n\nA policy of screening and brief intervention at next GP registration is a more phased approach over time than screening at next GP consultation. The former approach would screen an estimated 39% of the population, with 36% of hazardous and harmful drinkers receiving a brief intervention over the modelled 10-year screening programme. A policy of screening and brief intervention at next GP consultation is a very large-scale implementation, with an estimated 96% of the population screened after 10 years (of whom the majority would be screened in the first year of implementation), and 79% of hazardous and harmful drinkers receiving a brief intervention.\n\n## Modelling statement M3\n\nScreening and brief intervention in an A&E setting is estimated to screen 78% of the population within 10 years, but because the estimated uptake of brief interventions is just 30%, only 18% of hazardous and harmful drinkers are estimated to receive the brief intervention.\n\n## Modelling statement M6\n\nSensitivity analysis shows that even fairly long brief interventions (for example, 25 minutes) would appear cost effective versus a 'do nothing' policy. There is currently no conclusive evidence of the differential effectiveness of delivery by different types of staff. On this basis, decision makers might consider the less costly staffing options that were modelled for screening and the brief intervention to be attractive. Evidence around the differential effectiveness of interventions of different duration is also inconclusive. Sensitivity analyses show that shorter duration interventions remain cost effective when using the best available evidence on the relationship between duration and effectiveness.\n\n## Modelling statement M12\n\nIncreasing levels of minimum pricing show very steep increases in effectiveness. Overall changes in consumption for 20p, 25p, 30p, 35p, 40p, 45p, 50p, 60p, 70p are: 0.0%, -0.1%, -0.4%, -1.1%, -2.4%, -4.3%, -6.7%, -11.9% and -17.7%. Higher minimum prices reduce switching effects. Note that estimates for lower minimum prices are subject to less modelling uncertainty than those for higher minimum prices. This is because the consideration of supply-side responses and, in particular, a possible restructuring of the market following large mandated price increases in sections of the market, was outside the scope of the model. As an example, a minimum price of 40p per unit has the following estimated effects:\n\n% change in consumption: -2.4%\n\nDeaths p.a. (full effect): -1,190\n\nHospital admissions p.a.: -39,000\n\nCrimes pa: -10,000\n\nWork absences (days p.a.): -134,000\n\nUnemployment (persons p.a.): -11,500\n\n## Modelling statement M21\n\nAs prices increase, alcohol-attributable hospital admissions and deaths are estimated to reduce. Prevented deaths occur disproportionately in harmful drinkers. On balance, the health-harm reductions mostly relate to chronic diseases rather than acute conditions such as injuries. This is because much of the alcohol-attributable health harm occurs in middle or older age groups at significant risk of developing and potentially dying from chronic disease.\n\n## Modelling statement M22\n\nFor chronic diseases, the time for a change in consumption to achieve the full effect in changing the prevalence of disease is important in the modelling. The reductions in health-harms, for chronic disease, observed 1-year following implementation are estimated to be around one tenth of the level that will accrue when the full effect of consumption changes occurs.\n\n## Modelling statement M23\n\nCrime harms are estimated to reduce as prices are increased. The crime reductions observed for policies take place across the spectrum of violent crime, criminal damage and theft, robbery and other crimes. A minimum price of 40p is estimated to reduce total crimes by 9,000 per annum.\n\n## Modelling statement M24\n\nThe evidence base for under-age purchasing is limited (because the youngest ages for which purchasing data exists in the 'Expenditure and food survey' are 16 and 17, and there are concerns on reliability even for this). Given this caveat, crime harms are estimated to reduce particularly for young people aged 11 to 18 years because they are disproportionately involved in alcohol-related crime and are affected significantly by targeting price rises at low-priced products.\n\n## Modelling statement M26\n\nUnemployment harm estimates (that is, estimated unemployment due to alcohol consumption), reduce proportionately more than health or crime harms. Generally, all policy options that target harmful and hazardous drinkers are effective in reducing alcohol-related harm in the workplace. The size of the effect is dependent on the extent of price increases.\n\n## Modelling statement M27\n\nUnemployment due to alcohol problems among harmful drinkers is estimated to reduce as prices increase: for example, a 40p minimum price is estimated to result in 11,500 avoided unemployment cases, while a 50p minimum price is estimated to result in 25,900 avoided unemployment cases. Absence reductions are particularly focused on hazardous and harmful drinkers: for example, for 40p, the 134,000 estimated reduction in days absence is made up of 38,000 days for hazardous and 78,000 days for harmful drinkers.\n\n## Modelling statement M29\n\nThe societal value of harm reduction for many of the potential policies can be substantial. When accumulated over the 10-year time horizon of the model, many policies have estimated reductions in harm valued over £500m. For example, a 40p minimum price is valued at £4bn over the 10-year period. The financial value of harm reductions becomes larger as prices are increased.\n\n## Modelling statement M34\n\nModerate drinkers are affected in only very small ways by the policy options examined, both in terms of their consumption of alcohol and their spending.\n\n## Modelling statement M35\n\nIn terms of the differential effectiveness for priority groups, harmful drinkers are expected to reduce their absolute consumption the most, but in the more effective policy options, they also spend significantly more on their purchases.\n\n## Modelling statement M36\n\nPolicies which target low-priced alcohol affect harmful drinkers disproportionately. This is because moderate drinkers tend to drink a smaller proportion of the very low priced products available.\n\n## Modelling statement M37\n\nThere are significant effects on harmful drinkers, but important health gains also occur in hazardous and moderate drinkers. Even though moderate drinkers are at a lower risk of health-related harms, small changes in the consumption of the large number of moderate drinkers feed through in the model to small changes in risk and appreciable changes in population health.\n\n## Modelling statement M51\n\nThough smaller than price effects, outlet density reductions have been proven to reduce both consumption and harm. As an example, the 10% reduction in outlet density has the following estimated effects:\n\n% change in consumption: -2.3%\n\nDeaths per annum (full effect): -710\n\nHospital admissions per annum: -25,000\n\nCrimes per annum: -61,000\n\nWork absences (days per annum): -284,000\n\nUnemployment (persons per annum): -8100\n\n## Modelling statement M55\n\nModelling a 10% change in licensing hours produces changes in alcohol consumption based on 3 studies of -1.2% (Canadian), +0.2% (US), and -3.5% (Swedish). As an example, the 10% reduction in licensing hours has the following estimated effects:\n\n% change in consumption: -1.2%\n\nDeaths per annum (full effect): -420\n\nHospital admissions per annum: -14,000\n\nCrimes per annum: -27,000\n\nWork absences (days per annum): -138,000\n\nUnemployment (persons per annum): -3400\n\n# Economic analysis\n\nThe cost-effectiveness reviews and economic modelling showed that increasing the price of alcohol is likely to be a cost effective way of reducing consumption and alcohol-related harm. This could involve a general price increase, imposing a minimum price per unit or placing restrictions on discounting.\n\nThere was limited evidence on the effectiveness of reducing the availability of alcohol and restricting or banning advertising. Exploratory analyses suggested that policies to address these issues would probably have a smaller positive effect than that expected by a price increase.\n\nThe cost-effectiveness reviews and economic modelling suggested that screening plus a brief intervention at the next GP consultation, the next registration with a new GP, or the next A&E visit would be cost effective when compared against 'doing nothing'.\n\n# Fieldwork findings\n\nFieldwork aimed to test the relevance, usefulness and feasibility of putting the recommendations into practice. The PDG considered the findings when developing the final recommendations. For details, go to the fieldwork section in appendix B and 'Alcohol-use disorders: preventing the development of hazardous or harmful drinking'.\n\nFieldwork participants who work within the alcohol field were positive about the recommendations and their potential to help prevent alcohol-use disorders. However, they felt that a number of areas should be given further consideration as follows.\n\nA treatment pathway should be provided which not only illustrates the stages of care that the recommendations cover, but also outlines the roles and responsibilities of different professional groups.\n\nGood communication is needed between NICE and organisations in non-healthcare settings to ensure alcohol is tackled as part of partnership working.\n\nNICE should work closely with the National Treatment Agency (NTA) to ensure commissioners' concerns about the relative lack of investment in alcohol services (compared with drug services) is considered.\n\nThe term 'motivational counselling' should be reconsidered or clearly differentiated from other motivational approaches.\n\nThe presentation of the guidance will contribute to its impact and likely adoption. A standard approach should be used whereby each recommendation is preceded by a short statement of the evidence and a discussion of the likely outcomes of implementing the proposed actions.\n\nThe contribution that community and voluntary groups make to reducing alcohol-related harm should be acknowledged and organisations working in these sectors should be mentioned throughout the guidance.", 'Appendix D: Gaps in the evidence': 'The PDG identified a number of gaps in the evidence related to the programmes under examination, based on an assessment of the evidence. These gaps are set out below.\n\n. There is only limited evidence on how alcohol advertising affects consumption among the adult population.\n\n. There is only limited evidence on the effectiveness of brief alcohol-related interventions aimed at those under the age of 18 and those from black and minority ethnic groups within the UK.\n\n. Little is known about how brief interventions work and which elements are particularly effective. For example, there is only limited evidence on the settings and populations where brief advice or motivational interviewing will be more effective or cost effective.\n\n. There is variable evidence on the effectiveness of using brief interventions outside primary care and emergency departments.\n\n. There is little UK-based evidence on the cost effectiveness of different types of brief intervention.\n\n. There is a lack of good quality evaluations of UK community-based programmes to prevent alcohol problems.\n\nSource: Review 1, review 2 and review 4 (see appendix E for details).\n\nThe Group made 7 recommendations for research.', 'Appendix E: supporting documents': "Supporting documents include the following:\n\nEffectiveness reviews:\n\n\n\nReview 1: 'Interventions on control of alcohol price, promotion and availability for prevention of alcohol-use disorders in adults and young people'\n\nReview 2: 'Screening and brief interventions for prevention and early identification of alcohol-use disorders in adults and young people'.\n\n\n\nEconomic analysis:\n\n\n\nReview 3: 'Prevention and early identification of alcohol-use disorders in adults and young people. Macro-level interventions for alcohol use-disorders: cost-effectiveness review'\n\nReview 4: 'Prevention and early identification of alcohol-use disorders in adults and young people. Screening and brief interventions: cost-effectiveness review'\n\nEconomic modelling report: 'Modelling to assess the effectiveness and cost effectiveness of public health-related strategies and interventions to reduce alcohol attributable harm in England using the Sheffield alcohol policy model version 2.0'.\n\n\n\nFieldwork report: Alcohol-use disorders: preventing the development of hazardous or harmful drinking'."}	https://www.nice.org.uk/guidance/ph24	This guideline covers alcohol problems among people over 10. It aims to prevent and identify such problems as early as possible using a mix of policy and practice.
6ce98299594875fd87dd26ab681e100df58ab69a	nice	Human growth hormone (somatropin) for the treatment of growth failure in children	Human growth hormone (somatropin) for the treatment of growth failure in children Evidence-based recommendations on human growth hormone (somatropin; Genotropin, Humatrope, Norditropin, NutropinAq, Omnitrope, Saizen, Zomacton) for treating growth failure in children. # Guidance This guidance replaces NICE technology appraisal guidance 42 issued in May 2002. For details, see about this guidance. Somatropin (recombinant human growth hormone) is recommended as a treatment option for children with growth failure associated with any of the following conditions: growth hormone deficiency Turner syndrome Prader–Willi syndrome chronic renal insufficiency born small for gestational age with subsequent growth failure at 4 years of age or later short stature homeobox‑containing gene (SHOX) deficiency. Treatment with somatropin should always be initiated and monitored by a paediatrician with specialist expertise in managing growth hormone disorders in children. The choice of product should be made on an individual basis after informed discussion between the responsible clinician and the patient and/or their carer about the advantages and disadvantages of the products available, taking into consideration therapeutic need and the likelihood of adherence to treatment. If, after that discussion, more than one product is suitable, the least costly product should be chosen. Treatment with somatropin should be discontinued if any of the following apply: growth velocity increases less than 50% from baseline in the first year of treatment final height is approached and growth velocity is less than 2 cm total growth in 1 year there are insurmountable problems with adherence final height is attained.In Prader–Willi syndrome evaluation of response to therapy should also consider body composition.Treatment should not be discontinued by default. The decision to stop treatment should be made in consultation with the patient and/or carers either by: a paediatrician with specialist expertise in managing growth hormone disorders in children, or an adult endocrinologist, if care of the patient has been transferred from paediatric to adult services.# Clinical need and practice Human growth hormone is produced by the anterior pituitary gland. The synthetic form is called somatropin (recombinant human growth hormone). Human growth hormone is essential for normal growth in children. It increases growth by a direct action on the growth plates and by production of insulin‑like growth factors (especially IGF‑1), mainly in the liver. Human growth hormone also has important effects on the metabolism of proteins, lipids and carbohydrates, not only during childhood, but also throughout adult life. Growth failure in children can be a result of growth hormone deficiency, but also occurs in children with Turner syndrome, chronic renal insufficiency (CRI), short stature homeobox‑containing gene (SHOX) deficiency, and in children born small for gestational age. Growth hormone deficiency occurs when the pituitary gland does not produce enough human growth hormone, which is the most common endocrine cause of short stature. Growth hormone deficiency may occur as an isolated hormonal deficiency or in combination with deficiencies in several pituitary hormones arising from hypopituitarism, tumours in the central nervous system, cranial irradiation or other physiological causes. The prevalence of growth hormone deficiency is estimated to be between 1 in 3500 and 1 in 4000 children. In about half of the children with growth hormone deficiency (50%), the cause is unknown (idiopathic growth hormone deficiency). Turner syndrome is a chromosomal disorder characterised by the complete or partial lack of one X chromosome in girls. The two most common clinical features are short stature and ovarian failure. Girls with Turner syndrome do not have a deficiency in human growth hormone, although they may have a relative lack of sensitivity to human growth hormone because of haploinsufficiency of the short stature homeobox‑containing gene. Not all girls with Turner syndrome need treatment with somatropin. Turner syndrome occurs in between 1 in 1500 and 1 in 2500 live female births. If untreated, girls with Turner syndrome have a final adult height of 136–147 cm. Adult women with Turner syndrome are on average 20 cm shorter than other adult women. Prader–Willi syndrome is a genetic disorder caused by an abnormality of chromosome 15. Common clinical characteristics include hypogonadism, short stature, hypotonia, dysmorphic features, hypoventilation, changes in body composition, obesity and obesity‑related diseases, and behavioural problems. Prader–Willi syndrome occurs in between 1 in 15,000 and 1 in 25,000 live births. Men with Prader–Willi syndrome have a final adult height of about 154 cm; women have a final adult height of 145–159 cm. Chronic renal insufficiency (CRI), which may include end‑stage renal disease, is defined as a persistent elevation of serum creatinine and/or urea. It can be caused by a variety of conditions, including congenital disorders, glomerular disorders and infections. Growth failure associated with CRI usually begins when the glomerular filtration rate falls to 50% of normal. Not all people with CRI in childhood will be shorter than average; figures from the UK Renal Registry indicate that 29% of children who undergo renal transplantation and 41% of children on dialysis are below the 2nd percentile for height within their first year and remain so throughout childhood because of more pronounced deceleration in height velocity. Children with congenital disorders leading to CRI (approximately 60% of children with CRI) are of normal length at birth, but are below the 3rd percentile for height within their first year and remain so throughout childhood. Various thresholds for height and weight at birth are used to define 'small for gestational age', the three most commonly used being: a height at birth that is 2 standard deviations or more below the population average, or a weight at birth that is 2 standard deviations or more below the population average, or a weight at birth below the 10th percentile.In addition to accurate measurements of a newborn's weight, length and head circumference, the diagnosis of small for gestational age requires accurate assessment of gestational age and valid data from a reference population. The international consensus definition of 'small for gestational age' is a length or weight at birth that is 2 standard deviations below ( −2 SD) the population average for birth or weight. The licensed indication for somatropin is for growth disturbance (current height standard deviation score −2.5 and parental adjusted height SDS −1) in short children born small for gestational age, with a birth weight and/or length below −2 SD, who failed to show catch‑up growth (height velocity SDS less than 0 during the past year) by 4 years of age or later. Children classified as born small for gestational age may have concurrent diagnoses such as familial short stature, Turner syndrome, or growth hormone deficiency. Approximately 10% of children born small for gestational age do not reach the normal height range. Those whose growth has not caught up by 4 years of age are candidates for treatment with growth hormone. The short stature homeobox‑containing gene (SHOX) is located on the distal ends of X and Y chromosomes and plays a role in long bone growth. Normal growth requires two functional copies of the gene. Consequently, growth impairment can occur if one copy of the SHOX gene has been inactivated by mutation or deleted (haploinsufficiency). SHOX deficiency can cause short stature in people with conditions such as Turner syndrome, Leri–Weil syndrome and dyschondrosteosis. Based on a small study (26 people with SHOX haploinsufficiency compared with 45 of their unaffected relatives), children with SHOX haploinsufficiency were 3.8 cm shorter (2.1 standard deviations shorter) than their unaffected relatives and this difference persisted throughout their childhood. Somatropin (recombinant human growth hormone) is currently the only active treatment option for growth failure in children with growth hormone deficiency, Turner syndrome, CRI, Prader–Willi syndrome, in short children born small for gestational age and in children with SHOX deficiency. The place of somatropin in the treatment pathway depends on the child's particular condition, his or her age at diagnosis and the licensed indications of the seven somatropin preparations that are available for use in UK practice. For girls with Turner syndrome, oxandrolone, an anabolic steroid, may be added to growth hormone treatment. In the UK, conservative strategies for the management of growth failure in children with CRI include advice on diet and nutritional supplementation.# The technologies In the UK, seven preparations of somatropin are available: Genotropin, Pfizer; Humatrope, Lilly; Norditropin, Novo Nordisk; NutropinAq, Ipsen; Omnitrope, Sandoz; Saizen, Merck Serono; Zomacton, Ferring. Each product is produced by recombinant DNA technology and has a sequence identical to that of human growth hormone produced by the pituitary gland. The licensed indications are as follows (for the different products the wording may differ): growth disturbance in children due to insufficient secretion of growth hormone (growth hormone deficiency). growth failure in girls associated with gonadal dysgenesis (Turner syndrome). growth retardation in prepubertal children associated with chronic renal insufficiency (CRI). improvement of growth and body composition in children with Prader–Willi syndrome. The diagnosis of Prader–Willi syndrome should be confirmed by appropriate genetic testing. growth disturbance (current height standard deviation score −2.5 and parental adjusted height SDS −1) in short children born small for gestational age, with a birth weight and/or length below −2 SD, who failed to show catch‑up growth (height velocity SDS less than 0 during the past year) by 4 years of age or later. growth failure associated with SHOX deficiency, as confirmed by DNA analysis. The seven manufacturers have UK marketing authorisations for somatropin for the following indications: Lilly (Humatrope): growth hormone deficiency; Turner syndrome; CRI; short children born small for gestational age and SHOX deficiency. Ferring (Zomacton): growth hormone deficiency and Turner syndrome. Ipsen (NutropinAq): growth hormone deficiency; Turner syndrome and CRI. Novo Nordisk (Norditropin SimpleXx): growth hormone deficiency; Turner syndrome; CRI and short children born small for gestational age. Pfizer (Genotropin): growth hormone deficiency; Turner syndrome; CRI; Prader–Willi syndrome and short children born small for gestational age. Sandoz (Omnitrope): growth hormone deficiency; Turner syndrome; CRI; Prader–Willi syndrome and short children born small for gestational age. Merck Serono (Saizen): growth hormone deficiency; Turner syndrome; CRI and short children born small for gestational age. The summary of product characteristics for somatropin states that the dosage and the administration of somatropin should be tailored to the needs of each individual child. The dosage varies according to the condition being treated: 23–39 microgram/kg daily or 0.7–1.0 mg/m² daily for growth hormone deficiency; 45–50 microgram/kg daily or 1.4 mg/m² daily for Turner syndrome and CRI; 35 microgram/kg daily or 1.0 mg/m² daily for growth disturbance in children born small for gestational age; 35 microgram/kg daily or 1.0 mg/m² daily (with a maximum of 2.7 mg daily) for Prader–Willi syndrome; and 45–50 microgram/kg daily for SHOX deficiency. Somatropin is self‑administered or given to the child by an adult, at home, usually as a subcutaneous injection, 6–7 times a week. The summary of product characteristics for somatropin states that side effects include headache, visual problems, nausea and vomiting, fluid retention (peripheral oedema), arthralgia, myalgia, carpal tunnel syndrome, paraesthesia, antibody formation, hypothyroidism and reactions at injection site. Paediatricians should pay particular attention when giving somatropin to children with diabetes mellitus or its risk factors, slipped capital epiphyses, idiopathic intracranial hypertension or malignancies. For full details of side effects and contraindications, see the summary of product characteristics. The cost of treatment with somatropin depends on the dose, which is determined by the weight or body surface area of the child as well as by the indication for growth hormone treatment. The costs of the different somatropin products (excluding VAT; 'British national formulary' edition 58) are: £23.18 per mg for Genotropin, £18.00 per mg for Humatrope, £21.39 per mg for Norditropin (since January 2010 £21.27 per mg), £20.70 per mg for Nutropin, £18.26 per mg for Omnitrope, £23.18 per mg for Saizen and £19.92 per mg for Zomacton. Costs may vary in different settings because of negotiated procurement discounts. Omnitrope is a 'similar biological medicinal product' or 'biosimilar'. Genotropin is the biological reference medicine for Omnitrope. 'British national formulary' 58 states the following: A similar biological medicinal product is a new biological product that is similar to a medicine that has already been authorised to be marketed (the 'biological reference medicine') in the European Union. The active substance of a biosimilar medicine is similar, but not identical, to the biological reference medicine. Biological products are different from standard chemical products in terms of their complexity and although theoretically there should be no important differences between the biosimilar and the biological reference medicine in terms of safety or efficacy, when prescribing biological products, it is good practice to use the brand name. This will ensure that substitution of a biosimilar medicine does not occur when the medicine is dispensed.# Evidence and interpretation The Appraisal Committee (appendix A) considered evidence from a number of sources (appendix B). # Clinical effectiveness ## Published reviews The Assessment Group identified three systematic reviews: one carried out for NICE technology appraisal guidance 42, a Cochrane review relating to that appraisal, and a more recent systematic review of growth hormone in Turner syndrome undertaken by the Canadian Agency for Drugs and Technologies in Health (CADTH) in 2007. The systematic review for NICE technology appraisal guidance 42 included randomised controlled trials (RCTs) comparing somatropin with placebo or no treatment in children with growth hormone deficiency, Turner syndrome, CRI and Prader–Willi syndrome. Non‑randomised and observational studies were included when RCTs lacked data on change to final height. The Assessment Group concluded that although the quality of evidence was variable, there was evidence that treatment with somatropin could increase short‑term growth and improve final height. Results suggested that effects of somatropin on short‑term growth velocity (1 year) ranged from no improvement to approximately 1 standard deviation above the normal growth velocity for children of the same age. Gains in final height for children treated with somatropin compared with untreated children ranged from approximately 3 to 11 cm (for growth hormone deficiency 8–11 cm, for Turner syndrome 5 cm, for CRI 3–9 cm, for Prader–Willi syndrome 10–11 cm). The systematic review undertaken by the CADTH included 19 RCTs or observational studies that compared somatropin with placebo or no treatment in girls with Turner syndrome. All studies included measurements of growth (final height, interim height, growth velocity), documentation of adverse events and measures of quality of life. The review found that growth was accelerated and height increased in girls taking somatropin for Turner syndrome. No serious adverse events were reported. ## Assessment Group's systematic review The Assessment Group conducted a systematic review for RCTs of somatropin in children with growth disturbance, according to the marketing authorisations for somatropin (see sections 3.1 and 3.2). The Assessment Group could not identify any RCTs meeting the inclusion criteria for children born small for gestational age. The Assessment Group included studies that compared the effectiveness of somatropin with management strategies that did not include treatment with somatropin. The Assessment Group identified a total of 28 RCTs from 34 publications. The Assessment Group excluded a number of studies that had been included in the review for NICE technology appraisal guidance 42. This was partly because the Assessment Group included only RCTs in its review whereas the review for NICE technology appraisal guidance 42 had included non‑randomised studies. The Assessment Group also excluded three RCTs (two for Turner syndrome and one for Prader–Willi syndrome) that were included in the review for the previous appraisal. One of the excluded studies used methionyl growth hormone rather than somatropin and two others reported outcomes not included in the Assessment Group's inclusion criteria. The studies included in the Assessment Group's systematic review reported at least one of the following outcomes: final height; height standard deviation score (height SDS); growth velocity; growth velocity SDS; body composition; biochemical and metabolic markers; and adverse events. None of the studies reported health‑related quality of life. The Assessment Group did not perform a meta‑analysis because of heterogeneity in study design and participants. For conciseness, only growth outcomes and adverse events are presented here for growth hormone deficiency, Turner syndrome, CRI, small for gestational age and SHOX deficiency. For Prader–Willi syndrome, a summary of outcomes for body composition is also presented. The Assessment Group identified one RCT comparing treatment with somatropin against no treatment in children with growth hormone deficiency. Children in the treated group (n = 9) grew an average of 2.7 cm per year faster than those receiving no treatment (n = 10) in the 12 months of the study. The difference between the groups was statistically significant (p < 0.05). Children in the treated group had a statistically significantly higher height SDS (−2.3 ± 0.45) than children in the untreated group (−2.8 ± 0.45; p < 0.05). The study did not report adverse events. The study was unblinded and did not report an intention‑to‑treat analysis. The Assessment Group considered the reporting and the methodological quality of the study to be mixed. The Assessment Group identified six RCTs of somatropin for the treatment of growth restriction in girls with Turner syndrome. All six studies were published after the publication of NICE technology appraisal guidance 42. Two of the included studies (of 9 and 12 girls respectively) had a crossover design that compared somatropin with placebo. Of the four remaining studies, two (of 89 and 154 girls) compared somatropin with no treatment, one (of 58 girls) compared somatropin with low‑dose oestrogen, and one (of 232 girls) compared somatropin with placebo. The Assessment Group considered the reporting and methodological quality of the studies to be generally poor. The two studies that reported final height as an outcome found a statistically significant difference in height between the treated and untreated groups at the end of the studies (p < 0.001). In one of the studies, girls grew an average of 9.3 cm more from baseline than those in the untreated group. In the other study, which recruited younger girls, the difference was 7.6 cm. Both studies reported statistically significantly higher height SDS in girls treated with somatropin than in untreated girls. Height velocity was statistically significantly greater in the treated groups in the three studies reporting height velocity as an outcome. One study reported height velocity at the end of the first and second years; height velocity was greater in the first year and fell in the second year in both treatment groups. Adverse events were reported in four studies. One study reported higher rates of adverse events in the treated group, one reported similar levels across groups, and one reported a significantly more frequent occurrence or worsening of ear infections. One study reported four withdrawals because of problems with adherence. The Assessment Group identified eight RCTs from 13 publications that investigated somatropin for the treatment of Prader–Willi syndrome and that met the inclusion criteria for this review. Three had been considered previously for NICE technology appraisal guidance 42 and five were new studies published after the guidance. Seven of the RCTs compared somatropin at a dosage of 1 mg/m2 body surface area per day with no treatment for 1 year (six studies) or 2 years (two studies, including one which treated infants for 1 year only). One study (of 14 children) was a crossover RCT that compared somatropin at a dosage of 43 microgram/kg body weight per day with placebo over 6 months in each treatment group. The doses used in the included studies reflect the marketing authorisations for the different preparations of somatropin. The Assessment Group considered the reporting of the studies to be generally poor. In the only study that reported changes in height, infants who received somatropin for 1 year grew an average of 6.2 cm more than those in the untreated group (p < 0.001). Two studies reported a statistically significant difference in height SDS at end of treatment between participants randomised to treatment and those randomised to no treatment. A difference of 1 SDS (favouring somatropin treatment) was reported in one study at 1 year (p 0.01) and more than 2 SDS in the other at 2 years (p < 0.0001). Three studies reported growth velocity as an outcome. Children treated with somatropin grew 3 cm per year more than untreated children in one study and 5 cm per year more in another. Another study reported a positive growth velocity SDS for children treated with somatropin and a negative growth velocity SDS for untreated children (5.5 versus −2.3). The differences between groups were statistically significant in all three studies. Four studies reported a statistically significantly lower percentage of body fat in children treated with somatropin compared with children who received no treatment or who received placebo. In one study, the mean percentage of body fat was 10% lower for children treated with somatropin than for untreated children (p = 0.03). In this study children treated with somatropin experienced approximately a 5% reduction in body fat, compared with an average 4% increase in body fat in the untreated children (p = 0.001). Two other two studies reported that treated children had approximately 4% or 7% less body fat than those in the comparator group. The fourth study did not report the percentage body fat for infants, but did report this outcome for children over 4 years. Children who received somatropin for a year had a median percentage body fat SDS of 1.5, compared with 2.3 in the control group (p < 0.001). After 2 years of treatment, the SDS values were 1.9 versus 2.4 for the treated and untreated groups respectively (p < 0.001). Four studies reported that children treated with somatropin had a statistically significantly higher lean body mass or a larger increase in lean body mass than untreated children. In one study, the lean body mass of children treated with somatropin increased by 1.8 kg more than in the untreated group (3.6 versus 1.8 kg, p < 0.001). In two other studies children treated with somatropin had approximately 2 kg or 4 kg more lean body mass than untreated children (p < 0.05 and p < 0.01 respectively). One study reported that change in trunk lean body mass was statistically significantly greater for treated than for untreated infants (1.7 versus 0.7 respectively). For children (but not infants), the study reported SDS for lean body mass adjusted for age and height, as well as change in trunk lean body mass. There was a statistically significant difference for all of these outcomes between treated and untreated children after both 1 and 2 years of treatment. Six studies reported body mass index (BMI), but results were mixed. Some studies showed higher values of BMI in treated groups, and others showed no difference. One study reported a BMI of 16.1 after 1 year for children treated with somatropin compared with 18.5 for untreated children (p < 0.05); results were similar after 2 years. A small crossover RCT also reported a statistically significant difference in BMI for treated children compared with those receiving placebo (31.2 compared with 32.8, p < 0.05). In contrast, two studies found no statistically significant difference in BMI for children treated with somatropin and untreated children. Neither of the remaining two studies that reported BMI gave a value for between‑group statistical significance, but both treated and untreated children had similar values of BMI. No serious adverse events were reported in the five studies that presented data. The Assessment Group identified six RCTs that investigated somatropin treatment in children with CRI. Four had been considered for NICE technology appraisal guidance 42 (TA 42) and two were new studies published after TA 42. Two RCTs were crossover studies and four were parallel‑group studies. Three of the four parallel‑group RCTs (of 23, 69 and 203 children) had an open‑label design, with the comparator groups receiving no treatment. One trial (of 125 children) was placebo controlled. The two crossover studies (of 20 and 11 children) had placebo and treatment phases. Three of the studies investigated somatropin treatment in children who had received a kidney transplant and the other three studied children who had CRI but no renal transplant. The Assessment Group considered the reporting of the trials to be generally poor. One study reported gain in absolute height and found that after 1 year children treated with somatropin grew an average of 3.6 cm more than those who were untreated (height gain 9.1 cm versus 5.5 cm, p < 0.0001). Two studies reported that height SDS showed statistically significant greater growth in children treated with somatropin than those who were untreated. Five studies reported that change in growth velocity or growth velocity SDS was statistically significantly greater for children who received somatropin treatment than for those children who did not. The between‑group differences in growth velocity ranged from 3.2 cm per year to 4.2 cm per year in the parallel‑group trials. No serious adverse events were reported in the four studies that presented data. The Assessment Group did not identify any RCTs that met the criteria for use of somatropin in children as prescribed in the licence for growth hormone in children born small for gestational age (see section 3.1). Therefore, the Assessment Group amended the criteria for the review to the following: growth disturbance (current height SDS −2.5, no reference to parental height) in children with a birth weight and/or length < −2 SD and no catch‑up growth (no stated criteria) by the age of 3 years. The Assessment Group identified six RCTs that met the amended inclusion criteria for the review (of 13, 40, 40, 54, 151 and 168 children). All studies compared somatropin with no treatment. Duration of treatment was comparable across five of the six studies. In the sixth study children received treatment for 2 years, but only the first year allowed a randomised comparison between somatropin and no treatment. Only one study included a treatment arm with the licensed dose of somatropin; the other studies all used approximately two to three times the dose licensed for use in the UK. The Assessment Group considered the studies to be generally of poor methodological quality. One study reported a total gain in adult height of approximately 4 cm in people who had received somatropin. The difference between groups was statistically significant (p < 0.005). Adult height SDS was also statistically significantly higher in people who had received somatropin. However, the study used a dose approximately twice that licensed for use in the UK, and the study included children with a mean age of 12.7 years at start of treatment. The Assessment Group cautioned that generalisability of the results may be limited. One study reported that children who received somatropin at a dosage of 33 microgram/kg body weight per day (licensed dosage 35 microgram/kg per day) gained an additional 3.3 cm in height compared with untreated children, and those who received a higher dose of 100 microgram/kg per day gained 6.5 cm after 1 year's treatment. Height SDS was statistically significantly higher in children treated with somatropin in two studies, and higher (but with no reported p value) in two others. Treatment was associated with a greater growth velocity at the end of year 2 in the two studies that reported this outcome, but the difference was reported to be statistically significant in only one study (p < 0.001). Four studies reported limited information on adverse events. One study reported two adverse events in treated children. A second reported only that there were 'no noteworthy' adverse events. A third study reported four serious adverse events that were not linked to the study drug. In the remaining study, three adverse events were linked to somatropin and resolved or stabilised after stopping treatment. The Assessment Group identified one study of children with SHOX deficiency. The 2‑year multicentre RCT compared a daily injection of 50 micrograms of somatropin with no treatment in 52 prepubertal children with confirmed SHOX deficiency. The Assessment Group stated that because the study did not report the mean baseline weight of participants it was not possible to calculate dosage by body weight and to know whether or not the study used a licensed dose of somatropin. The unblinded study did not report an intention‑to‑treat analysis. By the end of the second year, children treated with somatropin had gained statistically significantly more height and had higher values of height SDS than those in the control group. Treatment with somatropin led to a statistically significantly greater growth velocity in both years 1 and 2 (3.5 cm/year greater than in untreated children in year 1, and 1.9 cm/year greater in year 2). Somatropin treatment in children with SHOX deficiency was not associated with any serious adverse events in this study. ## Summary of clinical effectiveness The identified studies reported statistically significantly greater values for height SDS for children treated with somatropin than for untreated children for all indications. For children with Prader–Willi syndrome, treatment with somatropin was also associated with statistically significant changes in measures of body composition. None of the studies reported data on health‑related quality of life and the reporting of adverse events was limited. ## Health‑related quality of life Because there were no data on health‑related quality of life in studies included in the systematic reviews, the Assessment Group undertook a literature search to identify publications reporting utility values in relation to height. One study was identified that provided estimates for utility based on the EuroQoL (EQ‑5D) for different height SDS from the Health Survey for England for an adult general population (14,416 adults). Inter‑relationships using linear regression between height SDS and quality of life were assessed for height SDS alone, and also controlling for age, body weight, sex, social class and long‑standing illness. The study identified a positive correlation between an increase in height and a participant's EQ‑5D score. Mean EQ‑5D scores were lower in people who were shorter than in people who were taller, as well as lower than the overall population mean. The study categorised participants into three groups: people shorter than −2.0 height SDS, people with a height SDS between −2.0 and 0.0, and people with average or above average height. The EQ‑5D scores for these groups were statistically significantly different from each other (p < 0.05). Adjusted for potential confounders, increasing values of height were associated with greater gains in quality of life in shorter people compared with taller people. An increase in height SDS of 1.0 was associated with an increase in EQ‑5D score in the shortest group of 0.061, an increase of 0.010 in the middle group, and an increase of 0.002 in the group with average or above average height. The Assessment Group concluded that there was likely to be a gain in utility associated with height gain for people receiving treatment with somatropin. The Assessment Group acknowledged that the available evidence for utility excludes potential benefits of treatment with somatropin which include change in body composition and lipid profiles. # Cost effectiveness ## Published studies The economic evaluation undertaken for NICE technology appraisal guidance 42 consisted of separate cost‑effectiveness models for each condition under review comparing somatropin treatment with no treatment (defined as growth monitoring). Importantly, this analysis estimated under base‑case conditions the cost per centimetre gained in final height. The economic analysis estimated this cost as approximately £6000 per cm final height for growth hormone deficiency, from £15,800 to £17,300 per cm for Turner syndrome, from £7400 to £24,100 per cm for CRI, and approximately £7030 per cm for Prader–Willi syndrome. The Assessment Group identified two North American economic evaluations for somatropin treatment, which had been published since the economic evaluation for NICE technology appraisal guidance 42: one for children with Turner syndrome (by the CADTH) and one for children with growth hormone deficiency. The economic evaluation of somatropin treatment in children with Turner syndrome estimated an incremental cost‑effectiveness ratio (ICER) of C$243,078 per quality‑adjusted life year (QALY) gained. The economic evaluation of somatropin treatment in children with growth hormone deficiency estimated ICERs of US$36,995 per QALY for the 5‑ to 16‑year‑old cohort and US$42,556 per QALY gained for the 3‑ to 18‑year‑old cohort. The Assessment Group stated that the two different estimates of cost effectiveness were largely because of differences in the choice of estimates of utility (the utility increment associated with growth hormone treatment ranged from 0.040 to 0.189) and difference in assumptions on effectiveness. The Assessment Group considered the economic evaluation undertaken by the CADTH to be of higher quality, and the parameter estimates more appropriate, because the group established the effectiveness of the treatment from a systematic review. The Assessment Group concluded that the previous economic evaluations lacked reliable estimates of gains in utility associated with treatment with somatropin, and that the results should be treated with caution. ## Manufacturers' economic model Six of the seven manufacturers submitted cost‑effectiveness evidence. The Assessment Group stated that the cost‑effectiveness evidence submitted by Sandoz, a cost‑minimisation analysis using Genotropin as a comparator, did not comply with the requirements for the NICE reference case The submission contained a comparison of the annual cost of treatment with Omnitrope and with Genotropin in children with growth hormone deficiency and Turner syndrome. Five of the six manufacturers (Lilly, Ipsen, Novo Nordisk, Pfizer and Merck Serono) collaborated to develop a de novo core economic model to estimate the cost effectiveness of somatropin treatment in children with growth hormone deficiency, Turner syndrome, Prader–Willi syndrome, CRI or children born small for gestational age. The model was developed by Pfizer, but each of the collaborating manufacturers presented the model with minor modifications (for example, changes in the unit price of somatropin). Merck Serono's economic model included a waste elimination model to examine the differences in costs likely to be associated with using the Easypod device rather than other delivery systems. Novo Nordisk constructed a decision tree model to assess the cost effectiveness of somatropin treatment for the four licensed indications for Norditropin (that is, growth hormone deficiency, Turner syndrome, CRI and being born small for gestational age). The assumptions underpinning the model, source of clinical effect, and utility data were identical to those in the core economic model. ## Manufacturers' core economic model The manufacturers developed a Markov cohort model for the economic evaluation containing two health states: 'alive' and 'dead'. The manufacturers estimated the transition probabilities between states using UK‑specific mortality rates observed in the general population. The economic model considered a 1‑year cycle length. Two alternative model structures were also presented. One allowed for a reduction in the risk of osteoporosis in children with growth hormone deficiency treated with somatropin and assumed that some children with growth hormone deficiency would continue treatment until they reached 25 years of age. A second model incorporated a cost‑effectiveness analysis of somatropin in Prader–Willi syndrome. This model assumed that people with Prader–Willi syndrome and diabetes would have a 10% lower quality of life than those without diabetes. The manufacturers assumed no difference in life expectancy between the general population and those with growth hormone deficiency, Turner syndrome, Prader–Willi, CRI, being born small for gestational age or SHOX deficiency. For Prader–Willi syndrome, the manufacturers assumed that changes in body composition associated with somatropin treatment would result in a reduction in the risk of developing diabetes and death related to diabetes. They assumed that the prevalence of diabetes among people with Prader–Willi syndrome would be reduced from 8% to 2%. The utility values used in the model for children with growth hormone deficiency, Turner syndrome, CRI and children born small for gestational age were taken from the study described in section 4.1.29. The manufacturers assumed that a gain in height was associated with improvement in quality of life, which was assessed using the EQ‑5D utility scale. The values were interpolated from the association between height SDS and EQ‑5D score unadjusted for other factors that might be associated with both height and quality of life. The gain in utility value for Prader–Willi syndrome was based on a study of 13 adults with Prader–Willi syndrome who received somatropin for 2 years. The estimate for clinical effectiveness and many of the other parameters used in the model were derived from the Kabi International Growth (KIGS) observational database, a large‑scale collaborative database developed by Pfizer to store data on the safety and efficacy of treatment with somatropin. As SHOX deficiency is not a licensed indication of Genotropin, it is not included in the KIGS database Therefore the same values were assumed for SHOX deficiency as for Turner syndrome. The costs used in the model were those used in the model for NICE technology appraisal guidance 42 and were adjusted for inflation to current prices. The mean daily per patient cost for each manufacturer's formulation of somatropin was based on the unit costs described in section 3.5. For comparison with NICE technology appraisal guidance 42, the base‑case analyses estimated the incremental cost of somatropin per centimetre of height gained relative to no treatment. Costs ranged from £1699 to £2136 per cm gained for growth hormone deficiency, from £2022 to £2596 per cm gained for growth hormone deficiency with somatropin continued through the transition years from age 18 to 25 years, from £8258 to £10,576 per cm gained for Turner syndrome, from £7048 to £11,345 per cm gained for CRI and from £1932 to £9123 per cm gained for small for gestational age. The base‑case analyses for Prader–Willi syndrome and SHOX deficiency produced costs per centimetre gained of £2925 and £8258 respectively. The incremental cost effectiveness ratios (ICERs) for the base case ranged from: £15,730 to £17,522 per QALY gained for growth hormone deficiency; £18,721 to £20,881 per QALY gained for growth hormone deficiency with somatropin continued through the transition years from age 18 to 25; £26,630 to £29,757 per QALY gained for Turner syndrome, £12,498 to £15,962 per QALY gained for CRI and from £14,221 to £18,655 per QALY gained for small for gestational age. The base‑case analyses for Prader–Willi syndrome and SHOX deficiency produced ICERs of £32,540 and £23,237 per QALY gained respectively. The ICERs were most sensitive to the choice of utility values, time horizon, discount rates, treatment duration, doses during the transition phase for those with growth hormone deficiency, the proportion of people achieving final height, and drug price. ## Assessment Group's model The Assessment Group developed a state transition Markov model based on the model developed for NICE technology appraisal guidance 42. The modelled health states were 'alive' and 'dead'. The economic model considered a cycle length of 1 year and a life time horizon of 100 years. The mortality rates for the population in England and Wales were applied in each cycle and the rates were adjusted upward using the standard mortality rates for each of the conditions. The Assessment Group presented an additional scenario for growth hormone deficiency in which it assumed that 34% of people with growth hormone deficiency continued treatment until age 25 years at a dosage of 40 microgram/day. The model assumes that this group does not receive additional benefits from somatropin beyond those associated with attaining final height. The Assessment Group assumed that life expectancy for all conditions considered in this appraisal was lower than for the UK general population. Life expectancy for the UK general population was assumed to be 75 years for men and 79 years for women. Life expectancy for people with growth hormone deficiency, Prader–Willi syndrome, born small for gestational age and SHOX deficiency was assumed to be reduced to 68 years for men and 70 years for women. Life expectancy for women with Turner syndrome was assumed to be 70 years. For men with CRI life expectancy was assumed to be 35 years and 42 years for women with CRI. Ages at start and end of treatment and duration of treatment for growth hormone deficiency, CRI, Prader–Willi syndrome and small for gestational age were taken from the KIGS database. For SHOX deficiency, age at start of treatment was taken from the study described in section 4.1.25. The clinical effectiveness of somatropin was taken from the systematic review (sections 4.1.4 to 4.1.27) and where possible from the best quality RCT with at least 2 years of treatment duration. Data for clinical effectiveness were not available for growth hormone deficiency, so the Assessment Group used data from the KIGS database. For the children born small for gestational age, data were used from a study with 1 year of treatment. In addition, for Turner syndrome, age‑specific height SDS data were taken from the KIGS database. For the studies that had not reported height gain in centimetres, the Assessment Group converted height SDS values to centimetres using the height table from the Health Survey for England 2003. The Assessment Group assumed an adherence rate of 85% based on a study identified by Merck Serono. The Assessment Group's model used utility values derived from the study described in section 4.1.29. The Assessment Group assumed that children in the treated and untreated groups would have no difference in terms of age, sex, social class, weight and long‑standing illness, and would differ only in height. Therefore the Assessment Group derived the utility estimates for health‑related quality of life for the treated and untreated groups from the differences in height alone. When estimating cost effectiveness, the Assessment Group used utility values from regression analyses, whereby a gain of 1 height SDS was associated with a change in health‑related quality of life utility of 0.061 for people shorter than −2.0 height SDS. For the subgroup with a height SDS between −2.0 and 0.0, an increase in height SDS of 1 was associated with an increase in utility of 0.01. For people with Prader–Willi syndrome, the Assessment Group considered that treatment with somatropin may be associated with an additional health benefit linked to a change in body composition, which in turn may lead to a reduced likelihood of diabetes and cardiovascular disease. Because of the high uncertainty around the estimates of health‑related quality of life, the Assessment Group assumed no benefit associated with a change in body composition in the base case. The Assessment Group also conducted a scenario analysis using changes in utility from a study that found that a one‑unit decrease in BMI over 1 year was associated with a gain in utility of 0.017. This value was applied independent of age and sex. The Assessment Group used costs in the model based upon those used in the model for NICE technology appraisal guidance 42. The Assessment Group assumed an average drug cost of £21.06 in the base case and varied the price in sensitivity analyses from £18.00 to £23.18. Drug costs were calculated according to the dosage recommended and the weight of the child. The Assessment Group obtained weight of children at different ages from the KIGS database. The ICERs (cost per cm) for the base case were £2798 per cm gained for growth hormone deficiency; £3407 per cm gained for growth hormone deficiency with treatment continued through the transition phase of early adulthood; £6536 per cm gained for Turner syndrome; £5869 per cm gained for Prader–Willi syndrome; £3696 per cm gained for CRI; £9697 per cm gained for small for gestation age and £8062 per cm gained for SHOX deficiency. The ICERs (cost per QALY gained) for the base case were £23,196 per QALY gained for growth hormone deficiency; £28,244 per QALY gained for growth hormone deficiency with treatment continued through the transition phase of early adulthood; £39,460 per QALY gained for Turner syndrome; £135,311 per QALY gained for Prader–Willi syndrome; £39,273 per QALY gained for CRI; £33,079 per QALY gained for small for gestation age and £40,531 per QALY gained for SHOX deficiency. Sensitivity analyses revealed that, in general, the ICERs were not sensitive to the source of the estimate for clinical effectiveness (that is, whether the data came from the KIGS database or from RCTs). However, using the KIGS database to estimate clinical effectiveness reduced the ICER for somatropin in children born small for gestational age from £33,079 to £18,980 per QALY gained. The Assessment Group noted that the gain in height in children born small for gestational age was higher in the KIGS database than in the RCT. The discount rates used for the analyses had a large effect on the results. Using discount rates that were used in the model for NICE technology appraisal guidance 42 (that is costs 6% and benefits 1.5%), the costs per QALY gained were less than £30,000 for all the conditions except Prader–Willi syndrome. In addition, for all conditions, the results of the model were most sensitive to age at the start of treatment, length of treatment, adherence and utility gain. When the lowest available price of somatropin was used in the modelling, the ICERs for growth hormone deficiency, Turner syndrome, Prader–Willi syndrome, CRI, being born small for gestational age and SHOX deficiency were reduced to £19,895, £33,766, £115,755, £33,585, £28,296 and £34,664 per QALY gained respectively. The Assessment Group also presented a scenario analysis for Prader–Willi syndrome that included a life‑long change in body composition (BMI) of 1.8 kg/m2 and an associated additional utility of 0.031. Under this analysis, the cost‑effectiveness estimate for Prader–Willi syndrome was £54,800 per QALY gained. A probabilistic sensitivity analysis undertaken for each of the conditions showed that the mean probabilistic ICERs were slightly lower than the deterministic ICERs for growth hormone deficiency, Turner syndrome, CRI, born small for gestational age and SHOX deficiency. The ICER from the probabilistic sensitivity analysis for Prader–Willi syndrome, however, was lower than the deterministic estimate. This was because of non‑linearity in the model for Prader–Willi syndrome as a result of the baseline height SDS for the treated group being –2.0, the point at which the utility gain changes. The sampling drew across two different utility gains for height SDS and therefore decreased the ICER in the probabilistic sensitivity analysis. Probabilistic sensitivity analysis estimated that the probability of cost effectiveness at thresholds of £20,000, £30,000 and £50,000 per QALY gained was 22%, 95% and 100% for growth hormone deficiency, 2%, 19% and 78% for Turner syndrome, 0%, 1% and 8% for Prader–Willi syndrome, 2%, 16% and 80% for CRI, 4%, 38% and 90% for born small for gestational age, and 1%, 15% and 74% for SHOX deficiency, respectively. ## Summary of cost effectiveness In the manufacturers' base case the ICERs for somatropin compared with no treatment were below £30,000 per QALY gained for all conditions apart from Prader–Willi syndrome for which the ICER was £32,540 per QALY gained. Using the average price for somatropin in the Assessment Group's model resulted in ICERs of £23,196 per QALY gained for growth hormone deficiency, £39,460 for Turner syndrome, £135,311 for Prader–Willi syndrome, £39,273 for CRI, £33,079 for small for gestational age and £40,531 for SHOX deficiency. The additional analysis undertaken by the Assessment Group for Prader–Willi syndrome, which assumed a lifelong change in BMI of 1.8 kg/m2 and an associated additional utility of 0.031, resulted in an ICER of £54,800 per QALY gained. # Consideration of the evidence The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of somatropin, having considered evidence on the nature of growth failure associated with growth hormone deficiency, Turner syndrome, Prader–Willi syndrome, CRI, being born small for gestational age and SHOX deficiency, and the value placed on the benefits of somatropin by people with growth failure, those who represent them, and clinical specialists. It also took into account the effective use of NHS resources. The Committee examined the evidence of clinical effectiveness presented by the manufacturers and the Assessment Group. It noted that treatment with somatropin resulted in a statistically significant increase in growth in children with the conditions under consideration and a change in body composition in children with Prader–Willi syndrome. The Committee was aware of the limitations of the evidence presented, in that the studies were small, of short duration, and reported no data on health‑related quality of life. In addition, the Committee was aware that the Assessment Group had identified only one study each for growth hormone deficiency and SHOX deficiency. However, the Committee concluded that there was sufficient evidence to demonstrate the efficacy of somatropin in promoting growth in children with these conditions. The Committee heard from the clinical specialists and patient experts that growth failure in children can be associated with considerable stigma, low‑self esteem, and learning and behavioural problems during childhood, and in some conditions may also increase the risk of diabetes, cardiovascular disease and osteoporosis later in life. The clinical specialists and patient experts highlighted that, in addition to increasing height and changing body composition, somatropin treatment has a number of other important beneficial effects. These include changes in lipid profile, increase in bone mineral density, behavioural changes, and improvement in self‑perception. The Committee therefore concluded that somatropin treatment can, in addition to promoting growth, improve quality of life and may also reduce long‑term risk of cardiovascular disease, diabetes and fracture. The Committee noted that one of the drugs appraised was a 'biosimilar' product (Omnitrope), that is, a new biopharmaceutical product that is similar to an off‑patent originator (or reference) biopharmaceutical product (Genotropin). The Committee understood that unlike conventional pharmaceuticals, which can be easily copied by chemical synthesis, biopharmaceuticals are highly complex molecules and are therefore difficult to replicate. The Committee was also aware that because the manufacturer of a 'biosimilar' product does not have access to the exact fermentation and purification process used by the manufacturer of the originator biopharmaceutical product, the originator biopharmaceutical product cannot be copied exactly. The Committee heard that this may lead to different immunological effects and therefore 'biosimilar' products may have a different safety profile from the originator biopharmaceutical product. The Committee noted that 'biosimilar' products are regulated by the European Medicines Agency (EMEA) via a centralised procedure, whereas generic versions of conventional pharmaceuticals are regulated at national level. The Committee heard that the biopharmaceutical reference product will have been authorised and marketed for several years before the introduction of a 'biosimilar' product. Therefore a substantial amount of information is available for regulatory requirements and this information will not need to be reproduced by the manufacturer of the 'biosimilar' product. It also heard, however, that significantly more data are required for 'biosimilars' than for chemical generic products and that EMEA legislation on 'biosimilars' defines the studies needed to demonstrate equivalent safety and efficacy to the biopharmaceutical reference product. The Committee was aware that making specific recommendations around the safety of a drug was outside the remit of NICE, that no evidence had been submitted on differences between the 'biosimilar' and the originator biopharmaceutical product in terms of safety or efficacy, and that current prescribing advice refers to prescription of biopharmaceutical products by brand name. Based on the marketing authorisation for Omnitrope, the Committee was satisfied that it could consider Omnitrope for the treatment of growth failure alongside the other six somatropin products. The Committee considered whether there were any differences in the clinical effectiveness of the various somatropin products. The Committee noted that the manufacturer of the 'biosimilar' product (Omnitrope) had undertaken head‑to‑head trials with the originator product as part of its regulatory submission to the EMEA and that the studies had provided evidence on the equivalence of the two products. The Committee heard from the clinical specialists that they were not aware of any differences in the products available in terms of safety and efficacy. It also heard that patient choice is an important factor in maximising adherence to therapy. However, the clinical specialists and patient experts highlighted that there appear to be no specific features that determine which product a patient will choose, and that the choice of product depends in part on the choice of delivery system and the support package offered by the manufacturer. The Committee agreed that there appeared to be no differences in the clinical effectiveness of the various somatropin products available. However, it concluded that it would be important to choose the product on an individual basis after informed discussion between the responsible clinician and the patient and/or their carer about the advantages and disadvantages of each product, particularly considering the likelihood of adherence to treatment. The Committee examined the economic modelling developed for the appraisal by the Assessment Group and by the manufacturers. The Committee was aware that the economic analysis undertaken for NICE technology appraisal guidance 42 did not take into account quality of life and presented cost‑effectiveness estimates only in terms of cost per centimetre gained. The Committee understood that TA 42 employed discount rates that are no longer recommended for use in the reference case. The Committee noted that the costs per centimetre gained calculated with the current manufacturers' and Assessment Group's models were more favourable than those reported in the economic evaluation for TA 42. The Committee discussed the utility values used in the manufacturers' and Assessment Group's economic models and noted that for all conditions except Prader–Willi syndrome these were derived from a single study that estimated utility values according to height in the general adult population using the EQ−5D. The Committee was disappointed that no attempt appeared to have been made by the manufacturers to measure the quality of life of children with growth failure despite the existence of the KIGS database, and it considered that there were a number of limitations associated with using the utility values from the only study identified. Firstly, the Committee was concerned that the utility estimates reflected the benefits of increased height in adulthood and may not capture the potential increased utility from normal height gain during childhood. Secondly, the Committee was mindful of the testimony from the clinical specialists and patient experts that somatropin treatment provides other benefits in addition to improved height (see section 4.3.3). These additional benefits would not be reflected in the utility values used. Thirdly, the Committee understood that the utility values used in the manufacturers' model were derived from an analysis that did not adjust for possible confounding factors, whereas the Assessment Group used an adjusted analysis from the same study. The Committee was concerned that the utility values from the fully adjusted regression model used by the Assessment Group may have over‑corrected with specific reference to chronic illness and social class. Finally, the Committee was not convinced that the impact of short stature would be captured adequately by the areas covered by the EQ‑5D (that is, mobility, self‑care, usual activities, pain/discomfort, and anxiety/depression). The Committee agreed therefore that the utility values used in the manufacturers' and Assessment Group's economic models were likely to underestimate both the true disutility associated with growth failure and the utility gain from somatropin treatment. For Prader–Willi syndrome, the Committee discussed the utility values used in the economic models presented by the manufacturers and the Assessment Group. The Committee noted that the manufacturers and the Assessment Group (in an exploratory scenario analysis) had modelled additional benefits associated with changes in body composition as well as those from increased height. The Committee agreed that it was appropriate to model the benefits associated with increased height and those associated with changes in body composition because both are included in the licensed indication for Prader–Willi syndrome. The Committee was aware that the manufacturers' economic model allowed an additional utility gain for the reduced diabetes risk associated with changes in body composition. However, the Committee was mindful of the limitations of the study used by the manufacturers to derive the additional utility gain for the reduction in diabetes risk. In the base case the Assessment Group did not include a utility gain associated with a change in body composition in Prader–Willi syndrome. The Committee was aware that children with Prader–Willi syndrome are in general taller at the start of treatment than children with the other conditions considered in this appraisal. The Committee understood that in the Assessment Group's model, utility gains were always lower at the taller end of the height continuum, and that this meant that the utility gains were smaller for Prader–Willi syndrome than those modelled in the base case for the other conditions (see section 4.2.16). The Committee acknowledged that BMI, as used in the Assessment Group's exploratory scenario analysis, is an accepted surrogate marker for obesity because of its broad applicability in the clinical setting; however, the Committee was not persuaded that it adequately captures the benefits associated with changes in body composition with somatropin treatment. The Committee therefore agreed that there were additional uncertainties surrounding the utility value associated with changes in body composition for children with Prader–Willi syndrome, but, as for the other conditions considered in this appraisal, the utility gains from somatropin treatment were underestimated in the economic models. The Committee considered the ICERs presented by the manufacturers and the Assessment Group. The Committee noted the large differences between the estimates presented. It recognised that the clinical effectiveness data used in the manufacturers' and the Assessment Group's economic models were obtained from different sources. The Assessment Group used data from RCTs (with the exception of growth hormone deficiency) and the manufacturers used data from the KIGS database. However, the Committee concluded that for most conditions the source of the clinical effectiveness data did not affect the magnitude of the Assessment Group's estimates. The Committee considered the cost‑effectiveness estimates presented by the manufacturers and the Assessment Group for growth hormone deficiency, CRI, Turner syndrome, born small for gestational age and SHOX deficiency. The Committee understood that the differences between the cost‑effectiveness estimates were driven largely by the different utility values used. However, the Committee agreed that neither the manufacturers' nor the Assessment Group's models took into account the likely true utility gain from increased height in childhood and from additional benefits associated with somatropin treatment (see section 4.3.8), that is, the ICERs presented were likely to be overestimates of the true values. The Committee then considered separately the ICERs for somatropin for children with Prader–Willi syndrome presented by the Assessment Group and the manufacturers. The Committee noted that the ICER presented in the Assessment Group's base case was substantially greater than that presented by the manufacturers (£135,000 per QALY gained and £32,500 per QALY gained respectively); this was a much bigger difference than observed for the other conditions. The Committee was aware, however, that the Assessments Group's base‑case analysis did not take account of any additional benefits associated with changes in body composition. It noted that when the Assessment Group modelled additional benefits associated with changes in body composition, the ICER for Prader–Willi syndrome was reduced to £54,800 per QALY gained. The Assessment Group presented to the Committee results from deterministic and probabilistic sensitivity analyses of cost effectiveness which differed markedly. The Assessment Group claimed that these differences were a result of non‑linearity in the model relating height to EQ‑5D for Prader–Willi syndrome. The Committee concluded that although the manufacturers' base case and the Assessment Group's exploratory scenario analysis did take account of some of the additional benefits associated with somatropin treatment, both models underestimated the utility gain (see section 4.3.8). The Committee considered that the true ICER for Prader–Willi syndrome was likely to be considerably less than that derived from the Assessment Group's exploratory analysis. The Committee was also aware that the ICERs presented by the manufacturers and the Assessment Group were sensitive to variation in the price of the somatropin products. It noted from sensitivity analyses undertaken by the Assessment Group that if the lowest available cost of somatropin was used the ICERs could be further substantially reduced by between £3300 and £19,600 per QALY gained. Taking the issues around utility values and the variation in price of somatropin into consideration, the Committee agreed that the ICER for somatropin for growth hormone deficiency was likely to fall below £20,000 per QALY, and the ICERs for somatropin for CRI, Turner syndrome, born small for gestational age and SHOX deficiency were likely to be between £20,000 and £30,000 per QALY gained. The Committee acknowledged the uncertainty surrounding the ICER for somatropin for Prader–Willi syndrome, with values ranging from £32,500 (the manufacturers' base‑case estimate) to £54,800 (the Assessment Group's exploratory scenario analysis including BMI effects). However, the Committee did not consider that a change in the recommendation made in NICE technology appraisal guidance 42 for the use of somatropin in this disabled and socially marginalised group of children was justified, particularly in light of duties under disability discrimination legislation to have due regard to the need to promote equality of opportunity for disabled people, and to take account of their disabilities. The Committee therefore concluded that within its marketing authorisation somatropin represents a cost‑effective treatment for children with growth failure associated with all the conditions under consideration. The Committee also concluded that in light of the apparent equivalence of the clinical effectiveness of the different somatropin products, the least costly product that, after discussion between the responsible clinician and the patient and/or their carer, has been agreed to meet the needs of the individual child and to maximise the likelihood of adherence to treatment should be chosen. The Committee considered the criteria for discontinuing treatment with somatropin. The Committee heard from the clinical specialists that the criteria used for the discontinuation of somatropin in UK clinical practice are consistent with those recommended in NICE technology appraisal guidance 42. It noted that neither the manufacturers' nor the Assessment Group's economic models sought to define rules for discontinuing somatropin treatment, including after attainment of final height as recommended in TA 42. The Committee concluded that criteria for the discontinuation of somatropin treatment should remain in line with those in TA 42. Treatment should be discontinued if any of the following apply: growth velocity increases less than 50% from baseline in the first year of treatment final height is approached and growth velocity is less than 2 cm total growth in 1 year there are insurmountable problems with adherence final height is attained.In Prader–Willi syndrome evaluation of response to therapy should also consider body composition.Treatment should not be discontinued by default. The decision to stop treatment should be made in consultation with the patient and/or carers either by: a paediatrician with specialist expertise in managing growth hormone disorders in children, or an adult endocrinologist, if care of the patient has been transferred from paediatric to adult services.# Recommendations for further research The following trials are currently ongoing: Study NCT00190658 aims to compare the mean first year growth velocity of prepubertal children with SHOX deficiency treated with somatropin with the growth velocity of a control group of untreated prepubertal children with SHOX deficiency. Estimated end date: December 2010. Study NCT00625872 focuses on the effect of a 1‑year somatropin treatment (35 microgram/kg per day or 67 microgram/kg per day) in short children born small for gestational age on neuromuscular function and cognitive performance. End date not reported. There is a controlled cohort study examining health‑related quality of life in family members of children prescribed growth hormone treatment for idiopathic growth hormone deficiency, acquired growth hormone deficiency and Turner syndrome. In September 2009, one of the investigators informed NICE that results were not expected until the end of 2010. A standardised quality‑of‑life assessment measuring quality of life in children and in adults is needed for use in future RCTs and studies designed to measure quality of life. Good quality research is needed on the long‑term effects of somatropin treatment during childhood on body composition, psychological health, diabetes, cardiovascular disease and bone health, and life expectancy, particularly for people with Prader–Willi syndrome. Good quality research is needed on somatropin treatment in short children born small for gestational age using dosages of somatropin matching the licensing criteria.# Related NICE guidance There is no related NICE guidance.# Review of guidance The guidance was last considered for review in June 2022. It was concluded that no new evidence was identified as likely to change the existing recommendations in TA188. The guidance will therefore remain unchanged, in its current form, unless or until NICE becomes aware of substantive information which would make it reconsider.Andrew DillonChief ExecutiveMay 2010# Changes after publication December 2014: minor maintenance. February 2014: implementation section updated to clarify human growth hormone (somatropin) is recommended as an option for treating growth failure in children. Additional minor maintenance update also carried out. March 2012: minor maintenance. A minor correction was made to section 6.1 of the guidance in July 2010. This does not affect the funding direction, which applies from the original date of publication in May 2010.# About this guidance NICE technology appraisal guidance is about the use of new and existing medicines and treatments in the NHS in England and Wales. This guidance was developed using the NICE multiple technology appraisal process. It replaces NICE technology appraisal guidance 42 issued in May 2002. The review and re‑appraisal of human growth hormone (somatropin) for the treatment of growth failure in children has resulted in a change in the guidance. Human growth hormone (somatropin) is still recommended for the treatment of growth failure in children with growth hormone deficiency, Turner syndrome, Prader–Willi syndrome and chronic renal insufficiency, but there has been an extension of the guidance to include growth failure associated with either of the two following conditions: born small for gestational age with subsequent growth failure at 4 years of age or later short stature homeobox‑containing gene (SHOX) deficiency. We have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available. Your responsibility This guidance represents the views of NICE and was arrived at after careful consideration of the evidence available. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. However, the guidance does not override the individual responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or guardian or carer. Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties. Copyright © National Institute for Health and Clinical Excellence 2010. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not‑for‑profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.	{'Guidance': 'This guidance replaces NICE technology appraisal guidance 42 issued in May 2002.\n\nFor details, see about this guidance.\n\nSomatropin (recombinant human growth hormone) is recommended as a treatment option for children with growth failure associated with any of the following conditions:\n\ngrowth hormone deficiency\n\nTurner syndrome\n\nPrader–Willi syndrome\n\nchronic renal insufficiency\n\nborn small for gestational age with subsequent growth failure at 4 years of age or later\n\nshort stature homeobox‑containing gene (SHOX) deficiency.\n\nTreatment with somatropin should always be initiated and monitored by a paediatrician with specialist expertise in managing growth hormone disorders in children. The choice of product should be made on an individual basis after informed discussion between the responsible clinician and the patient and/or their carer about the advantages and disadvantages of the products available, taking into consideration therapeutic need and the likelihood of adherence to treatment. If, after that discussion, more than one product is suitable, the least costly product should be chosen.\n\nTreatment with somatropin should be discontinued if any of the following apply:\n\ngrowth velocity increases less than 50% from baseline in the first year of treatment\n\nfinal height is approached and growth velocity is less than 2\xa0cm total growth in 1\xa0year\n\nthere are insurmountable problems with adherence\n\nfinal height is attained.In Prader–Willi syndrome evaluation of response to therapy should also consider body composition.Treatment should not be discontinued by default. The decision to stop treatment should be made in consultation with the patient and/or carers either by:\n\na paediatrician with specialist expertise in managing growth hormone disorders in children, or\n\nan adult endocrinologist, if care of the patient has been transferred from paediatric to adult services.', 'Clinical need and practice': "Human growth hormone is produced by the anterior pituitary gland. The synthetic form is called somatropin (recombinant human growth hormone). Human growth hormone is essential for normal growth in children. It increases growth by a direct action on the growth plates and by production of insulin‑like growth factors (especially IGF‑1), mainly in the liver. Human growth hormone also has important effects on the metabolism of proteins, lipids and carbohydrates, not only during childhood, but also throughout adult life. Growth failure in children can be a result of growth hormone deficiency, but also occurs in children with Turner syndrome, chronic renal insufficiency (CRI), short stature homeobox‑containing gene (SHOX) deficiency, and in children born small for gestational age.\n\nGrowth hormone deficiency occurs when the pituitary gland does not produce enough human growth hormone, which is the most common endocrine cause of short stature. Growth hormone deficiency may occur as an isolated hormonal deficiency or in combination with deficiencies in several pituitary hormones arising from hypopituitarism, tumours in the central nervous system, cranial irradiation or other physiological causes. The prevalence of growth hormone deficiency is estimated to be between 1 in 3500 and 1 in 4000 children. In about half of the children with growth hormone deficiency (50%), the cause is unknown (idiopathic growth hormone deficiency).\n\nTurner syndrome is a chromosomal disorder characterised by the complete or partial lack of one X chromosome in girls. The two most common clinical features are short stature and ovarian failure. Girls with Turner syndrome do not have a deficiency in human growth hormone, although they may have a relative lack of sensitivity to human growth hormone because of haploinsufficiency of the short stature homeobox‑containing gene. Not all girls with Turner syndrome need treatment with somatropin. Turner syndrome occurs in between 1 in 1500 and 1 in 2500 live female births. If untreated, girls with Turner syndrome have a final adult height of 136–147\xa0cm. Adult women with Turner syndrome are on average 20 cm shorter than other adult women.\n\nPrader–Willi syndrome is a genetic disorder caused by an abnormality of chromosome 15. Common clinical characteristics include hypogonadism, short stature, hypotonia, dysmorphic features, hypoventilation, changes in body composition, obesity and obesity‑related diseases, and behavioural problems. Prader–Willi syndrome occurs in between 1 in 15,000 and 1 in 25,000 live births. Men with Prader–Willi syndrome have a final adult height of about 154\xa0cm; women have a final adult height of 145–159\xa0cm.\n\nChronic renal insufficiency (CRI), which may include end‑stage renal disease, is defined as a persistent elevation of serum creatinine and/or urea. It can be caused by a variety of conditions, including congenital disorders, glomerular disorders and infections. Growth failure associated with CRI usually begins when the glomerular filtration rate falls to 50% of normal. Not all people with CRI in childhood will be shorter than average; figures from the UK Renal Registry indicate that 29% of children who undergo renal transplantation and 41% of children on dialysis are below the 2nd percentile for height within their first year and remain so throughout childhood because of more pronounced deceleration in height velocity. Children with congenital disorders leading to CRI (approximately 60% of children with CRI) are of normal length at birth, but are below the 3rd percentile for height within their first year and remain so throughout childhood.\n\nVarious thresholds for height and weight at birth are used to define 'small for gestational age', the three most commonly used being:\n\na height at birth that is 2 standard deviations or more below the population average, or\n\na weight at birth that is 2 standard deviations or more below the population average, or\n\na weight at birth below the 10th percentile.In addition to accurate measurements of a newborn's weight, length and head circumference, the diagnosis of small for gestational age requires accurate assessment of gestational age and valid data from a reference population. The international consensus definition of 'small for gestational age' is a length or weight at birth that is 2 standard deviations below (\xa0−2\xa0SD) the population average for birth or weight. The licensed indication for somatropin is for growth disturbance (current height standard deviation score [SDS] \xa0−2.5 and parental adjusted height SDS \xa0−1) in short children born small for gestational age, with a birth weight and/or length below −2\xa0SD, who failed to show catch‑up growth (height velocity SDS less than 0 during the past year) by 4\xa0years of age or later. Children classified as born small for gestational age may have concurrent diagnoses such as familial short stature, Turner syndrome, or growth hormone deficiency. Approximately 10% of children born small for gestational age do not reach the normal height range. Those whose growth has not caught up by 4\xa0years of age are candidates for treatment with growth hormone.\n\nThe short stature homeobox‑containing gene (SHOX) is located on the distal ends of X and Y chromosomes and plays a role in long bone growth. Normal growth requires two functional copies of the gene. Consequently, growth impairment can occur if one copy of the SHOX gene has been inactivated by mutation or deleted (haploinsufficiency). SHOX deficiency can cause short stature in people with conditions such as Turner syndrome, Leri–Weil syndrome and dyschondrosteosis. Based on a small study (26\xa0people with SHOX haploinsufficiency compared with 45 of their unaffected relatives), children with SHOX haploinsufficiency were 3.8\xa0cm shorter (2.1 standard deviations shorter) than their unaffected relatives and this difference persisted throughout their childhood.\n\nSomatropin (recombinant human growth hormone) is currently the only active treatment option for growth failure in children with growth hormone deficiency, Turner syndrome, CRI, Prader–Willi syndrome, in short children born small for gestational age and in children with SHOX deficiency. The place of somatropin in the treatment pathway depends on the child's particular condition, his or her age at diagnosis and the licensed indications of the seven somatropin preparations that are available for use in UK practice. For girls with Turner syndrome, oxandrolone, an anabolic steroid, may be added to growth hormone treatment. In the UK, conservative strategies for the management of growth failure in children with CRI include advice on diet and nutritional supplementation.", 'The technologies': "In the UK, seven preparations of somatropin are available: Genotropin, Pfizer; Humatrope, Lilly; Norditropin, Novo Nordisk; NutropinAq, Ipsen; Omnitrope, Sandoz; Saizen, Merck Serono; Zomacton, Ferring. Each product is produced by recombinant DNA technology and has a sequence identical to that of human growth hormone produced by the pituitary gland. The licensed indications are as follows (for the different products the wording may differ):\n\ngrowth disturbance in children due to insufficient secretion of growth hormone (growth hormone deficiency).\n\ngrowth failure in girls associated with gonadal dysgenesis (Turner syndrome).\n\ngrowth retardation in prepubertal children associated with chronic renal insufficiency (CRI).\n\nimprovement of growth and body composition in children with Prader–Willi syndrome. The diagnosis of Prader–Willi syndrome should be confirmed by appropriate genetic testing.\n\ngrowth disturbance (current height standard deviation score [SDS] \xa0−2.5 and parental adjusted height SDS \xa0−1) in short children born small for gestational age, with a birth weight and/or length below −2 SD, who failed to show catch‑up growth (height velocity SDS less than 0 during the past year) by 4\xa0years of age or later.\n\ngrowth failure associated with SHOX deficiency, as confirmed by DNA analysis.\n\nThe seven manufacturers have UK marketing authorisations for somatropin for the following indications:\n\nLilly (Humatrope): growth hormone deficiency; Turner syndrome; CRI; short children born small for gestational age and SHOX deficiency.\n\nFerring (Zomacton): growth hormone deficiency and Turner syndrome.\n\nIpsen (NutropinAq): growth hormone deficiency; Turner syndrome and CRI.\n\nNovo Nordisk (Norditropin SimpleXx): growth hormone deficiency; Turner syndrome; CRI and short children born small for gestational age.\n\nPfizer (Genotropin): growth hormone deficiency; Turner syndrome; CRI; Prader–Willi syndrome and short children born small for gestational age.\n\nSandoz (Omnitrope): growth hormone deficiency; Turner syndrome; CRI; Prader–Willi syndrome and short children born small for gestational age.\n\nMerck Serono (Saizen): growth hormone deficiency; Turner syndrome; CRI and short children born small for gestational age.\n\nThe summary of product characteristics for somatropin states that the dosage and the administration of somatropin should be tailored to the needs of each individual child. The dosage varies according to the condition being treated: 23–39\xa0microgram/kg daily or 0.7–1.0\xa0mg/m² daily for growth hormone deficiency; 45–50\xa0microgram/kg daily or 1.4\xa0mg/m² daily for Turner syndrome and CRI; 35\xa0microgram/kg daily or 1.0\xa0mg/m² daily for growth disturbance in children born small for gestational age; 35\xa0microgram/kg daily or 1.0\xa0mg/m² daily (with a maximum of 2.7\xa0mg daily) for Prader–Willi syndrome; and 45–50\xa0microgram/kg daily for SHOX deficiency. Somatropin is self‑administered or given to the child by an adult, at home, usually as a subcutaneous injection, 6–7 times a week.\n\nThe summary of product characteristics for somatropin states that side effects include headache, visual problems, nausea and vomiting, fluid retention (peripheral oedema), arthralgia, myalgia, carpal tunnel syndrome, paraesthesia, antibody formation, hypothyroidism and reactions at injection site. Paediatricians should pay particular attention when giving somatropin to children with diabetes mellitus or its risk factors, slipped capital epiphyses, idiopathic intracranial hypertension or malignancies. For full details of side effects and contraindications, see the summary of product characteristics.\n\nThe cost of treatment with somatropin depends on the dose, which is determined by the weight or body surface area of the child as well as by the indication for growth hormone treatment. The costs of the different somatropin products (excluding VAT; 'British national formulary' [BNF] edition 58) are: £23.18 per mg for Genotropin, £18.00 per mg for Humatrope, £21.39 per mg for Norditropin (since January 2010 £21.27 per mg), £20.70 per mg for Nutropin, £18.26 per mg for Omnitrope, £23.18 per mg for Saizen and £19.92 per mg for Zomacton. Costs may vary in different settings because of negotiated procurement discounts.\n\n Omnitrope is a 'similar biological medicinal product' or 'biosimilar'. Genotropin is the biological reference medicine for Omnitrope. 'British national formulary' 58 states the following: A similar biological medicinal product is a new biological product that is similar to a medicine that has already been authorised to be marketed (the 'biological reference medicine') in the European Union. The active substance of a biosimilar medicine is similar, but not identical, to the biological reference medicine. Biological products are different from standard chemical products in terms of their complexity and although theoretically there should be no important differences between the biosimilar and the biological reference medicine in terms of safety or efficacy, when prescribing biological products, it is good practice to use the brand name. This will ensure that substitution of a biosimilar medicine does not occur when the medicine is dispensed.", 'Evidence and interpretation': "The Appraisal Committee (appendix A) considered evidence from a number of sources (appendix B).\n\n# Clinical effectiveness\n\n## Published reviews\n\nThe Assessment Group identified three systematic reviews: one carried out for NICE technology appraisal guidance 42, a Cochrane review relating to that appraisal, and a more recent systematic review of growth hormone in Turner syndrome undertaken by the Canadian Agency for Drugs and Technologies in Health (CADTH) in 2007.\n\nThe systematic review for NICE technology appraisal guidance 42 included randomised controlled trials (RCTs) comparing somatropin with placebo or no treatment in children with growth hormone deficiency, Turner syndrome, CRI and Prader–Willi syndrome. Non‑randomised and observational studies were included when RCTs lacked data on change to final height. The Assessment Group concluded that although the quality of evidence was variable, there was evidence that treatment with somatropin could increase short‑term growth and improve final height. Results suggested that effects of somatropin on short‑term growth velocity (1\xa0year) ranged from no improvement to approximately 1 standard deviation above the normal growth velocity for children of the same age. Gains in final height for children treated with somatropin compared with untreated children ranged from approximately 3 to 11\xa0cm (for growth hormone deficiency 8–11\xa0cm, for Turner syndrome 5\xa0cm, for CRI 3–9\xa0cm, for Prader–Willi syndrome 10–11\xa0cm).\n\nThe systematic review undertaken by the CADTH included 19 RCTs or observational studies that compared somatropin with placebo or no treatment in girls with Turner syndrome. All studies included measurements of growth (final height, interim height, growth velocity), documentation of adverse events and measures of quality of life. The review found that growth was accelerated and height increased in girls taking somatropin for Turner syndrome. No serious adverse events were reported.\n\n## Assessment Group's systematic review\n\nThe Assessment Group conducted a systematic review for RCTs of somatropin in children with growth disturbance, according to the marketing authorisations for somatropin (see sections 3.1 and 3.2). The Assessment Group could not identify any RCTs meeting the inclusion criteria for children born small for gestational age. The Assessment Group included studies that compared the effectiveness of somatropin with management strategies that did not include treatment with somatropin.\n\nThe Assessment Group identified a total of 28 RCTs from 34 publications. The Assessment Group excluded a number of studies that had been included in the review for NICE technology appraisal guidance 42. This was partly because the Assessment Group included only RCTs in its review whereas the review for NICE technology appraisal guidance 42 had included non‑randomised studies. The Assessment Group also excluded three RCTs (two for Turner syndrome and one for Prader–Willi syndrome) that were included in the review for the previous appraisal. One of the excluded studies used methionyl growth hormone rather than somatropin and two others reported outcomes not included in the Assessment Group's inclusion criteria.\n\nThe studies included in the Assessment Group's systematic review reported at least one of the following outcomes: final height; height standard deviation score (height SDS); growth velocity; growth velocity SDS; body composition; biochemical and metabolic markers; and adverse events. None of the studies reported health‑related quality of life. The Assessment Group did not perform a meta‑analysis because of heterogeneity in study design and participants. For conciseness, only growth outcomes and adverse events are presented here for growth hormone deficiency, Turner syndrome, CRI, small for gestational age and SHOX deficiency. For Prader–Willi syndrome, a summary of outcomes for body composition is also presented.\n\nThe Assessment Group identified one RCT comparing treatment with somatropin against no treatment in children with growth hormone deficiency. Children in the treated group (n\xa0=\xa09) grew an average of 2.7\xa0cm per year faster than those receiving no treatment (n\xa0=\xa010) in the 12\xa0months of the study. The difference between the groups was statistically significant (p\xa0<\xa00.05). Children in the treated group had a statistically significantly higher height SDS (−2.3\xa0±\xa00.45) than children in the untreated group (−2.8\xa0±\xa00.45; p\xa0<\xa00.05). The study did not report adverse events. The study was unblinded and did not report an intention‑to‑treat analysis. The Assessment Group considered the reporting and the methodological quality of the study to be mixed.\n\nThe Assessment Group identified six RCTs of somatropin for the treatment of growth restriction in girls with Turner syndrome. All six studies were published after the publication of NICE technology appraisal guidance 42. Two of the included studies (of 9 and 12\xa0girls respectively) had a crossover design that compared somatropin with placebo. Of the four remaining studies, two (of\xa089\xa0and 154 girls) compared somatropin with no treatment, one (of\xa058 girls) compared somatropin with low‑dose oestrogen, and one (of 232 girls) compared somatropin with placebo. The Assessment Group considered the reporting and methodological quality of the studies to be generally poor.\n\nThe two studies that reported final height as an outcome found a statistically significant difference in height between the treated and untreated groups at the end of the studies (p\xa0<\xa00.001). In one of the studies, girls grew an average of 9.3\xa0cm more from baseline than those in the untreated group. In the other study, which recruited younger girls, the difference was 7.6\xa0cm. Both studies reported statistically significantly higher height SDS in girls treated with somatropin than in untreated girls. Height velocity was statistically significantly greater in the treated groups in the three studies reporting height velocity as an outcome. One study reported height velocity at the end of the first and second years; height velocity was greater in the first year and fell in the second year in both treatment groups.\n\nAdverse events were reported in four studies. One study reported higher rates of adverse events in the treated group, one reported similar levels across groups, and one reported a significantly more frequent occurrence or worsening of ear infections. One study reported four withdrawals because of problems with adherence.\n\nThe Assessment Group identified eight RCTs from 13 publications that investigated somatropin for the treatment of Prader–Willi syndrome and that met the inclusion criteria for this review. Three had been considered previously for NICE technology appraisal guidance 42 and five were new studies published after the guidance. Seven of the RCTs compared somatropin at a dosage of 1\xa0mg/m2 body surface area per day with no treatment for 1\xa0year (six\xa0studies) or 2\xa0years (two studies, including one which treated infants for 1\xa0year only). One study (of 14 children) was a crossover RCT that compared somatropin at a dosage of 43\xa0microgram/kg body weight per day with placebo over 6\xa0months in each treatment group. The doses used in the included studies reflect the marketing authorisations for the different preparations of somatropin. The Assessment Group considered the reporting of the studies to be generally poor.\n\nIn the only study that reported changes in height, infants who received somatropin for 1\xa0year grew an average of 6.2\xa0cm more than those in the untreated group (p\xa0<\xa00.001). Two studies reported a statistically significant difference in height SDS at end of treatment between participants randomised to treatment and those randomised to no treatment. A difference of 1\xa0SDS (favouring somatropin treatment) was reported in one study at 1\xa0year (p\xa0\xa00.01) and more than\xa02\xa0SDS in the other at 2\xa0years (p\xa0<\xa00.0001).\n\nThree studies reported growth velocity as an outcome. Children treated with somatropin grew 3\xa0cm per year more than untreated children in one study and 5\xa0cm per year more in another. Another study reported a positive growth velocity SDS for children treated with somatropin and a negative growth velocity SDS for untreated children (5.5 versus −2.3). The differences between groups were statistically significant in all three studies.\n\nFour studies reported a statistically significantly lower percentage of body fat in children treated with somatropin compared with children who received no treatment or who received placebo. In one study, the mean percentage of body fat was 10% lower for children treated with somatropin than for untreated children (p\xa0=\xa00.03). In this study children treated with somatropin experienced approximately a 5% reduction in body fat, compared with an average 4% increase in body fat in the untreated children (p\xa0=\xa00.001). Two other two studies reported that treated children had approximately 4% or 7% less body fat than those in the comparator group. The fourth study did not report the percentage body fat for infants, but did report this outcome for children over 4\xa0years. Children who received somatropin for a year had a median percentage body fat SDS of 1.5, compared with 2.3 in the control group (p\xa0<\xa00.001). After 2 years of treatment, the SDS values were 1.9 versus 2.4 for the treated and untreated groups respectively (p\xa0<\xa00.001).\n\nFour studies reported that children treated with somatropin had a statistically significantly higher lean body mass or a larger increase in lean body mass than untreated children. In one study, the lean body mass of children treated with somatropin increased by 1.8\xa0kg more than in the untreated group (3.6 versus 1.8\xa0kg, p\xa0<\xa00.001). In two other studies children treated with somatropin had approximately 2\xa0kg or 4\xa0kg more lean body mass than untreated children (p\xa0<\xa00.05 and p\xa0<\xa00.01 respectively). One study reported that change in trunk lean body mass was statistically significantly greater for treated than for untreated infants (1.7 versus 0.7 respectively). For children (but not infants), the study reported SDS for lean body mass adjusted for age and height, as well as change in trunk lean body mass. There was a statistically significant difference for all of these outcomes between treated and untreated children after both 1 and 2\xa0years of treatment.\n\nSix studies reported body mass index (BMI), but results were mixed. Some studies showed higher values of BMI in treated groups, and others showed no difference. One study reported a BMI of 16.1 after 1\xa0year for children treated with somatropin compared with 18.5 for untreated children (p\xa0<\xa00.05); results were similar after 2\xa0years. A small crossover RCT also reported a statistically significant difference in BMI for treated children compared with those receiving placebo (31.2 compared with 32.8, p\xa0<\xa00.05). In contrast, two studies found no statistically significant difference in BMI for children treated with somatropin and untreated children. Neither of the remaining two studies that reported BMI gave a value for between‑group statistical significance, but both treated and untreated children had similar values of BMI.\n\nNo serious adverse events were reported in the five studies that presented data.\n\nThe Assessment Group identified six RCTs that investigated somatropin treatment in children with CRI. Four had been considered for NICE technology appraisal guidance 42 (TA 42) and two were new studies published after TA 42. Two RCTs were crossover studies and four were parallel‑group studies. Three of the four parallel‑group RCTs (of 23, 69 and 203 children) had an open‑label design, with the comparator groups receiving no treatment. One trial (of 125 children) was placebo controlled. The two crossover studies (of 20 and 11 children) had placebo and treatment phases. Three of the studies investigated somatropin treatment in children who had received a kidney transplant and the other three studied children who had CRI but no renal transplant. The Assessment Group considered the reporting of the trials to be generally poor.\n\nOne study reported gain in absolute height and found that after 1\xa0year children treated with somatropin grew an average of 3.6\xa0cm more than those who were untreated (height gain 9.1\xa0cm versus 5.5\xa0cm, p\xa0<\xa00.0001). Two studies reported that height SDS showed statistically significant greater growth in children treated with somatropin than those who were untreated. Five studies reported that change in growth velocity or growth velocity SDS was statistically significantly greater for children who received somatropin treatment than for those children who did not. The between‑group differences in growth velocity ranged from 3.2\xa0cm per year to 4.2\xa0cm per year in the parallel‑group trials.\n\nNo serious adverse events were reported in the four studies that presented data.\n\nThe Assessment Group did not identify any RCTs that met the criteria for use of somatropin in children as prescribed in the licence for growth hormone in children born small for gestational age (see section 3.1). Therefore, the Assessment Group amended the criteria for the review to the following: growth disturbance (current height SDS \xa0−2.5, no reference to parental height) in children with a birth weight and/or length <\xa0−2\xa0SD and no catch‑up growth (no stated criteria) by the age of 3\xa0years.\n\nThe Assessment Group identified six RCTs that met the amended inclusion criteria for the review (of 13, 40, 40, 54, 151 and 168 children). All studies compared somatropin with no treatment. Duration of treatment was comparable across five of the six studies. In the sixth study children received treatment for 2\xa0years, but only the first year allowed a randomised comparison between somatropin and no treatment. Only one study included a treatment arm with the licensed dose of somatropin; the other studies all used approximately two to three times the dose licensed for use in the UK. The Assessment Group considered the studies to be generally of poor methodological quality.\n\nOne study reported a total gain in adult height of approximately 4\xa0cm in people who had received somatropin. The difference between groups was statistically significant (p\xa0<\xa00.005). Adult height SDS was also statistically significantly higher in people who had received somatropin. However, the study used a dose approximately twice that licensed for use in the UK, and the study included children with a mean age of 12.7\xa0years at start of treatment. The Assessment Group cautioned that generalisability of the results may be limited. One study reported that children who received somatropin at a dosage of 33\xa0microgram/kg body weight per day (licensed dosage 35\xa0microgram/kg per day) gained an additional 3.3\xa0cm in height compared with untreated children, and those who received a higher dose of 100\xa0microgram/kg per day gained 6.5\xa0cm after 1 year's treatment. Height SDS was statistically significantly higher in children treated with somatropin in two studies, and higher (but with no reported p value) in two others. Treatment was associated with a greater growth velocity at the end of year 2 in the two studies that reported this outcome, but the difference was reported to be statistically significant in only one study (p\xa0<\xa00.001).\n\nFour studies reported limited information on adverse events. One study reported two adverse events in treated children. A second reported only that there were 'no noteworthy' adverse events. A third study reported four serious adverse events that were not linked to the study drug. In the remaining study, three adverse events were linked to somatropin and resolved or stabilised after stopping treatment.\n\nThe Assessment Group identified one study of children with SHOX deficiency. The 2‑year multicentre RCT compared a daily injection of 50\xa0micrograms of somatropin with no treatment in 52 prepubertal children with confirmed SHOX deficiency. The Assessment Group stated that because the study did not report the mean baseline weight of participants it was not possible to calculate dosage by body weight and to know whether or not the study used a licensed dose of somatropin. The unblinded study did not report an intention‑to‑treat analysis.\n\nBy the end of the second year, children treated with somatropin had gained statistically significantly more height and had higher values of height SDS than those in the control group. Treatment with somatropin led to a statistically significantly greater growth velocity in both years 1 and 2 (3.5\xa0cm/year greater than in untreated children in year 1, and 1.9\xa0cm/year greater in year 2).\n\nSomatropin treatment in children with SHOX deficiency was not associated with any serious adverse events in this study.\n\n## Summary of clinical effectiveness\n\nThe identified studies reported statistically significantly greater values for height SDS for children treated with somatropin than for untreated children for all indications. For children with Prader–Willi syndrome, treatment with somatropin was also associated with statistically significant changes in measures of body composition. None of the studies reported data on health‑related quality of life and the reporting of adverse events was limited.\n\n## Health‑related quality of life\n\nBecause there were no data on health‑related quality of life in studies included in the systematic reviews, the Assessment Group undertook a literature search to identify publications reporting utility values in relation to height. One study was identified that provided estimates for utility based on the EuroQoL (EQ‑5D) for different height SDS from the Health Survey for England for an adult general population (14,416 adults). Inter‑relationships using linear regression between height SDS and quality of life were assessed for height SDS alone, and also controlling for age, body weight, sex, social class and long‑standing illness. The study identified a positive correlation between an increase in height and a participant's EQ‑5D score. Mean EQ‑5D scores were lower in people who were shorter than in people who were taller, as well as lower than the overall population mean. The study categorised participants into three groups: people shorter than −2.0 height SDS, people with a height SDS between −2.0 and 0.0, and people with average or above average height. The EQ‑5D scores for these groups were statistically significantly different from each other (p\xa0<\xa00.05). Adjusted for potential confounders, increasing values of height were associated with greater gains in quality of life in shorter people compared with taller people. An increase in height SDS of 1.0 was associated with an increase in EQ‑5D score in the shortest group of 0.061, an increase of 0.010 in the middle group, and an increase of 0.002 in the group with average or above average height.\n\nThe Assessment Group concluded that there was likely to be a gain in utility associated with height gain for people receiving treatment with somatropin. The Assessment Group acknowledged that the available evidence for utility excludes potential benefits of treatment with somatropin which include change in body composition and lipid profiles.\n\n# Cost effectiveness\n\n## Published studies\n\nThe economic evaluation undertaken for NICE technology appraisal guidance 42 consisted of separate cost‑effectiveness models for each condition under review comparing somatropin treatment with no treatment (defined as growth monitoring). Importantly, this analysis estimated under base‑case conditions the cost per centimetre gained in final height. The economic analysis estimated this cost as approximately £6000 per cm final height for growth hormone deficiency, from £15,800 to £17,300 per cm for Turner syndrome, from £7400 to £24,100 per cm for CRI, and approximately £7030 per cm for Prader–Willi syndrome.\n\nThe Assessment Group identified two North American economic evaluations for somatropin treatment, which had been published since the economic evaluation for NICE technology appraisal guidance 42: one for children with Turner syndrome (by the CADTH) and one for children with growth hormone deficiency. The economic evaluation of somatropin treatment in children with Turner syndrome estimated an incremental cost‑effectiveness ratio (ICER) of C$243,078 per quality‑adjusted life year (QALY) gained. The economic evaluation of somatropin treatment in children with growth hormone deficiency estimated ICERs of US$36,995 per QALY for the 5‑ to 16‑year‑old cohort and US$42,556 per QALY gained for the 3‑ to 18‑year‑old cohort.\n\nThe Assessment Group stated that the two different estimates of cost effectiveness were largely because of differences in the choice of estimates of utility (the utility increment associated with growth hormone treatment ranged from 0.040 to 0.189) and difference in assumptions on effectiveness. The Assessment Group considered the economic evaluation undertaken by the CADTH to be of higher quality, and the parameter estimates more appropriate, because the group established the effectiveness of the treatment from a systematic review. The Assessment Group concluded that the previous economic evaluations lacked reliable estimates of gains in utility associated with treatment with somatropin, and that the results should be treated with caution.\n\n## Manufacturers' economic model\n\nSix of the seven manufacturers submitted cost‑effectiveness evidence. The Assessment Group stated that the cost‑effectiveness evidence submitted by Sandoz, a cost‑minimisation analysis using Genotropin as a comparator, did not comply with the requirements for the NICE reference case The submission contained a comparison of the annual cost of treatment with Omnitrope and with Genotropin in children with growth hormone deficiency and Turner syndrome.\n\nFive of the six manufacturers (Lilly, Ipsen, Novo Nordisk, Pfizer and Merck Serono) collaborated to develop a de novo core economic model to estimate the cost effectiveness of somatropin treatment in children with growth hormone deficiency, Turner syndrome, Prader–Willi syndrome, CRI or children born small for gestational age. The model was developed by Pfizer, but each of the collaborating manufacturers presented the model with minor modifications (for example, changes in the unit price of somatropin). Merck Serono's economic model included a waste elimination model to examine the differences in costs likely to be associated with using the Easypod device rather than other delivery systems. Novo Nordisk constructed a decision tree model to assess the cost effectiveness of somatropin treatment for the four licensed indications for Norditropin (that is, growth hormone deficiency, Turner syndrome, CRI and being born small for gestational age). The assumptions underpinning the model, source of clinical effect, and utility data were identical to those in the core economic model.\n\n## Manufacturers' core economic model\n\nThe manufacturers developed a Markov cohort model for the economic evaluation containing two health states: 'alive' and 'dead'. The manufacturers estimated the transition probabilities between states using UK‑specific mortality rates observed in the general population. The economic model considered a 1‑year cycle length. Two alternative model structures were also presented. One allowed for a reduction in the risk of osteoporosis in children with growth hormone deficiency treated with somatropin and assumed that some children with growth hormone deficiency would continue treatment until they reached 25\xa0years of age. A second model incorporated a cost‑effectiveness analysis of somatropin in Prader–Willi syndrome. This model assumed that people with Prader–Willi syndrome and diabetes would have a 10% lower quality of life than those without diabetes.\n\nThe manufacturers assumed no difference in life expectancy between the general population and those with growth hormone deficiency, Turner syndrome, Prader–Willi, CRI, being born small for gestational age or SHOX deficiency. For Prader–Willi syndrome, the manufacturers assumed that changes in body composition associated with somatropin treatment would result in a reduction in the risk of developing diabetes and death related to diabetes. They assumed that the prevalence of diabetes among people with Prader–Willi syndrome would be reduced from 8% to 2%.\n\nThe utility values used in the model for children with growth hormone deficiency, Turner syndrome, CRI and children born small for gestational age were taken from the study described in section 4.1.29. The manufacturers assumed that a gain in height was associated with improvement in quality of life, which was assessed using the EQ‑5D utility scale. The values were interpolated from the association between height SDS and EQ‑5D score unadjusted for other factors that might be associated with both height and quality of life. The gain in utility value for Prader–Willi syndrome was based on a study of 13 adults with Prader–Willi syndrome who received somatropin for 2\xa0years. The estimate for clinical effectiveness and many of the other parameters used in the model were derived from the Kabi International Growth (KIGS) observational database, a large‑scale collaborative database developed by Pfizer to store data on the safety and efficacy of treatment with somatropin. As SHOX deficiency is not a licensed indication of Genotropin, it is not included in the KIGS database Therefore the same values were assumed for SHOX deficiency as for Turner syndrome.\n\nThe costs used in the model were those used in the model for NICE technology appraisal guidance 42 and were adjusted for inflation to current prices. The mean daily per patient cost for each manufacturer's formulation of somatropin was based on the unit costs described in section 3.5.\n\nFor comparison with NICE technology appraisal guidance 42, the base‑case analyses estimated the incremental cost of somatropin per centimetre of height gained relative to no treatment. Costs ranged from £1699 to £2136 per cm gained for growth hormone deficiency, from £2022 to £2596 per cm gained for growth hormone deficiency with somatropin continued through the transition years from age 18 to 25\xa0years, from £8258 to £10,576 per cm gained for Turner syndrome, from £7048 to £11,345 per cm gained for CRI and from £1932 to £9123 per cm gained for small for gestational age. The base‑case analyses for Prader–Willi syndrome and SHOX deficiency produced costs per centimetre gained of £2925 and £8258 respectively.\n\nThe incremental cost effectiveness ratios (ICERs) for the base case ranged from: £15,730 to £17,522 per QALY gained for growth hormone deficiency; £18,721 to £20,881 per QALY gained for growth hormone deficiency with somatropin continued through the transition years from age 18 to 25; £26,630 to £29,757 per QALY gained for Turner syndrome, £12,498 to £15,962 per QALY gained for CRI and from £14,221 to £18,655 per QALY gained for small for gestational age. The base‑case analyses for Prader–Willi syndrome and SHOX deficiency produced ICERs of £32,540 and £23,237 per QALY gained respectively.\n\nThe ICERs were most sensitive to the choice of utility values, time horizon, discount rates, treatment duration, doses during the transition phase for those with growth hormone deficiency, the proportion of people achieving final height, and drug price.\n\n## Assessment Group's model\n\nThe Assessment Group developed a state transition Markov model based on the model developed for NICE technology appraisal guidance 42. The modelled health states were 'alive' and 'dead'. The economic model considered a cycle length of 1\xa0year and a life time horizon of 100\xa0years. The mortality rates for the population in England and Wales were applied in each cycle and the rates were adjusted upward using the standard mortality rates for each of the conditions. The Assessment Group presented an additional scenario for growth hormone deficiency in which it assumed that 34% of people with growth hormone deficiency continued treatment until age 25\xa0years at a dosage of 40\xa0microgram/day. The model assumes that this group does not receive additional benefits from somatropin beyond those associated with attaining final height.\n\nThe Assessment Group assumed that life expectancy for all conditions considered in this appraisal was lower than for the UK general population. Life expectancy for the UK general population was assumed to be 75\xa0years for men and 79\xa0years for women. Life expectancy for people with growth hormone deficiency, Prader–Willi syndrome, born small for gestational age and SHOX deficiency was assumed to be reduced to 68\xa0years for men and 70\xa0years for women. Life expectancy for women with Turner syndrome was assumed to be 70\xa0years. For men with CRI life expectancy was assumed to be 35\xa0years and 42 years for women with CRI.\n\nAges at start and end of treatment and duration of treatment for growth hormone deficiency, CRI, Prader–Willi syndrome and small for gestational age were taken from the KIGS database. For SHOX deficiency, age at start of treatment was taken from the study described in section 4.1.25. The clinical effectiveness of somatropin was taken from the systematic review (sections 4.1.4 to 4.1.27) and where possible from the best quality RCT with at least 2\xa0years of treatment duration. Data for clinical effectiveness were not available for growth hormone deficiency, so the Assessment Group used data from the KIGS database. For the children born small for gestational age, data were used from a study with 1\xa0year of treatment. In addition, for Turner syndrome, age‑specific height SDS data were taken from the KIGS database. For the studies that had not reported height gain in centimetres, the Assessment Group converted height SDS values to centimetres using the height table from the Health Survey for England 2003. The Assessment Group assumed an adherence rate of 85% based on a study identified by Merck Serono.\n\nThe Assessment Group's model used utility values derived from the study described in section 4.1.29. The Assessment Group assumed that children in the treated and untreated groups would have no difference in terms of age, sex, social class, weight and long‑standing illness, and would differ only in height. Therefore the Assessment Group derived the utility estimates for health‑related quality of life for the treated and untreated groups from the differences in height alone. When estimating cost effectiveness, the Assessment Group used utility values from regression analyses, whereby a gain of 1 height SDS was associated with a change in health‑related quality of life utility of 0.061 for people shorter than −2.0 height SDS. For the subgroup with a height SDS between −2.0 and 0.0, an increase in height SDS of 1 was associated with an increase in utility of 0.01.\n\nFor people with Prader–Willi syndrome, the Assessment Group considered that treatment with somatropin may be associated with an additional health benefit linked to a change in body composition, which in turn may lead to a reduced likelihood of diabetes and cardiovascular disease. Because of the high uncertainty around the estimates of health‑related quality of life, the Assessment Group assumed no benefit associated with a change in body composition in the base case. The Assessment Group also conducted a scenario analysis using changes in utility from a study that found that a one‑unit decrease in BMI over 1\xa0year was associated with a gain in utility of 0.017. This value was applied independent of age and sex.\n\nThe Assessment Group used costs in the model based upon those used in the model for NICE technology appraisal guidance 42. The Assessment Group assumed an average drug cost of £21.06 in the base case and varied the price in sensitivity analyses from £18.00 to £23.18. Drug costs were calculated according to the dosage recommended and the weight of the child. The Assessment Group obtained weight of children at different ages from the KIGS database.\n\nThe ICERs (cost per cm) for the base case were £2798 per cm gained for growth hormone deficiency; £3407 per cm gained for growth hormone deficiency with treatment continued through the transition phase of early adulthood; £6536 per cm gained for Turner syndrome; £5869 per cm gained for Prader–Willi syndrome; £3696 per cm gained for CRI; £9697 per cm gained for small for gestation age and £8062 per cm gained for SHOX deficiency.\n\nThe ICERs (cost per QALY gained) for the base case were £23,196 per QALY gained for growth hormone deficiency; £28,244 per QALY gained for growth hormone deficiency with treatment continued through the transition phase of early adulthood; £39,460 per QALY gained for Turner syndrome; £135,311 per QALY gained for Prader–Willi syndrome; £39,273 per QALY gained for CRI; £33,079 per QALY gained for small for gestation age and £40,531 per QALY gained for SHOX deficiency.\n\nSensitivity analyses revealed that, in general, the ICERs were not sensitive to the source of the estimate for clinical effectiveness (that is, whether the data came from the KIGS database or from RCTs). However, using the KIGS database to estimate clinical effectiveness reduced the ICER for somatropin in children born small for gestational age from £33,079 to £18,980 per QALY gained. The Assessment Group noted that the gain in height in children born small for gestational age was higher in the KIGS database than in the RCT.\n\nThe discount rates used for the analyses had a large effect on the results. Using discount rates that were used in the model for NICE technology appraisal guidance 42 (that is costs 6% and benefits 1.5%), the costs per QALY gained were less than £30,000 for all the conditions except Prader–Willi syndrome. In addition, for all conditions, the results of the model were most sensitive to age at the start of treatment, length of treatment, adherence and utility gain.\n\nWhen the lowest available price of somatropin was used in the modelling, the ICERs for growth hormone deficiency, Turner syndrome, Prader–Willi syndrome, CRI, being born small for gestational age and SHOX deficiency were reduced to £19,895, £33,766, £115,755, £33,585, £28,296 and £34,664 per QALY gained respectively.\n\nThe Assessment Group also presented a scenario analysis for Prader–Willi syndrome that included a life‑long change in body composition (BMI) of 1.8\xa0kg/m2 and an associated additional utility of 0.031. Under this analysis, the cost‑effectiveness estimate for Prader–Willi syndrome was £54,800 per QALY gained.\n\nA probabilistic sensitivity analysis undertaken for each of the conditions showed that the mean probabilistic ICERs were slightly lower than the deterministic ICERs for growth hormone deficiency, Turner syndrome, CRI, born small for gestational age and SHOX deficiency. The ICER from the probabilistic sensitivity analysis for Prader–Willi syndrome, however, was lower than the deterministic estimate. This was because of non‑linearity in the model for Prader–Willi syndrome as a result of the baseline height SDS for the treated group being –2.0, the point at which the utility gain changes. The sampling drew across two different utility gains for height SDS and therefore decreased the ICER in the probabilistic sensitivity analysis.\n\nProbabilistic sensitivity analysis estimated that the probability of cost effectiveness at thresholds of £20,000, £30,000 and £50,000 per QALY gained was 22%, 95% and 100% for growth hormone deficiency, 2%, 19% and 78% for Turner syndrome, 0%, 1% and 8% for Prader–Willi syndrome, 2%, 16% and 80% for CRI, 4%, 38% and 90% for born small for gestational age, and 1%, 15% and 74% for SHOX deficiency, respectively.\n\n## Summary of cost effectiveness\n\nIn the manufacturers' base case the ICERs for somatropin compared with no treatment were below £30,000 per QALY gained for all conditions apart from Prader–Willi syndrome for which the ICER was £32,540 per QALY gained. Using the average price for somatropin in the Assessment Group's model resulted in ICERs of £23,196 per QALY gained for growth hormone deficiency, £39,460 for Turner syndrome, £135,311 for Prader–Willi syndrome, £39,273 for CRI, £33,079 for small for gestational age and £40,531 for SHOX deficiency. The additional analysis undertaken by the Assessment Group for Prader–Willi syndrome, which assumed a lifelong change in BMI of 1.8\xa0kg/m2 and an associated additional utility of 0.031, resulted in an ICER of £54,800 per QALY gained.\n\n# Consideration of the evidence\n\nThe Appraisal Committee reviewed the data available on the clinical and cost effectiveness of somatropin, having considered evidence on the nature of growth failure associated with growth hormone deficiency, Turner syndrome, Prader–Willi syndrome, CRI, being born small for gestational age and SHOX deficiency, and the value placed on the benefits of somatropin by people with growth failure, those who represent them, and clinical specialists. It also took into account the effective use of NHS resources.\n\nThe Committee examined the evidence of clinical effectiveness presented by the manufacturers and the Assessment Group. It noted that treatment with somatropin resulted in a statistically significant increase in growth in children with the conditions under consideration and a change in body composition in children with Prader–Willi syndrome. The Committee was aware of the limitations of the evidence presented, in that the studies were small, of short duration, and reported no data on health‑related quality of life. In addition, the Committee was aware that the Assessment Group had identified only one study each for growth hormone deficiency and SHOX deficiency. However, the Committee concluded that there was sufficient evidence to demonstrate the efficacy of somatropin in promoting growth in children with these conditions.\n\nThe Committee heard from the clinical specialists and patient experts that growth failure in children can be associated with considerable stigma, low‑self esteem, and learning and behavioural problems during childhood, and in some conditions may also increase the risk of diabetes, cardiovascular disease and osteoporosis later in life. The clinical specialists and patient experts highlighted that, in addition to increasing height and changing body composition, somatropin treatment has a number of other important beneficial effects. These include changes in lipid profile, increase in bone mineral density, behavioural changes, and improvement in self‑perception. The Committee therefore concluded that somatropin treatment can, in addition to promoting growth, improve quality of life and may also reduce long‑term risk of cardiovascular disease, diabetes and fracture.\n\nThe Committee noted that one of the drugs appraised was a 'biosimilar' product (Omnitrope), that is, a new biopharmaceutical product that is similar to an off‑patent originator (or reference) biopharmaceutical product (Genotropin). The Committee understood that unlike conventional pharmaceuticals, which can be easily copied by chemical synthesis, biopharmaceuticals are highly complex molecules and are therefore difficult to replicate. The Committee was also aware that because the manufacturer of a 'biosimilar' product does not have access to the exact fermentation and purification process used by the manufacturer of the originator biopharmaceutical product, the originator biopharmaceutical product cannot be copied exactly. The Committee heard that this may lead to different immunological effects and therefore 'biosimilar' products may have a different safety profile from the originator biopharmaceutical product. The Committee noted that 'biosimilar' products are regulated by the European Medicines Agency (EMEA) via a centralised procedure, whereas generic versions of conventional pharmaceuticals are regulated at national level. The Committee heard that the biopharmaceutical reference product will have been authorised and marketed for several years before the introduction of a 'biosimilar' product. Therefore a substantial amount of information is available for regulatory requirements and this information will not need to be reproduced by the manufacturer of the 'biosimilar' product. It also heard, however, that significantly more data are required for 'biosimilars' than for chemical generic products and that EMEA legislation on 'biosimilars' defines the studies needed to demonstrate equivalent safety and efficacy to the biopharmaceutical reference product. The Committee was aware that making specific recommendations around the safety of a drug was outside the remit of NICE, that no evidence had been submitted on differences between the 'biosimilar' and the originator biopharmaceutical product in terms of safety or efficacy, and that current prescribing advice refers to prescription of biopharmaceutical products by brand name. Based on the marketing authorisation for Omnitrope, the Committee was satisfied that it could consider Omnitrope for the treatment of growth failure alongside the other six somatropin products.\n\nThe Committee considered whether there were any differences in the clinical effectiveness of the various somatropin products. The Committee noted that the manufacturer of the 'biosimilar' product (Omnitrope) had undertaken head‑to‑head trials with the originator product as part of its regulatory submission to the EMEA and that the studies had provided evidence on the equivalence of the two products. The Committee heard from the clinical specialists that they were not aware of any differences in the products available in terms of safety and efficacy. It also heard that patient choice is an important factor in maximising adherence to therapy. However, the clinical specialists and patient experts highlighted that there appear to be no specific features that determine which product a patient will choose, and that the choice of product depends in part on the choice of delivery system and the support package offered by the manufacturer. The Committee agreed that there appeared to be no differences in the clinical effectiveness of the various somatropin products available. However, it concluded that it would be important to choose the product on an individual basis after informed discussion between the responsible clinician and the patient and/or their carer about the advantages and disadvantages of each product, particularly considering the likelihood of adherence to treatment.\n\nThe Committee examined the economic modelling developed for the appraisal by the Assessment Group and by the manufacturers. The Committee was aware that the economic analysis undertaken for NICE technology appraisal guidance 42 did not take into account quality of life and presented cost‑effectiveness estimates only in terms of cost per centimetre gained. The Committee understood that TA 42 employed discount rates that are no longer recommended for use in the reference case. The Committee noted that the costs per centimetre gained calculated with the current manufacturers' and Assessment Group's models were more favourable than those reported in the economic evaluation for TA\xa042.\n\nThe Committee discussed the utility values used in the manufacturers' and Assessment Group's economic models and noted that for all conditions except Prader–Willi syndrome these were derived from a single study that estimated utility values according to height in the general adult population using the EQ−5D. The Committee was disappointed that no attempt appeared to have been made by the manufacturers to measure the quality of life of children with growth failure despite the existence of the KIGS database, and it considered that there were a number of limitations associated with using the utility values from the only study identified. Firstly, the Committee was concerned that the utility estimates reflected the benefits of increased height in adulthood and may not capture the potential increased utility from normal height gain during childhood. Secondly, the Committee was mindful of the testimony from the clinical specialists and patient experts that somatropin treatment provides other benefits in addition to improved height (see section 4.3.3). These additional benefits would not be reflected in the utility values used. Thirdly, the Committee understood that the utility values used in the manufacturers' model were derived from an analysis that did not adjust for possible confounding factors, whereas the Assessment Group used an adjusted analysis from the same study. The Committee was concerned that the utility values from the fully adjusted regression model used by the Assessment Group may have over‑corrected with specific reference to chronic illness and social class. Finally, the Committee was not convinced that the impact of short stature would be captured adequately by the areas covered by the EQ‑5D (that is, mobility, self‑care, usual activities, pain/discomfort, and anxiety/depression). The Committee agreed therefore that the utility values used in the manufacturers' and Assessment Group's economic models were likely to underestimate both the true disutility associated with growth failure and the utility gain from somatropin treatment.\n\nFor Prader–Willi syndrome, the Committee discussed the utility values used in the economic models presented by the manufacturers and the Assessment Group. The Committee noted that the manufacturers and the Assessment Group (in an exploratory scenario analysis) had modelled additional benefits associated with changes in body composition as well as those from increased height. The Committee agreed that it was appropriate to model the benefits associated with increased height and those associated with changes in body composition because both are included in the licensed indication for Prader–Willi syndrome. The Committee was aware that the manufacturers' economic model allowed an additional utility gain for the reduced diabetes risk associated with changes in body composition. However, the Committee was mindful of the limitations of the study used by the manufacturers to derive the additional utility gain for the reduction in diabetes risk. In the base case the Assessment Group did not include a utility gain associated with a change in body composition in Prader–Willi syndrome. The Committee was aware that children with Prader–Willi syndrome are in general taller at the start of treatment than children with the other conditions considered in this appraisal. The Committee understood that in the Assessment Group's model, utility gains were always lower at the taller end of the height continuum, and that this meant that the utility gains were smaller for Prader–Willi syndrome than those modelled in the base case for the other conditions (see section 4.2.16). The Committee acknowledged that BMI, as used in the Assessment Group's exploratory scenario analysis, is an accepted surrogate marker for obesity because of its broad applicability in the clinical setting; however, the Committee was not persuaded that it adequately captures the benefits associated with changes in body composition with somatropin treatment. The Committee therefore agreed that there were additional uncertainties surrounding the utility value associated with changes in body composition for children with Prader–Willi syndrome, but, as for the other conditions considered in this appraisal, the utility gains from somatropin treatment were underestimated in the economic models.\n\nThe Committee considered the ICERs presented by the manufacturers and the Assessment Group. The Committee noted the large differences between the estimates presented. It recognised that the clinical effectiveness data used in the manufacturers' and the Assessment Group's economic models were obtained from different sources. The Assessment Group used data from RCTs (with the exception of growth hormone deficiency) and the manufacturers used data from the KIGS database. However, the Committee concluded that for most conditions the source of the clinical effectiveness data did not affect the magnitude of the Assessment Group's estimates.\n\nThe Committee considered the cost‑effectiveness estimates presented by the manufacturers and the Assessment Group for growth hormone deficiency, CRI, Turner syndrome, born small for gestational age and SHOX deficiency. The Committee understood that the differences between the cost‑effectiveness estimates were driven largely by the different utility values used. However, the Committee agreed that neither the manufacturers' nor the Assessment Group's models took into account the likely true utility gain from increased height in childhood and from additional benefits associated with somatropin treatment (see section 4.3.8), that is, the ICERs presented were likely to be overestimates of the true values.\n\nThe Committee then considered separately the ICERs for somatropin for children with Prader–Willi syndrome presented by the Assessment Group and the manufacturers. The Committee noted that the ICER presented in the Assessment Group's base case was substantially greater than that presented by the manufacturers (£135,000 per QALY gained and £32,500 per QALY gained respectively); this was a much bigger difference than observed for the other conditions. The Committee was aware, however, that the Assessments Group's base‑case analysis did not take account of any additional benefits associated with changes in body composition. It noted that when the Assessment Group modelled additional benefits associated with changes in body composition, the ICER for Prader–Willi syndrome was reduced to £54,800 per QALY gained. The Assessment Group presented to the Committee results from deterministic and probabilistic sensitivity analyses of cost effectiveness which differed markedly. The Assessment Group claimed that these differences were a result of non‑linearity in the model relating height to EQ‑5D for Prader–Willi syndrome. The Committee concluded that although the manufacturers' base case and the Assessment Group's exploratory scenario analysis did take account of some of the additional benefits associated with somatropin treatment, both models underestimated the utility gain (see section 4.3.8). The Committee considered that the true ICER for Prader–Willi syndrome was likely to be considerably less than that derived from the Assessment Group's exploratory analysis.\n\nThe Committee was also aware that the ICERs presented by the manufacturers and the Assessment Group were sensitive to variation in the price of the somatropin products. It noted from sensitivity analyses undertaken by the Assessment Group that if the lowest available cost of somatropin was used the ICERs could be further substantially reduced by between £3300 and £19,600 per QALY gained.\n\nTaking the issues around utility values and the variation in price of somatropin into consideration, the Committee agreed that the ICER for somatropin for growth hormone deficiency was likely to fall below £20,000 per QALY, and the ICERs for somatropin for CRI, Turner syndrome, born small for gestational age and SHOX deficiency were likely to be between £20,000 and £30,000 per QALY gained. The Committee acknowledged the uncertainty surrounding the ICER for somatropin for Prader–Willi syndrome, with values ranging from £32,500 (the manufacturers' base‑case estimate) to £54,800 (the Assessment Group's exploratory scenario analysis including BMI effects). However, the Committee did not consider that a change in the recommendation made in NICE technology appraisal guidance 42 for the use of somatropin in this disabled and socially marginalised group of children was justified, particularly in light of duties under disability discrimination legislation to have due regard to the need to promote equality of opportunity for disabled people, and to take account of their disabilities. The Committee therefore concluded that within its marketing authorisation somatropin represents a cost‑effective treatment for children with growth failure associated with all the conditions under consideration. The Committee also concluded that in light of the apparent equivalence of the clinical effectiveness of the different somatropin products, the least costly product that, after discussion between the responsible clinician and the patient and/or their carer, has been agreed to meet the needs of the individual child and to maximise the likelihood of adherence to treatment should be chosen.\n\nThe Committee considered the criteria for discontinuing treatment with somatropin. The Committee heard from the clinical specialists that the criteria used for the discontinuation of somatropin in UK clinical practice are consistent with those recommended in NICE technology appraisal guidance 42. It noted that neither the manufacturers' nor the Assessment Group's economic models sought to define rules for discontinuing somatropin treatment, including after attainment of final height as recommended in TA 42. The Committee concluded that criteria for the discontinuation of somatropin treatment should remain in line with those in TA\xa042. Treatment should be discontinued if any of the following apply:\n\ngrowth velocity increases less than 50% from baseline in the first year of treatment\n\nfinal height is approached and growth velocity is less than 2\xa0cm total growth in 1\xa0year\n\nthere are insurmountable problems with adherence\n\nfinal height is attained.In Prader–Willi syndrome evaluation of response to therapy should also consider body composition.Treatment should not be discontinued by default. The decision to stop treatment should be made in consultation with the patient and/or carers either by:\n\na paediatrician with specialist expertise in managing growth hormone disorders in children, or\n\nan adult endocrinologist, if care of the patient has been transferred from paediatric to adult services.", 'Recommendations for further research': 'The following trials are currently ongoing:\n\nStudy NCT00190658 aims to compare the mean first year growth velocity of prepubertal children with SHOX deficiency treated with somatropin with the growth velocity of a control group of untreated prepubertal children with SHOX deficiency. Estimated end date: December 2010.\n\nStudy NCT00625872 focuses on the effect of a 1‑year somatropin treatment (35\xa0microgram/kg per day or 67\xa0microgram/kg per day) in short children born small for gestational age on neuromuscular function and cognitive performance. End date not reported.\n\nThere is a controlled cohort study examining health‑related quality of life in family members of children prescribed growth hormone treatment for idiopathic growth hormone deficiency, acquired growth hormone deficiency and Turner syndrome. In September 2009, one of the investigators informed NICE that results were not expected until the end of 2010.\n\nA standardised quality‑of‑life assessment measuring quality of life in children and in adults is needed for use in future RCTs and studies designed to measure quality of life.\n\nGood quality research is needed on the long‑term effects of somatropin treatment during childhood on body composition, psychological health, diabetes, cardiovascular disease and bone health, and life expectancy, particularly for people with Prader–Willi syndrome.\n\nGood quality research is needed on somatropin treatment in short children born small for gestational age using dosages of somatropin matching the licensing criteria.', 'Related NICE guidance': 'There is no related NICE guidance.', 'Review of guidance': 'The guidance was last considered for review in June 2022. It was concluded that no new evidence was identified as likely to change the existing recommendations in TA188. The guidance will therefore remain unchanged, in its current form, unless or until NICE becomes aware of substantive information which would make it reconsider.Andrew DillonChief ExecutiveMay 2010', 'Changes after publication': 'December 2014: minor maintenance.\n\nFebruary 2014: implementation section updated to clarify human growth hormone (somatropin) is recommended as an option for treating growth failure in children. Additional minor maintenance update also carried out.\n\nMarch 2012: minor maintenance.\n\nA minor correction was made to section 6.1 of the guidance in July 2010. This does not affect the funding direction, which applies from the original date of publication in May 2010.', 'About this guidance': 'NICE technology appraisal guidance is about the use of new and existing medicines and treatments in the NHS in England and Wales.\n\nThis guidance was developed using the NICE multiple technology appraisal process.\n\nIt replaces NICE technology appraisal guidance 42 issued in May 2002.\n\nThe review and re‑appraisal of human growth hormone (somatropin) for the treatment of growth failure in children has resulted in a change in the guidance. Human growth hormone (somatropin) is still recommended for the treatment of growth failure in children with growth hormone deficiency, Turner syndrome, Prader–Willi syndrome and chronic renal insufficiency, but there has been an extension of the guidance to include growth failure associated with either of the two following conditions:\n\nborn small for gestational age with subsequent growth failure at 4 years of age or later\n\nshort stature homeobox‑containing gene (SHOX) deficiency.\n\nWe have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available.\n\nYour responsibility\n\nThis guidance represents the views of NICE and was arrived at after careful consideration of the evidence available. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. However, the guidance does not override the individual responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.\n\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.\n\nCopyright\n\n© National Institute for Health and Clinical Excellence 2010. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not‑for‑profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.'}	https://www.nice.org.uk/guidance/ta188	Evidence-based recommendations on human growth hormone (somatropin; Genotropin, Humatrope, Norditropin, NutropinAq, Omnitrope, Saizen, Zomacton) for treating growth failure in children.
edebb6177e1adda8a9ecc672b1e64e60dc158c00	nice	Therapeutic hypothermia with intracorporeal temperature monitoring for hypoxic perinatal brain injury	Therapeutic hypothermia with intracorporeal temperature monitoring for hypoxic perinatal brain injury # Guidance Current evidence on the safety and efficacy of therapeutic hypothermia with intracorporeal temperature monitoring for hypoxic perinatal brain injury is adequate to support the use of this procedure in carefully selected neonates provided that normal arrangements are in place for clinical governance, consent and audit (See section 2.5.1 for comments on selection). This procedure should only be carried out in units experienced in the care of severely ill neonates, by staff who have been specifically trained in the use of therapeutic hypothermia. NICE encourages clinicians to enter details about all neonates undergoing this procedure into the UK TOBY cooling register. The register provides a suggested management algorithm. Submitting data to the register will contribute to the evidence on long-term follow-up and may lead to improvements in the management algorithm.# The procedure # Indications and current treatments Hypoxic perinatal brain injury is caused by a decrease in the amount of oxygen supplied to an infant's brain close to the time of birth. Surviving infants may develop hypoxic-ischaemic encephalopathy and other organ damage, which can lead to severe, lifelong disability or death. Hypoxic perinatal brain injury is characterised by fetal distress and is associated with acidosis. Diagnosis includes clinical examination, paired umbilical arterial and venous blood gas analysis and amplitude-integrated electroencephalography. Hypoxic perinatal brain injury is traditionally treated with supportive care only, since no specific pharmacological agents or interventions have been shown to prevent the neuronal damage that perinatal hypoxia causes. This procedure is usually carried out on infants with a gestational age of 36 weeks or more and this is reflected in the published literature. # Outline of the procedure In therapeutic hypothermia the infant is cooled to between 33°C and 35°C, with the aim of preventing further neuronal loss in the days following the hypoxic injury. Hypothermia is usually induced by cooling the whole body with a blanket or mattress (or sometimes by cooling the head only with a purpose-made cap). Intracorporeal temperature is continuously monitored, using a rectal or nasopharyngeal thermometer, as a proxy for brain temperature. Treatment is started as soon as possible after diagnosis, usually within 6 hours of birth, and continued for approximately 72 hours. The infant is then slowly warmed to normal body temperature. Sections 2.3 and 2.4 describe efficacy and safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview. # Efficacy A systematic review of 10 randomised controlled trials (RCTs) (1320 infants in total) reported a lower risk of death in cooled infants (whole body or head) in the first 18 months of life than in infants treated by standard care (relative risk 0.78; 95% confidence interval 0.66 to 0.93) (follow-up not stated). In 3 of these RCTs with 18-month follow-up (767 infants in total) the combined risk of death and severe disability was significantly lower in cooled infants compared with infants treated by standard care (RR 0.81;95% CI 0.71 to 0.93) and cooling increased survival with normal neurological function compared with standard care (RR 1.53; 95% CI 1.22 to 1.93) at 18-month follow-up. An RCT of 325 infants treated by whole body cooling or standard care reported survival without neurological abnormality in 44% (71/163) and 28% (45/162) of infants respectively at 18-month follow-up (RR 1.57; 95% CI 1.16 to 2.12). Among the surviving infants, there was a lower rate of cerebral palsy in those treated by cooling (28% vs 41% ; RR 0.67; 95% CI 0.47 to 0.96). An RCT of 234 infants treated by head cooling or standard care reported death or severe neurodevelopmental disability at 18-month follow-up in 55% (59/108) and 66% (73/110) of infants respectively (odds ratio 0.61; 95% CI 0.34 to 1.09). In the systematic review, the 3 RCTs with a total of 767 infants reported that the rates of severe disability and cerebral palsy in surviving infants were significantly lower in the cooled infants than infants treated by standard care at 18-month follow-up (RR 0.71; 95% CI 0.56 to 0.91 and RR 0.69; 95% CI 0.54 to 0.89, respectively). The Specialist Advisers listed key efficacy outcomes as improvement in survival without neurological impairment, reduction in severe disability, improvement in Motor and Psychomotor Development Index scores and reduction in cerebral palsy. # Safety An RCT of 208 infants reported a higher incidence of hypocalcaemia in cooled infants than in those treated by standard care (27% and 19% respectively; p values not reported). In the RCT of 234 infants, 1 cooled infant (who died of other causes) had skin breakdown and local haemorrhage under the cooling cap. A case report described fat necrosis in an infant treated by whole body cooling using ice packs applied to the skin. At 9 months the infant had asymptomatic firm nodules with no calcification present. In another case report, an infant treated by whole body cooling using a water-filled mattress developed sclerema on the area of the back that was in contact with the cooling mattress at 3-week follow-up; this resolved without scarring after 3 months. The Specialist Advisers considered theoretical or anecdotal adverse events to include metabolic disturbances, blood hyperviscosity syndrome, increased infections, and seizures during rewarming if it is carried out too quickly. # Other comments The Committee noted the uncertainties and difficulties in selecting neonates for this procedure. Specifically, they noted the lack of evidence for using the procedure in neonates with less severe hypoxic brain injury, and the difficulties in deciding not to use the procedure for neonates whose degree of brain injury or comorbidities are too severe to expect survival without severe neurological deficit.# Further information # Information for patients NICE has produced information on this procedure for patients and carers ('Understanding NICE guidance'). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.# About this guidance NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland. This guidance was developed using the NICE interventional procedure guidance process. We have produced a summary of this guidance for patients and carers. Information about the evidence it is based on is also available. Changes since publication January 2012: minor maintenance. Your responsibility This guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer. Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties. Copyright © National Institute for Health and Clinical Excellence 2010. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE. Contact NICE National Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT www.nice.org.uk nice@nice.org.uk	{'Guidance': 'Current evidence on the safety and efficacy of therapeutic hypothermia with intracorporeal temperature monitoring for hypoxic perinatal brain injury is adequate to support the use of this procedure in carefully selected neonates provided that normal arrangements are in place for clinical governance, consent and audit (See section 2.5.1 for comments on selection).\n\nThis procedure should only be carried out in units experienced in the care of severely ill neonates, by staff who have been specifically trained in the use of therapeutic hypothermia.\n\nNICE encourages clinicians to enter details about all neonates undergoing this procedure into the UK TOBY cooling register. The register provides a suggested management algorithm. Submitting data to the register will contribute to the evidence on long-term follow-up and may lead to improvements in the management algorithm.', 'The procedure': "# Indications and current treatments\n\nHypoxic perinatal brain injury is caused by a decrease in the amount of oxygen supplied to an infant's brain close to the time of birth. Surviving infants may develop hypoxic-ischaemic encephalopathy and other organ damage, which can lead to severe, lifelong disability or death.\n\nHypoxic perinatal brain injury is characterised by fetal distress and is associated with acidosis. Diagnosis includes clinical examination, paired umbilical arterial and venous blood gas analysis and amplitude-integrated electroencephalography.\n\nHypoxic perinatal brain injury is traditionally treated with supportive care only, since no specific pharmacological agents or interventions have been shown to prevent the neuronal damage that perinatal hypoxia causes.\n\nThis procedure is usually carried out on infants with a gestational age of 36 weeks or more and this is reflected in the published literature.\n\n# Outline of the procedure\n\nIn therapeutic hypothermia the infant is cooled to between 33°C and 35°C, with the aim of preventing further neuronal loss in the days following the hypoxic injury.\n\nHypothermia is usually induced by cooling the whole body with a blanket or mattress (or sometimes by cooling the head only with a purpose-made cap). Intracorporeal temperature is continuously monitored, using a rectal or nasopharyngeal thermometer, as a proxy for brain temperature.\n\nTreatment is started as soon as possible after diagnosis, usually within 6 hours of birth, and continued for approximately 72 hours. The infant is then slowly warmed to normal body temperature.\n\nSections 2.3 and 2.4 describe efficacy and safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview.\n\n# Efficacy\n\nA systematic review of 10 randomised controlled trials (RCTs) (1320 infants in total) reported a lower risk of death in cooled infants (whole body or head) in the first 18 months of life than in infants treated by standard care (relative risk [RR] 0.78; 95% confidence interval [CI] 0.66 to 0.93) (follow-up not stated). In 3 of these RCTs with 18-month follow-up (767 infants in total) the combined risk of death and severe disability was significantly lower in cooled infants compared with infants treated by standard care (RR 0.81;95% CI 0.71 to 0.93) and cooling increased survival with normal neurological function compared with standard care (RR 1.53; 95% CI 1.22 to 1.93) at 18-month follow-up.\n\nAn RCT of 325 infants treated by whole body cooling or standard care reported survival without neurological abnormality in 44% (71/163) and 28% (45/162) of infants respectively at 18-month follow-up (RR 1.57; 95% CI 1.16 to 2.12). Among the surviving infants, there was a lower rate of cerebral palsy in those treated by cooling (28% [33/120] vs 41% [48/117]; RR 0.67; 95% CI 0.47 to 0.96).\n\nAn RCT of 234 infants treated by head cooling or standard care reported death or severe neurodevelopmental disability at 18-month follow-up in 55% (59/108) and 66% (73/110) of infants respectively (odds ratio 0.61; 95% CI 0.34 to 1.09). In the systematic review, the 3 RCTs with a total of 767 infants reported that the rates of severe disability and cerebral palsy in surviving infants were significantly lower in the cooled infants than infants treated by standard care at 18-month follow-up (RR 0.71; 95% CI 0.56 to 0.91 and RR 0.69; 95% CI 0.54 to 0.89, respectively).\n\nThe Specialist Advisers listed key efficacy outcomes as improvement in survival without neurological impairment, reduction in severe disability, improvement in Motor and Psychomotor Development Index scores and reduction in cerebral palsy.\n\n# Safety\n\nAn RCT of 208 infants reported a higher incidence of hypocalcaemia in cooled infants than in those treated by standard care (27% [28/102] and 19% [20/106] respectively; p values not reported).\n\nIn the RCT of 234 infants, 1 cooled infant (who died of other causes) had skin breakdown and local haemorrhage under the cooling cap. A case report described fat necrosis in an infant treated by whole body cooling using ice packs applied to the skin. At 9 months the infant had asymptomatic firm nodules with no calcification present. In another case report, an infant treated by whole body cooling using a water-filled mattress developed sclerema on the area of the back that was in contact with the cooling mattress at 3-week follow-up; this resolved without scarring after 3 months.\n\nThe Specialist Advisers considered theoretical or anecdotal adverse events to include metabolic disturbances, blood hyperviscosity syndrome, increased infections, and seizures during rewarming if it is carried out too quickly.\n\n# Other comments\n\nThe Committee noted the uncertainties and difficulties in selecting neonates for this procedure. Specifically, they noted the lack of evidence for using the procedure in neonates with less severe hypoxic brain injury, and the difficulties in deciding not to use the procedure for neonates whose degree of brain injury or comorbidities are too severe to expect survival without severe neurological deficit.", 'Further information': "# Information for patients\n\nNICE has produced information on this procedure for patients and carers ('Understanding NICE guidance'). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.", 'About this guidance': 'NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland.\n\nThis guidance was developed using the NICE interventional procedure guidance process.\n\nWe have produced a summary of this guidance for patients and carers. Information about the evidence it is based on is also available.\n\nChanges since publication\n\nJanuary 2012: minor maintenance.\n\nYour responsibility\n\nThis guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.\n\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.\n\nCopyright\n\n© National Institute for Health and Clinical Excellence 2010. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.\n\nContact NICE\n\nNational Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT\n\nwww.nice.org.uk\n \n nice@nice.org.uk\n 0845 033 7780'}	https://www.nice.org.uk/guidance/ipg347
1ed4daea3e5bddebb1062a93660d189103b80bda	nice	Epithelial radiofrequency ablation for Barrett's oesophagus	Epithelial radiofrequency ablation for Barrett's oesophagus # Guidance This guidance replaces the previous guidance on Circumferential epithelial radiofrequency ablation for Barrett's oesophagus (Interventional Procedures Guidance no. 244 November 2008). This guidance has been partially updated by Endoscopic radiofrequency ablation for Barrett's oesophagus with low-grade dysplasia or no dysplasia (NICE interventional procedure guidance 496). Current evidence on the efficacy of epithelial radiofrequency ablation (RFA) in patients with Barrett's oesophagus with high-grade dysplasia (HGD) is adequate, provided that patients are followed up in the long term. There are no major safety concerns. Therefore this procedure may be used in patients with Barrett's oesophagus with HGD provided that normal arrangements are in place for clinical governance, consent and audit. This recommendation has been updated and replaced by NICE interventional procedure guidance 496 (Endoscopic radiofrequency ablation for Barrett's oesophagus with low-grade dysplasia or no dysplasia). This recommendation has been updated and replaced by NICE interventional procedure guidance 496 (Endoscopic radiofrequency ablation for Barrett's oesophagus with low-grade dysplasia or no dysplasia). Patient selection for epithelial RFA for Barrett's oesophagus should be done by a multidisciplinary team experienced in the management of Barrett's oesophagus. Epithelial RFA for Barrett's oesophagus should only be carried out by endoscopists with specific training in this procedure. NICE encourages further research into epithelial RFA for Barrett's oesophagus. This should address the balance of risks and benefits of the procedure in patients with Barrett's oesophagus and either LGD or no dysplasia, and long-term outcomes in patients with Barrett's oesophagus of any histological type. This recommendation has been partially updated by NICE interventional procedure guidance 496 (Endoscopic radiofrequency ablation for Barrett's oesophagus with low-grade dysplasia or no dysplasia).# The procedure # Indications and current treatments Barrett's oesophagus is a condition characterised by abnormal epithelium of the oesophagus. In some patients, Barrett's oesophagus may progress, through metaplasia and dysplasia, to oesophageal adenocarcinoma. Cancer risk is higher for patients with HGD (some of whom may already have developed early-stage cancer) and lower for patients with LGD or no dysplasia. Patients with HGD are usually offered oesophagectomy, or frequent endoscopic surveillance and re-biopsy (with the aim of detecting neoplastic changes early). Endoscopic treatments that aim to remove or ablate abnormal epithelium have also been developed, including endoscopic mucosal resection and photodynamic therapy. Patients with LGD or no dysplasia are usually offered regular endoscopic surveillance and re-biopsy (with the aim of detecting potential progression to HGD or cancer). # Outline of the procedure The aim of RFA is to destroy the Barrett's epithelium in order to allow re-epithelialisation with squamous epithelium. The procedure is carried out with the patient under conscious sedation, usually in an outpatient setting. Using endoscopic visualisation, an appropriately sized RFA probe is inserted into the oesophagus and advanced to the target area. Controlled pulses of RF energy are delivered to thermally ablate a thin epithelial layer in the affected areas. RFA is sometimes used after previous endoscopic mucosal resection. If follow-up endoscopy and re-biopsy show residual Barrett's changes, repeat treatment sessions may be necessary. Sections 2.3 and 2.4 describe efficacy and safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview. # Efficacy A randomised controlled trial (RCT) of 127 patients (63 with HGD and 64 with LGD) treated by RFA or a sham procedure reported complete eradication of Barrett's oesophagus in 77% (65/84) and 2% (1/43) of patients respectively at 12-month follow-up (p < 0.001). In the same RCT, among patients with HGD, fewer RFA-treated patients progressed to cancer at 12-month follow-up (2% ) compared with those in the sham group (19% ) (p = 0.04). A register of 142 patients with HGD reported efficacy data on 92 patients with at least 1 follow-up endoscopy. At a median 1-year follow-up, HGD resolution had occurred in 90% (83/92) of patients; 80% (74/92) had no dysplasia (HGD or LGD) and 54% (50/92) had no Barrett's at all. The Specialist Advisers listed key efficacy outcomes as eradication of metaplasia and dysplasia, relapse rate and reduction in development of cancer. # Safety Oesophageal stricture was reported in 6% (5/84) of patients treated by RFA in the RCT of 127 patients (successfully treated by endoscopic dilatation) and 8 patients (denominator not stated) from a register of 106 patients treated by RFA (timing of events and management not stated). Buried glandular mucosa detected on surveillance biopsy was reported in 15% (4/27) of patients 6–12 weeks after RFA (precise timing of detection not stated) in a case series of 27 patients. All were treated with additional RFA. One buried glandular mucosa was reported in neosquamous epithelium among 1475 biopsies (less than 1%) in a case series of 44 patients (subsequent treatment not described). In the RCT of 127 patients, 1 patient developed new-onset chest pain and 1 patient developed chest discomfort and nausea. Both patients required overnight admission to hospital. The Specialist Advisers listed anecdotal adverse events as dysphagia, minor bleeding, oesophageal perforation and pain (such as retrosternal pain).# Further information This guidance requires that clinicians undertaking the procedure in patients with LGD or no dysphagia make special arrangements for audit. NICE has identified relevant audit criteria and developed an audit tool (which is for use at local discretion). For related NICE guidance see our website. # Information for patients NICE has produced information on this procedure for patients and carers ('Understanding NICE guidance'). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.# Other NICE recommendations on epithelial radiofrequency ablation Further recommendations have been made as part of the clinical guideline on Barrett's oesophagus – ablative therapy published in August 2010, as follows: Consider using radiofrequency ablation alone or photodynamic therapy alone for flat high-grade dysplasia, taking into account the evidence of their long-term efficacy, cost and complication rates. Clinical and cost-effectiveness evidence was reviewed in the development of this guideline which has led to this more specific recommendation. More information is available. The IP guidance on epithelial radiofrequency ablation for Barrett's oesophagus remains current, and should be read in conjunction with the clinical guideline.# About this guidance NICE interventional procedures guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHS Scotland. This guidance was developed using the NICE interventional procedures guidance process. It updates and replaces NICE interventional procedure guidance 244. We have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available. Changes since publication July 2014: This guidance has been partially updated by Endoscopic radiofrequency ablation for Barrett's oesophagus with low-grade dysplasia or no dysplasia (NICE interventional procedure guidance 496). January 2012: minor maintenance. Your responsibility This guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer. Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties. Copyright © National Institute for Health and Clinical Excellence 2010. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE. Contact NICE National Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT www.nice.org.uk nice@nice.org.uk	{'Guidance': "This guidance replaces the previous guidance on Circumferential epithelial radiofrequency ablation for Barrett's oesophagus (Interventional Procedures Guidance no. 244 November 2008). This guidance has been partially updated by Endoscopic radiofrequency ablation for Barrett's oesophagus with low-grade dysplasia or no dysplasia (NICE interventional procedure guidance 496).\n\nCurrent evidence on the efficacy of epithelial radiofrequency ablation (RFA) in patients with Barrett's oesophagus with high-grade dysplasia (HGD) is adequate, provided that patients are followed up in the long term. There are no major safety concerns. Therefore this procedure may be used in patients with Barrett's oesophagus with HGD provided that normal arrangements are in place for clinical governance, consent and audit.\n\nThis recommendation has been updated and replaced by NICE interventional procedure guidance 496 (Endoscopic radiofrequency ablation for Barrett's oesophagus with low-grade dysplasia or no dysplasia).\n\nThis recommendation has been updated and replaced by NICE interventional procedure guidance 496 (Endoscopic radiofrequency ablation for Barrett's oesophagus with low-grade dysplasia or no dysplasia).\n\nPatient selection for epithelial RFA for Barrett's oesophagus should be done by a multidisciplinary team experienced in the management of Barrett's oesophagus.\n\nEpithelial RFA for Barrett's oesophagus should only be carried out by endoscopists with specific training in this procedure.\n\nNICE encourages further research into epithelial RFA for Barrett's oesophagus. This should address the balance of risks and benefits of the procedure in patients with Barrett's oesophagus and either LGD or no dysplasia, and long-term outcomes in patients with Barrett's oesophagus of any histological type. This recommendation has been partially updated by NICE interventional procedure guidance 496 (Endoscopic radiofrequency ablation for Barrett's oesophagus with low-grade dysplasia or no dysplasia).", 'The procedure': "# Indications and current treatments\n\nBarrett's oesophagus is a condition characterised by abnormal epithelium of the oesophagus. In some patients, Barrett's oesophagus may progress, through metaplasia and dysplasia, to oesophageal adenocarcinoma. Cancer risk is higher for patients with HGD (some of whom may already have developed early-stage cancer) and lower for patients with LGD or no dysplasia.\n\nPatients with HGD are usually offered oesophagectomy, or frequent endoscopic surveillance and re-biopsy (with the aim of detecting neoplastic changes early). Endoscopic treatments that aim to remove or ablate abnormal epithelium have also been developed, including endoscopic mucosal resection and photodynamic therapy.\n\nPatients with LGD or no dysplasia are usually offered regular endoscopic surveillance and re-biopsy (with the aim of detecting potential progression to HGD or cancer).\n\n# Outline of the procedure\n\nThe aim of RFA is to destroy the Barrett's epithelium in order to allow re-epithelialisation with squamous epithelium.\n\nThe procedure is carried out with the patient under conscious sedation, usually in an outpatient setting. Using endoscopic visualisation, an appropriately sized RFA probe is inserted into the oesophagus and advanced to the target area. Controlled pulses of RF energy are delivered to thermally ablate a thin epithelial layer in the affected areas. RFA is sometimes used after previous endoscopic mucosal resection.\n\nIf follow-up endoscopy and re-biopsy show residual Barrett's changes, repeat treatment sessions may be necessary.\n\nSections 2.3 and 2.4 describe efficacy and safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview.\n\n# Efficacy\n\nA randomised controlled trial (RCT) of 127 patients (63 with HGD and 64 with LGD) treated by RFA or a sham procedure reported complete eradication of Barrett's oesophagus in 77% (65/84) and 2% (1/43) of patients respectively at 12-month follow-up (p < 0.001).\n\nIn the same RCT, among patients with HGD, fewer RFA-treated patients progressed to cancer at 12-month follow-up (2% [1/42]) compared with those in the sham group (19% [4/21]) (p = 0.04).\n\nA register of 142 patients with HGD reported efficacy data on 92 patients with at least 1 follow-up endoscopy. At a median 1-year follow-up, HGD resolution had occurred in 90% (83/92) of patients; 80% (74/92) had no dysplasia (HGD or LGD) and 54% (50/92) had no Barrett's at all.\n\nThe Specialist Advisers listed key efficacy outcomes as eradication of metaplasia and dysplasia, relapse rate and reduction in development of cancer.\n\n# Safety\n\nOesophageal stricture was reported in 6% (5/84) of patients treated by RFA in the RCT of 127 patients (successfully treated by endoscopic dilatation) and 8 patients (denominator not stated) from a register of 106 patients treated by RFA (timing of events and management not stated).\n\nBuried glandular mucosa detected on surveillance biopsy was reported in 15% (4/27) of patients 6–12 weeks after RFA (precise timing of detection not stated) in a case series of 27 patients. All were treated with additional RFA. One buried glandular mucosa was reported in neosquamous epithelium among 1475 biopsies (less than 1%) in a case series of 44 patients (subsequent treatment not described).\n\nIn the RCT of 127 patients, 1 patient developed new-onset chest pain and 1 patient developed chest discomfort and nausea. Both patients required overnight admission to hospital.\n\nThe Specialist Advisers listed anecdotal adverse events as dysphagia, minor bleeding, oesophageal perforation and pain (such as retrosternal pain).", 'Further information': "This guidance requires that clinicians undertaking the procedure in patients with LGD or no dysphagia make special arrangements for audit. NICE has identified relevant audit criteria and developed an audit tool (which is for use at local discretion).\n\nFor related NICE guidance see our website.\n\n# Information for patients\n\nNICE has produced information on this procedure for patients and carers ('Understanding NICE guidance'). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.", 'Other NICE recommendations on epithelial radiofrequency ablation': "Further recommendations have been made as part of the clinical guideline on Barrett's oesophagus – ablative therapy published in August 2010, as follows:\n\nConsider using radiofrequency ablation alone or photodynamic therapy alone for flat high-grade dysplasia, taking into account the evidence of their long-term efficacy, cost and complication rates.\n\nClinical and cost-effectiveness evidence was reviewed in the development of this guideline which has led to this more specific recommendation. More information is available.\n\nThe IP guidance on epithelial radiofrequency ablation for Barrett's oesophagus remains current, and should be read in conjunction with the clinical guideline.", 'About this guidance': "NICE interventional procedures guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHS Scotland.\n\nThis guidance was developed using the NICE interventional procedures guidance process.\n\nIt updates and replaces NICE interventional procedure guidance 244.\n\nWe have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available.\n\nChanges since publication\n\nJuly 2014: This guidance has been partially updated by Endoscopic radiofrequency ablation for Barrett's oesophagus with low-grade dysplasia or no dysplasia (NICE interventional procedure guidance 496).\n\nJanuary 2012: minor maintenance.\n\nYour responsibility\n\nThis guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.\n\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.\n\nCopyright\n\n© National Institute for Health and Clinical Excellence 2010. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.\n\nContact NICE\n\nNational Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT\n\nwww.nice.org.uk\n \n nice@nice.org.uk\n 0845 033 7780"}	https://www.nice.org.uk/guidance/ipg344
d145713311f5d43971c897ca7123a8bb33ed6cde	nice	Mini-incision surgery for total knee replacement	Mini-incision surgery for total knee replacement # Guidance This guidance replaces previous guidance on mini-incision surgery for total knee replacement (interventional procedure guidance 117). Current evidence on the safety and efficacy of mini-incision surgery for total knee replacement is adequate to support the use of this procedure provided that normal arrangements are in place for clinical governance, consent and audit. Mini-incision surgery for total knee replacement should only be carried out by surgeons with specific training in the procedure. Surgeons should submit details on all patients undergoing mini-incision surgery for total knee replacement to the National Joint Registry.# The procedure # Indications and current treatments The most common indication for a total knee replacement is symptomatic degenerative arthritis (osteoarthritis) of the knee joint. Conservative treatments for arthritis include medications for pain and inflammation, and physical therapies. Corticosteroids may be injected into the knee joint to relieve inflammation. If these therapies are insufficient, a partial or total knee replacement may be necessary. # Outline of the procedure The aim of mini-incision surgery is to improve both cosmesis and recovery time by reducing the length of incision and minimising damage to tendons and muscles. The procedure is carried out with the patient under general anaesthesia or spinal/epidural block. Specially designed instruments enable the surgeon to work through a small incision and avoid eversion of the patella or dislocation of the knee joint. The same types of joint prostheses are used in mini-incision procedures as in standard knee replacement. Computer-guided navigation may be used to improve placement of the prostheses. Sections 2.3 and 2.4 describe efficacy and safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview. # Efficacy A randomised controlled trial (RCT) of 108 patients treated by computer-assisted mini-incision (n = 52) or conventional knee replacement (n = 56) reported that 34 patients from each group were pain free at 6-month follow-up (denominator not stated) (p = 0.15). A non-randomised controlled trial of 200 knees reported that mean pain score (using a 10-point visual analogue scale; high score indicates worse pain) was significantly better in the mini-incision group (3.2 points) than in the conventional surgery group (3.8 points) at 1-year follow-up (p < 0.01). The RCT of 108 patients treated by mini-incision or conventional knee replacement reported no difference in mean Knee Society knee scores (on a scale from 0 to 100; high score indicates less pain and better functional mobility) of 84 points and 85 points respectively at 6-month follow-up (p = 0.06). In a case series of 237 patients undergoing revision surgery for reasons other than infection (not otherwise described) the mean time to revision surgery was significantly shorter in patients initially treated by mini-incision surgery than in patients treated by a standard approach (15.4 months and 79.2 months respectively) (p < 0.0001). A non-randomised controlled study of 747 knees reported that achievable flexion was significantly greater in knees treated by mini-incision surgery (124°) than following conventional surgery (113°) at 24-week follow-up (p < 0.001). The Specialist Advisers listed key efficacy outcomes as recovery time, functional long-term outcome and implant survival at 10 years. # Safety Deep wound infection requiring 2-stage revision surgery and haemarthrosis requiring evacuation were reported in less than 1% (2/725 and 1/725 respectively) of knees treated by mini-incision surgery in a non-randomised controlled study of 732 knees (mean 25-month follow-up). Deep infection requiring 2-stage reimplantation was reported in less than 1% (2/335) of patients in a case series of 335 patients at a median 2-year follow-up. Tibial component failure (requiring revision) was reported in less than 1% (2/725) of knees treated by mini-incision surgery in the non-randomised controlled trial of 732 knees (more than 12-month follow-up). Periprosthetic femur fracture after a fall was reported in 1 of 725 knees treated by mini-incision surgery at 2-week follow-up in the non-randomised controlled trial of 732 knees. Patella tendon rupture (requiring surgical repair) was reported in 1 of 725 knees treated by mini-incision surgery in the non-randomised controlled trial of 732 knees (timing of event not stated). In a non-randomised controlled study of 137 knees, patella tendon shortening of greater than 5% occurred in significantly more knees treated by conventional surgery (37% ) than knees treated by mini-incision surgery (12% ) at 2-year follow-up (p = 0.001). The non-randomised controlled study of 747 knees reported that 'patella clunk' occurred significantly more frequently following mini-incision surgery (6% of knees) than following conventional surgery using the same type of prosthesis (less than 1% of knees) at 1-year follow-up (p < 0.001). In the non-randomised controlled study of 137 knees, secondary manipulations for reduced range of movement at 6 weeks were reported in 3% (2/68) of patients treated by mini-incision surgery and 7% (4/61) of patients treated by conventional surgery (significance not stated). The Specialist Advisers listed anecdotal or published adverse events as increased operative time and malpositioning of the implant. They considered theoretical adverse events to include inadequate removal of bone cement from the back of the knee which may lead to early failure. # Other comments The Committee noted that there is no generally accepted definition of a 'mini-incision' approach to knee replacement. The Committee recognised that although concerns have been expressed about an increased revision rate after mini-incision surgery for total knee replacement, this may reflect the learning curve of a new procedure. The 2009 annual report of the Swedish Knee Arthroplasty Register stated that there was no increase in the revision rate of the procedure compared with standard arthrotomy at up to 8-year follow-up.# Further information For related NICE guidance see our website. # Information for patients NICE has produced information on this procedure for patients and carers ('Understanding NICE guidance'). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.# About this guidance NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland. This guidance was developed using the NICE interventional procedure guidance process. It updates and replaces NICE interventional procedure guidance 117. We have produced a summary of this guidance for patients and carers. Information about the evidence it is based on is also available. Changes since publication January 2012: minor maintenance. Your responsibility This guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer. Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties. Copyright © National Institute for Health and Clinical Excellence 2010. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE. Contact NICE National Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT www.nice.org.uk nice@nice.org.uk	{'Guidance': 'This guidance replaces previous guidance on mini-incision surgery for total knee replacement (interventional procedure guidance 117).\n\nCurrent evidence on the safety and efficacy of mini-incision surgery for total knee replacement is adequate to support the use of this procedure provided that normal arrangements are in place for clinical governance, consent and audit.\n\nMini-incision surgery for total knee replacement should only be carried out by surgeons with specific training in the procedure.\n\nSurgeons should submit details on all patients undergoing mini-incision surgery for total knee replacement to the National Joint Registry.', 'The procedure': "# Indications and current treatments\n\nThe most common indication for a total knee replacement is symptomatic degenerative arthritis (osteoarthritis) of the knee joint.\n\nConservative treatments for arthritis include medications for pain and inflammation, and physical therapies. Corticosteroids may be injected into the knee joint to relieve inflammation. If these therapies are insufficient, a partial or total knee replacement may be necessary.\n\n# Outline of the procedure\n\nThe aim of mini-incision surgery is to improve both cosmesis and recovery time by reducing the length of incision and minimising damage to tendons and muscles. The procedure is carried out with the patient under general anaesthesia or spinal/epidural block. Specially designed instruments enable the surgeon to work through a small incision and avoid eversion of the patella or dislocation of the knee joint. The same types of joint prostheses are used in mini-incision procedures as in standard knee replacement. Computer-guided navigation may be used to improve placement of the prostheses.\n\nSections 2.3 and 2.4 describe efficacy and safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview.\n\n# Efficacy\n\nA randomised controlled trial (RCT) of 108 patients treated by computer-assisted mini-incision (n = 52) or conventional knee replacement (n = 56) reported that 34 patients from each group were pain free at 6-month follow-up (denominator not stated) (p = 0.15).\n\nA non-randomised controlled trial of 200 knees reported that mean pain score (using a 10-point visual analogue scale; high score indicates worse pain) was significantly better in the mini-incision group (3.2 points) than in the conventional surgery group (3.8 points) at 1-year follow-up (p < 0.01).\n\nThe RCT of 108 patients treated by mini-incision or conventional knee replacement reported no difference in mean Knee Society knee scores (on a scale from 0 to 100; high score indicates less pain and better functional mobility) of 84 points and 85 points respectively at 6-month follow-up (p = 0.06).\n\nIn a case series of 237 patients undergoing revision surgery for reasons other than infection (not otherwise described) the mean time to revision surgery was significantly shorter in patients initially treated by mini-incision surgery than in patients treated by a standard approach (15.4 months and 79.2 months respectively) (p < 0.0001).\n\nA non-randomised controlled study of 747 knees reported that achievable flexion was significantly greater in knees treated by mini-incision surgery (124°) than following conventional surgery (113°) at 24-week follow-up (p < 0.001).\n\nThe Specialist Advisers listed key efficacy outcomes as recovery time, functional long-term outcome and implant survival at 10 years.\n\n# Safety\n\nDeep wound infection requiring 2-stage revision surgery and haemarthrosis requiring evacuation were reported in less than 1% (2/725 and 1/725 respectively) of knees treated by mini-incision surgery in a non-randomised controlled study of 732 knees (mean 25-month follow-up). Deep infection requiring 2-stage reimplantation was reported in less than 1% (2/335) of patients in a case series of 335 patients at a median 2-year follow-up.\n\nTibial component failure (requiring revision) was reported in less than 1% (2/725) of knees treated by mini-incision surgery in the non-randomised controlled trial of 732 knees (more than 12-month follow-up).\n\nPeriprosthetic femur fracture after a fall was reported in 1 of 725 knees treated by mini-incision surgery at 2-week follow-up in the non-randomised controlled trial of 732 knees.\n\nPatella tendon rupture (requiring surgical repair) was reported in 1 of 725 knees treated by mini-incision surgery in the non-randomised controlled trial of 732 knees (timing of event not stated).\n\nIn a non-randomised controlled study of 137 knees, patella tendon shortening of greater than 5% occurred in significantly more knees treated by conventional surgery (37% [21/57]) than knees treated by mini-incision surgery (12% [9/74]) at 2-year follow-up (p = 0.001).\n\nThe non-randomised controlled study of 747 knees reported that 'patella clunk' occurred significantly more frequently following mini-incision surgery (6% [17/275] of knees) than following conventional surgery using the same type of prosthesis (less than 1% [1/222] of knees) at 1-year follow-up (p < 0.001).\n\nIn the non-randomised controlled study of 137 knees, secondary manipulations for reduced range of movement at 6 weeks were reported in 3% (2/68) of patients treated by mini-incision surgery and 7% (4/61) of patients treated by conventional surgery (significance not stated).\n\nThe Specialist Advisers listed anecdotal or published adverse events as increased operative time and malpositioning of the implant. They considered theoretical adverse events to include inadequate removal of bone cement from the back of the knee which may lead to early failure.\n\n# Other comments\n\nThe Committee noted that there is no generally accepted definition of a 'mini-incision' approach to knee replacement.\n\nThe Committee recognised that although concerns have been expressed about an increased revision rate after mini-incision surgery for total knee replacement, this may reflect the learning curve of a new procedure. The 2009 annual report of the Swedish Knee Arthroplasty Register stated that there was no increase in the revision rate of the procedure compared with standard arthrotomy at up to 8-year follow-up.", 'Further information': "For related NICE guidance see our website.\n\n# Information for patients\n\nNICE has produced information on this procedure for patients and carers ('Understanding NICE guidance'). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.", 'About this guidance': 'NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland.\n\nThis guidance was developed using the NICE interventional procedure guidance process.\n\nIt updates and replaces NICE interventional procedure guidance 117.\n\nWe have produced a summary of this guidance for patients and carers. Information about the evidence it is based on is also available.\n\nChanges since publication\n\nJanuary 2012: minor maintenance.\n\nYour responsibility\n\nThis guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.\n\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.\n\nCopyright\n\n© National Institute for Health and Clinical Excellence 2010. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.\n\nContact NICE\n\nNational Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT\n\nwww.nice.org.uk\n \n nice@nice.org.uk\n 0845 033 7780'}	https://www.nice.org.uk/guidance/ipg345
c8388c328846c4a2e9745cb2f963c4e3ebc135a2	nice	Infliximab and adalimumab for the treatment of Crohn's disease	Infliximab and adalimumab for the treatment of Crohn's disease Evidence-based recommendations on infliximab (Remicade) and adalimumab (Humira) for treating severe active Crohn's disease in adults. # Guidance This guidance replaces 'NICE technology appraisal guidance 40' issued in April 2002. For details, see 'About this guidance'. Infliximab and adalimumab, within their licensed indications, are recommended as treatment options for adults with severe active Crohn's disease (see 1.6) whose disease has not responded to conventional therapy (including immunosuppressive and/or corticosteroid treatments), or who are intolerant of or have contraindications to conventional therapy. Infliximab or adalimumab should be given as a planned course of treatment until treatment failure (including the need for surgery), or until 12 months after the start of treatment, whichever is shorter. People should then have their disease reassessed (see 1.4) to determine whether ongoing treatment is still clinically appropriate. Treatment as described in 1.1 should normally be started with the less expensive drug (taking into account drug administration costs, required dose and product price per dose). This may need to be varied for individual patients because of differences in the method of administration and treatment schedules. Infliximab, within its licensed indication, is recommended as a treatment option for people with active fistulising Crohn's disease whose disease has not responded to conventional therapy (including antibiotics, drainage and immunosuppressive treatments), or who are intolerant of or have contraindications to conventional therapy. Infliximab should be given as a planned course of treatment until treatment failure (including the need for surgery) or until 12 months after the start of treatment, whichever is shorter. People should then have their disease reassessed (see 1.4) to determine whether ongoing treatment is still clinically appropriate. Treatment with infliximab or adalimumab (see 1.1 and 1.3) should only be continued if there is clear evidence of ongoing active disease as determined by clinical symptoms, biological markers and investigation, including endoscopy if necessary. Specialists should discuss the risks and benefits of continued treatment with patients and consider a trial withdrawal from treatment for all patients who are in stable clinical remission. People who continue treatment with infliximab or adalimumab should have their disease reassessed at least every 12 months to determine whether ongoing treatment is still clinically appropriate. People whose disease relapses after treatment is stopped should have the option to start treatment again. Infliximab, within its licensed indication, is recommended for the treatment of people aged 6–17 years with severe active Crohn's disease whose disease has not responded to conventional therapy (including corticosteroids, immunomodulators and primary nutrition therapy), or who are intolerant of or have contraindications to conventional therapy. The need to continue treatment should be reviewed at least every 12 months. For the purposes of this guidance, severe active Crohn's disease is defined as very poor general health and one or more symptoms such as weight loss, fever, severe abdominal pain and usually frequent (3–4 or more) diarrhoeal stools daily. People with severe active Crohn's disease may or may not develop new fistulae or have extra-intestinal manifestations of the disease. This clinical definition normally, but not exclusively, corresponds to a Crohn's Disease Activity Index (CDAI) score of 300 or more, or a Harvey-Bradshaw score of 8 to 9 or above. When using the CDAI and Harvey-Bradshaw Index, healthcare professionals should take into account any physical, sensory or learning disabilities, or communication difficulties that could affect the scores and make any adjustments they consider appropriate. Treatment with infliximab or adalimumab should only be started and reviewed by clinicians with experience of TNF inhibitors and of managing Crohn's disease.# Clinical need and practice Crohn's disease is a chronic inflammatory condition affecting the gastrointestinal tract (gut). It can affect any part of the gut from the mouth to the anus. The lining of the affected area becomes inflamed and may be ulcerated, and the wall of the intestine thickens. The clinical features of Crohn's disease vary and are determined partly by the site of the disease. Symptoms include diarrhoea, abdominal pain, weight loss, malaise, lethargy, anorexia, nausea, vomiting and fever. Crohn's disease can be complicated by the development of strictures (narrowing of the intestine), obstructions, fistulae and perianal disease. Fistulae – abnormal connections between areas of the intestine or adjacent organs – develop in 17–43% of people with Crohn's disease. Perianal disease includes fissures, fistulae and abscesses. Other complications of Crohn's disease include acute dilation, perforation and massive haemorrhage of the gut, and carcinoma of the small bowel or colon. People with Crohn's disease have acute 'flares' of the disease in between periods of remission or less active disease. These flares can affect any part of the gut. They may be defined by location (terminal ileal, colonic, ileocolonic, upper gastrointestinal), or by the pattern of the disease (inflammatory, fistulising or stricturing). The prevalence of Crohn's disease in the UK is estimated to be about 50–100 per 100,000 people. It affects approximately 60,000 people in the UK. The incidence of Crohn's disease is greatest in people aged between 15 and 30 years. However, it may affect people of any age: 15% of people with the disease are older than 60 years at diagnosis and 20–30% are younger than 20 years. Mortality among people with Crohn's disease is only slightly higher than in the general population. Crohn's disease is not medically or surgically curable. Treatment aims to control manifestations of Crohn's disease to reduce symptoms, and to maintain or improve quality of life while minimising short- and long-term adverse effects. Clinical management depends on disease activity, site, behaviour of disease (inflammatory, fistulising or stricturing), response to previous medications, side-effect profiles of medications and extra-intestinal manifestations. Because Crohn's disease is unpredictable, successful treatment focuses on inducing and maintaining clinical remission. Current treatment includes aminosalicylates, corticosteroids, immunosuppressants, TNF inhibitors, antibiotics, nutritional supplementation and dietary measures. Crohn's disease is typically treated in the short term (4–8 weeks) with corticosteroids. In severe active disease, hospital admission and intravenous administration of corticosteroids may be required. There is evidence that Crohn's disease in some people, despite a good initial response, becomes resistant to corticosteroids. Other people may become dependent on corticosteroid treatment, relapsing once the dose is reduced or treatment is stopped. Azathioprine and 6-mercaptopurine are widely used in the management of active Crohn's disease. Between 50 and 80% of people with Crohn's disease will require surgery at some stage. The main reasons for surgery are strictures causing obstructive symptoms, lack of response to medical therapy, and complications such as fistulae and perianal disease. The CDAI is frequently used to assess disease severity. It is a composite of overall activity of Crohn's disease as assessed by clinicians, and has eight variables weighted according to their ability to predict disease activity. It gives a score ranging from 0 to over 600, based on a diary of symptoms kept by the patient for 1–7 days, and other measurements such as the patient's weight and haematocrit. A CDAI score of less than 150 is considered to be remission, a score greater than 220 is considered to define moderate to severe disease, and a score greater than 300 is considered to be severe disease. The paediatric CDAI (PCDAI) is an instrument similar to the CDAI but with less emphasis on subjectively reported symptoms and more emphasis on laboratory parameters of intestinal inflammation. The Harvey-Bradshaw Index is another commonly used tool, which correlates well with CDAI. It is based on assessments of general wellbeing, abdominal pain, number of diarrhoeal stools per day, and the presence of abdominal mass and associated complications. Patients with a score of 8 to 9 or higher are considered to have severe disease.# The technologies # Infliximab Infliximab (Schering-Plough Ltd) is a chimeric human–murine monoclonal antibody that binds with high affinity to TNF-α and inhibits its functional activity. Infliximab has a UK marketing authorisation for the treatment of: severe, active Crohn's disease in people whose disease has not responded despite a full and adequate course of therapy with a corticosteroid and/or an immunosuppressant, or who are intolerant to or have medical contraindications for such therapies fistulising, active Crohn's disease in people whose disease has not responded despite a full and adequate course of therapy with conventional treatment (including antibiotics, drainage and immunosuppressive therapy) severe, active Crohn's disease in people aged 6–17 years whose disease has not responded to conventional therapy, including a corticosteroid, an immunomodulator and primary nutrition therapy, or who are intolerant to or have contraindications for such therapies. The most common adverse events reported during infliximab therapy include acute infusion-related reactions, infections and delayed hypersensitivity reactions. Infliximab is contraindicated in people with moderate or severe heart failure and active infections. Before treatment is started, people must be screened for active and inactive tuberculosis. The summary of product characteristics (SPC) specifies a number of uncommon but serious adverse events related to the immunomodulatory activity. For full details of side effects and contraindications, see the SPC. For severe, active Crohn's disease, infliximab is given as a 5-mg/kg intravenous infusion over a 2-hour period followed by another 5-mg/kg infusion 2 weeks after the first. If a person's disease does not respond after two doses, no additional treatment with infliximab should be given. In people whose disease responds, infliximab regimens include maintenance treatment (another 5-mg/kg infusion at 6 weeks after the initial dose, followed by infusions every 8 weeks) or re-administration, otherwise known as episodic treatment (an infusion of 5-mg/kg if signs and symptoms of the disease recur) in line with the marketing authorisation. In adults, dose escalation is an option for people whose disease has stopped responding. According to the SPC, continued therapy should be carefully reconsidered in patients who show no evidence of therapeutic benefit after dose adjustment. For fistulising, active Crohn's disease, infliximab is given as a 5-mg/kg infusion over a 2-hour period followed by additional 5-mg/kg infusions at 2 and 6 weeks after the first. If a person's disease does not respond after three doses, no further treatment with infliximab should be given. In people whose disease responds, infliximab can be given as maintenance treatment (5-mg/kg infusions every 8 weeks) or as re-administration treatment (5-mg/kg when signs and symptoms recur, followed by infusions of 5-mg/kg every 8 weeks). In adults, dose escalation is an option for people whose disease has stopped responding. For people aged 6–17 years, infliximab is given as a 5-mg/kg intravenous infusion followed by additional 5-mg/kg doses at 2 and 6 weeks after the first dose, then every 8 weeks thereafter. A 100-mg vial of infliximab costs £419.62 (excluding VAT; 'British national formulary' , 58th edition). The drug cost differs between individuals because the dose is adjusted to each person's body weight. For example, if it is assumed that vials are not shared between patients, for a person weighing 73 kg the cost per infusion would be £1678, corresponding to four 100-mg vials needed for a dose of 365 mg. For a course of two infusions, with an assumed drug administration cost for each infusion of £258, the total cost is approximately £3872. The total cost of continuing therapy at a standard dosage for 12 months is approximately £12,584. Costs may also vary in different settings because of negotiated procurement discounts. # Adalimumab Adalimumab (Abbott Laboratories) is a recombinant human monoclonal antibody that binds specifically to TNF-α, blocking interaction with its cell-surface receptors and thereby limiting the promotion of inflammatory pathways. Adalimumab is indicated for the treatment of severe, active Crohn's disease in people whose disease has not responded despite full and adequate treatment with an immunosuppressant and/or corticosteroid, or who are intolerant to or have contraindications to such therapies. For induction therapy adalimumab should be given in combination with corticosteroids. Adalimumab can be given as monotherapy if a person is intolerant to corticosteroids or when continued treatment with corticosteroids is inappropriate. Common adverse events associated with adalimumab include injection site reactions and infections. Before therapy is started, all patients must be screened for active and inactive tuberculosis. Adalimumab is contraindicated in patients with moderate to severe heart failure, active tuberculosis and other severe infections. For full details of side effects and contraindications, see the SPC. The adalimumab induction treatment dose regimen for adults with severe Crohn's disease is 80 mg via subcutaneous injection, followed by 40 mg 2 weeks later. If there is a need for a more rapid response to therapy, a dose of 160 mg followed by 80 mg 2 weeks later can be used, though the risk of adverse events with this higher dose is greater during induction. After induction treatment the recommended dose is 40 mg every other week. This can be increased to 40 mg every week in people whose disease shows a decrease in response to treatment. According to the SPC, continued therapy should be carefully reconsidered in patients whose disease does not respond within 12 weeks of initiating treatment. Adalimumab costs £357.50 per 40-mg prefilled syringe (excluding VAT; BNF, 58th edition). Normal induction treatment costs approximately £1073 and the cost to continue treatment at a standard dosage for 1 year is £9295. Costs may vary in different settings because of negotiated procurement discounts.# Evidence and interpretation The Appraisal Committee (appendix A) considered evidence from a number of sources (appendix B). # Clinical effectiveness Eleven randomised controlled trials (RCTs) that included licensed doses of infliximab and adalimumab met the criteria for inclusion in the assessment report (seven for infliximab and four for adalimumab). These trials covered short treatment regimens that aimed to induce remission in people with active Crohn's disease (induction regimens) and longer-term regular dosing regimens that aimed to prevent relapse in people who had already responded to an induction regimen (maintenance regimens). The RCTs included people with moderate to severe Crohn's disease. Seven studies wholly or predominantly included adults with non-fistulising disease, two trials included adults with fistulae and two studies were in children and young people. The outcomes reported in the clinical trials were mainly based on the CDAI. The PCDAI was reported in the paediatric studies. The inflammatory bowel disease questionnaire (IBDQ), a health-related quality-of-life measure, was also reported in some studies. Two placebo-controlled trials of induction regimens were identified for each of infliximab and adalimumab. Another study investigated infliximab induction treatment in children and young people with Crohn's disease, but there was no placebo arm in this study. One infliximab trial mainly included people with non-fistulising disease (n = 108), and the other included people with fistulising disease only (n = 94). One of the studies of adalimumab induction treatment (CLASSIC I, n = 299) included people with moderate to severe Crohn's disease (11% had fistulae at baseline) who had not previously received treatment with a TNF inhibitor. The second (GAIN, n = 325) included people who had previously been treated with infliximab, but had either not responded to the treatment or had not tolerated it. The Assessment Group was unable to carry out an indirect comparison or meta-analysis because of heterogeneity between the trials. The trial of infliximab that mainly included people with non-fistulising disease studied a single-dose regimen. Participants were randomised to infliximab 5 mg/kg, 10 mg/kg, 20 mg/kg or placebo. Results were reported at 4 weeks. Infliximab at the licensed dose of 5 mg/kg achieved significant improvements in remission rate versus placebo. The rate ratio (RR) for remission (the rate of remission in the 5 mg/kg group divided by the rate of remission in the placebo group; remission defined as CDAI score below 150) was 12.04 (95% confidence interval 1.70 to 85.44). There were also significantly greater rates of 70-point reductions in CDAI (referred to below as response 70) in the infliximab 5 mg/kg group. The study of infliximab induction treatment in fistulising disease compared infliximab at a dose of 5 mg/kg or 10 mg/kg with placebo. Follow-up extended to at least week 18. The primary outcome was a 50% reduction in the number of draining fistulae; the rate difference between the infliximab 5 mg/kg and placebo groups was 0.42 (95% CI 0.19 to 0.64). The secondary outcome was complete absence of fistulae; the rate difference between the infliximab 5 mg/kg and placebo groups was 0.42 (95% CI 0.21 to 0.63). Infliximab groups had statistically significant improvements in CDAI and PCDAI scores at week 2. The studies of adalimumab as induction treatment used a regimen of an initial dose followed by a second, lower dose 2 weeks later. In CLASSIC I, the participants were randomised to one of three dosing schedules (40 mg/20 mg, 80 mg/40 mg or 160 mg/80 mg) or placebo. Only the 80 mg/40 mg and 160 mg/80 mg doses were in line with the SPC. In the other study (GAIN) participants were randomised to 160 mg followed by 80 mg adalimumab or placebo. For the 160 mg/80 mg regimen versus placebo, both studies reported statistically significant improvements in the end points of remission (RR 2.92 and 2.96 for CLASSIC I and GAIN respectively), response 70 (RR 1.62 and 1.53 for CLASSIC I and GAIN respectively) and response 100 (RR 1.95 and 1.55 for CLASSIC I and GAIN respectively). The results for the 80 mg/40 mg regimen did not achieve statistical significance against placebo for the endpoints of remission (RR 1.97, 95% CI 0.95 to 4.11) or response 100 (RR 1.56, 95% CI 0.97 to 2.51). Four studies of maintenance treatment in adults that mainly included people with non-fistulising disease were identified for inclusion by the Assessment Group. For infliximab, two trials were identified. In one of these (ACCENT I, n = 573) all patients received a single infusion of 5 mg/kg infliximab and were then randomised to receive placebo, or infliximab at a dose of 5 mg/kg at weeks 2 and 6 and then every 8 weeks to week 54 (known as the 5 mg/kg group), or infliximab 5 mg/kg at weeks 2 and 6 and then 10 mg/kg every 8 weeks to week 54 (known as the 10 mg/kg group). However, those whose disease initially responded but then worsened were allowed to cross over to treatment with a higher dose of infliximab at week 14. Those who crossed over from the placebo group were considered to have had episodic treatment, and those who crossed over from an active treatment arm were considered to have disease that did not respond for most analyses. The other infliximab trial (n = 73) recruited patients from one of the infliximab induction trials. Only those who responded to infliximab in the induction trial were eligible to enter this study. Participants were randomised to placebo or infliximab 10 mg/kg at 8-week intervals (note that the dose recommended in the SPC is 5 mg/kg every 8 weeks). Follow-up was for 48 weeks. Results for ACCENT I demonstrated that infliximab improved the point prevalence of remission at weeks 30 and 54. At week 54 the point prevalence of remission RR for the infliximab 5 mg/kg group was 2.08 (95% CI 1.19 to 3.61), and the response 70 RR was 2.46 (95% CI 1.50 to 4.04). Two studies (CHARM, n = 778 and CLASSIC II, n = 55) examined adalimumab maintenance at a dose of 40 mg either every other week or every week in people whose disease had already responded to an induction regimen. They mainly included people with non-fistulising disease. In both studies, patients were followed up for 56 weeks, and the primary outcome was the proportion of patients in remission (at week 26 and 56 in CHARM and at week 56 in CLASSIC II). Patients were allowed to switch to open-label treatment if there was sustained non-response or a disease flare. In the CHARM trial, adalimumab every other week and weekly dosing schedules led to statistically significant improvements in the rate of remission at week 56 (RR versus placebo 3.06 for the every other week schedule, and 3.52 for the weekly schedule). In the CLASSIC II trial, the point estimate for remission RR versus placebo at week 56 was 1.78 (95% CI 1.01 to 3.13) for the every other week schedule and 1.88 (95% CI 1.08 to 3.27) for the weekly schedule. The Assessment Group identified an additional study that investigated maintenance treatment with infliximab in fistulising disease (n = 282). All participants received an induction course of three doses of infliximab 5 mg/kg and then responders and non-responders were randomised at week 14 to infliximab 5 mg/kg or placebo every 8 weeks for five doses. Patients were followed up for 54 weeks. After week 22 patients whose disease lost response could cross over to infliximab 5 mg/kg or 10 mg/kg. The primary outcome was time to loss of response (defined as a reappearance of a draining fistula, a change in therapy, a need for surgery, drop-out because of lack of efficacy, or worsening symptoms). Median time to loss of response after randomisation was 14 weeks for the placebo group and more than 40 weeks for the infliximab group. The Assessment Group identified two trials that analysed infliximab in children and young people: one 12-week trial of induction treatment (n = 21) and one 54-week trial of maintenance treatment (n = 103). Both trials included an arm that examined the licensed dose and neither trial included a placebo arm. The results presented suggested that both CDAI and PCDAI decreased and response improved with infliximab treatment. In the induction trial, infliximab 5 mg/kg was associated with a 13% median improvement in PCDAI from baseline at 12 weeks. For the groups receiving infliximab 1 mg/kg and 10 mg/kg the median improvements were 27% and 40% respectively. For the infliximab maintenance regimen a 27-point improvement in PCDAI was reported at week 54 for the treatment arms combined. In addition to the data from clinical trials, new research evidence was submitted by consultees. The National Association for Colitis and Crohn's Disease (NACC) circulated a questionnaire to 320 of its members who had been offered or refused treatment with biological therapies. It received responses from 183 members who had Crohn's disease. The questionnaire included sections on characteristics, experiences of the treatment and condition and an EQ-5D questionnaire to assess quality of life before and after treatment. The main findings from the questionnaire were that the participants' experiences of biological treatment were generally positive and this was demonstrated in an overall improvement in the EQ-5D scores. This trend was repeated in people with fistulae and in seven people aged between 11 and 18 years. Further data about the effect of discontinuing treatment with infliximab and adalimumab at 12 months was submitted in response to the appraisal consultation document (ACD) published in November 2009. An abstract by Louis et al. (2009), which reported the STORI study ('Stop infliximab in patients with Crohn's disease') by the GETAID research group, described outcomes when continuous treatment with infliximab was stopped after a period of at least 12 months. Overall 45 out of 115 (39%) people with Crohn's disease relapsed following treatment discontinuation after a median follow-up of 12 months. It was noted that patients in the study had been in steroid-free remission for at least 6 months before infliximab was stopped. Data from a retrospective study by Armuzzi et al. (2009) was also submitted. This stated that 44% of people relapsed during a median follow-up of 13 months, after infliximab treatment was stopped following sustained clinical benefit. In addition, a survival analysis in this study identified mucosal healing as a predictor of sustained clinical benefit after stopping treatment with infliximab. In response to the Committee's concerns about a lack of long-term data to support continued treatment, the manufacturer of adalimumab highlighted data from the ADHERE study (an open-label extension of the pivotal CHARM study) for patients on adalimumab treatment for 3 years. Remission rates were between 64% and 83% at week 108 depending on the analysis method used (clinical specialists predicted that the true value would be between these two figures). The clinical specialists confirmed that the evidence base would grow as a result of audits, registries and the development of alternative treatments but did not specify particular long-term studies. In response to the ACD published in November 2009, both manufacturers submitted further data on dose escalation for infliximab and adalimumab. The Committee noted that the number of patients who require dose escalation with both agents was different in each study. Another consultee confirmed dose escalation with both drugs was widespread in clinical practice but that precise numbers were difficult to obtain. It was noted that in both the clinical trial setting and in clinical practice, many patients who receive adalimumab may have already been treated with infliximab. Clinical specialists also described an increasing tendency for higher induction doses of 160/80 mg of adalimumab being used in the UK as in the USA. # Cost effectiveness The Assessment Group reviewed the cost-effectiveness data submitted by the manufacturers of infliximab and adalimumab. It also conducted a literature search for any published cost-effectiveness studies. The Assessment Group identified four published economic analyses that examined infliximab in fistulising and non-fistulising Crohn's disease (no published economic studies were found for adalimumab). The studies used an epidemiological model constructed by Silverstein et al. (1999) that reported a 2-monthly transition matrix estimated from 20 years of follow-up of a cohort of 174 people with Crohn's disease. The published analyses also used health-related quality-of-life values from Canadian people with Crohn's disease. The analyses produced incremental cost-effectiveness ratios (ICERs) above £50,000 per QALY gained for non-fistulising disease and above £100,000 per QALY gained for fistulising disease. Schering-Plough carried out three analyses comparing infliximab with standard care in adults with severe active Crohn's disease, in fistulising disease and in children and young people. The analyses used a Markov model with states representing progression over a 5-year period. For fistulising disease the same basic model was expanded to include health states relating to fistulae. The model considered two infliximab dosing schedules: maintenance treatment and infliximab clinical discretion (ICD). ICD approximates episodic treatment: an induction dose of 5 mg/kg at week 0, and 5 mg/kg thereafter according to clinical discretion. The Assessment Group noted that the definition didn't guarantee episodic treatment or rule out maintenance treatment. Maintenance was modelled as 5 mg/kg at weeks 0, 2 and 6 and every 8 weeks thereafter. The base-case ICER for severe active Crohn's disease for maintenance treatment compared with standard care was £25,903 per QALY gained. For ICD treatment, infliximab dominated standard care (that is, infliximab was more effective and less expensive than standard care). When maintenance treatment was compared with ICD the ICER was £457,386 per QALY gained. In fistulising disease the ICER was £30,005 per QALY gained, and for paediatric patients the ICER was £13,891 per QALY gained, both for maintenance treatment compared with standard care. Sensitivity analysis suggested that the results were most sensitive to changes in the average weight used for patients. When this was increased from 60 kg to 70 kg, it caused the ICERs to increase to over £30,000 per QALY gained in all adult analyses. Abbott produced two economic models, one comparing the cost effectiveness of adalimumab as a maintenance treatment against standard care, and the other comparing infliximab and adalimumab as maintenance treatments. The model comparing adalimumab with standard care had a lifetime horizon with a baseline age of 37 and a life expectancy of 66 years. The model was structured around states based on severity of disease and defined by CDAI score. Clinical data for adalimumab were derived from the CHARM trial, and data for the standard care arm were derived from the CLASSIC I trial. For the model comparing adalimumab with infliximab, data came from the published articles of ACCENT I. In Abbott's model, the base-case ICER for adalimumab compared with standard care for moderate and severe Crohn's disease was £30,319 per QALY gained. For severe disease only, the ICER was £11,998 per QALY gained. In this model it was assumed that people stay on treatment for life. To explore the effect of this, the Assessment Group modelled a scenario in which people were assumed to stop treatment at the same rate as was seen in the 40 mg every other week arm of the CHARM trial. At 56 weeks these ICERs changed to £56,621 and £30,964 for moderate and severe, and severe-only Crohn's disease respectively. When the time horizon was increased from 56 weeks to 4 years this reduced the ICER for the moderate-and-severe group from £56,621 to £52,713 per QALY gained. If this was increased to a lifetime horizon, the ICER fell to £24,385 per QALY gained. Abbott argued that it could not access enough data on infliximab to carry out a full comparative economic analysis. Therefore it simplified the analysis to one that examined the proportions of remission and non-remission and the associated costs. The results of this analysis were that adalimumab was more efficacious in achieving remission and was associated with lower costs. The manufacturer concluded that adalimumab dominated infliximab. The Assessment Group carried out analyses for courses of induction treatment given when required and scheduled maintenance treatment for moderate and severe Crohn's disease. In induction treatment patients received active treatment only when relapsing. The Assessment Group stated that this is comparable to episodic use. The Assessment Group constructed a four-stage Markov model based on the model by Silverstein et al., but included only four health states (out of an original seven): remission, relapse, surgery and post-surgery remission. The transition probabilities to model natural history were derived from the Silverstein data set. The treatments were then assumed to have an equivalent effect on the probability of remaining in remission or relapse for both moderate and severe Crohn's disease. A 1-year time horizon was used and the effect of increasing the time horizon was examined in the sensitivity analysis. In response to comments on the assessment report the Assessment Group made alterations to its cost-effectiveness analysis. The Assessment Group used the ACCENT I and CHARM 6-week trial data for all the effectiveness estimates for infliximab and adalimumab. It also added a transitional state to allow transitions to standard care. The Assessment Group presented sensitivity analyses to explore the effect of increasing the relapse rate on the cost-effectiveness estimates. The results reported in sections 4.2.9 to 4.2.14 are based on the updated analysis. The Assessment Group only presented ICERs for infliximab and adalimumab compared with standard care. Only the results for severe disease were presented because the drugs are not licensed for the treatment of moderate Crohn's disease. For induction treatment, both infliximab and adalimumab dominated standard care. For maintenance treatment in severe disease, the ICER for adalimumab relative to standard care was £7478 per QALY gained. However, because standard care is dominated by induction treatment, it is appropriate to compare maintenance treatment with induction treatment rather than with standard care. For this comparison the ICER was £4,980,000 per QALY gained. For infliximab maintenance treatment the ICER relative to standard care was £67,619 per QALY gained and the ICER relative to induction treatment was £5,030,000 per QALY gained. Following comments from consultees on the assumptions about relapse rates based on the model by Silverstein et al., the Assessment Group performed sensitivity analyses using various probabilities of relapsing from the remission state. This indicated that as the relapse rate increased, induction treatment became less cost effective, and maintenance treatment became more cost effective. When the probability of relapse was increased to 0.3 (a 51 times increase) the ICER for infliximab induction treatment in severe disease compared with standard care was £153,136 per QALY gained. For infliximab maintenance treatment compared with standard care the ICER was £43,744 per QALY gained. Using the same assumptions, maintenance treatment with adalimumab dominated standard care, and the ICER for adalimumab maintenance treatment compared with induction treatment was £37,007 per QALY gained. The Assessment Group presented a threshold analysis for the use of infliximab in children and young people. The Assessment Group extrapolated the utilities, effectiveness and non-drug costs from the adult analyses to children. Only the drug costs associated with infliximab that were because of the lower body weight were changed. The Assessment Group carried out analyses at body weights of 20–40kg and 40–60kg. If it was assumed that infliximab improved a child's health to 'full' (a full QALY) the ICER for maintenance treatment in severe disease was £193,328 per QALY gained. For induction treatment, infliximab dominated standard care in children with severe Crohn's disease for all body weights. In response to uncertainties raised by consultees and the Committee about the validity of the cost-effectiveness evidence, the Decision Support Unit (DSU) was commissioned to reconcile the economic models produced by the Assessment Group and the manufacturers. The DSU noted that the models were substantially different in terms of their structures and input parameters. However, one of the key causes for the differences in the cost-effectiveness estimates among the models was the relapse rate used. Given the importance of this parameter, the DSU carried out a systematic review to identify literature that specified the relapse rate of people having standard care with moderate to severe Crohn's disease who were already in remission. Four studies were identified that suggested that 4-week probabilities of relapse ranging from 7% to 14% in this population may be typical. This rate was noted to differ substantially from the relapse rate of 0.59% used in the Assessment Group model for initially severe disease, and from other relapse rates proposed by the manufacturers from their clinical trials. The DSU sought to reconcile the differences between the Schering Plough and Assessment Group models by populating the Assessment Group model with input parameters from Schering Plough's analysis. The DSU noted that these changes did align the models to an extent, but there were still substantial differences in the results produced by each model because it was not possible to reconcile every element of the Markov process. The revised Assessment Group model was also run with parameters from the Abbott model. The DSU noted that the outcomes from the revised Assessment Group model were not to be considered as representative of the most plausible ICERs for each treatment scenario; rather the intention was to demonstrate the impact each parameter had on the ICERs, to highlight the areas of uncertainty and the caution that the Committee should exercise when considering the economic evidence. Comments on the DSU report from consultees highlighted that the course of episodic treatment with infliximab used in the original Assessment Group model was not consistent with the marketing authorisation, and therefore the assumed cost of episodic treatment was incorrect. The DSU conducted additional analyses with the reconciled model using revised costs for episodic treatment with infliximab, and noted that this lowered the ICER. Consultees also highlighted that a publication by Bodger et al. (2009) compared the cost effectiveness of maintenance treatment with infliximab or adalimumab with standard care over a lifetime horizon in patients with moderate to severely active Crohn's disease. The publication suggested that after 1 year of maintenance treatment with infliximab in initial responders, the ICER was £19,050 per QALY gained, and £7190 per QALY gained for 1 year of maintenance treatment with adalimumab, both compared with standard care. After 2 years of maintenance treatment, the ICERs increased to £21,300 per QALY gained and £10,310 per QALY gained for infliximab and adalimumab respectively, compared with standard care. The authors noted that outcomes were sensitive to the time horizon chosen for the analysis, and that neither infliximab nor adalimumab maintenance treatment was cost effective compared with standard care when the time horizon was shortened to match the base-case treatment duration. In response to consultation on the ACD published in November 2009, consultees submitted further data on the annual treatment costs of infliximab and adalimumab. The data highlighted the variation in costs and the uncertainty about the true cost of infliximab and adalimumab. Further cost estimates were submitted by consultees incorporating varying levels of dose escalation, patient weight, administration cost, vial-sharing practice and local discounting arrangements. # Consideration of the evidence The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of infliximab and adalimumab, having considered evidence on the nature of Crohn's disease and the value placed on the benefits of infliximab and adalimumab by people with the condition, those who represent them, and clinical specialists. It also took into account the effective use of NHS resources and comments made during consultation on the previous appraisal consultation documents. The Committee heard from clinical specialists and patient experts about the effects of severe active Crohn's disease. The clinical specialists stated that the majority of people with Crohn's disease were diagnosed under the age of 30, emphasising the chronic long-term nature of the condition. The Committee heard that Crohn's disease and its treatment (in particular corticosteroids) could severely impair growth in children and young people, especially during puberty. The Committee heard from the patient experts about the difficulties of living with Crohn's disease, the substantial disruptive effects that relapses have on everyday activities and the major impact on quality of life in general. Effective treatment and avoidance of relapses were considered of paramount importance by people with Crohn's disease. The Committee considered the definition of severe Crohn's disease. It heard from clinical specialists and patient experts about the limitations of the CDAI in assessing the severity of a patient's condition. In particular, that the instrument takes into account the patient's prior treatment and may not be the most suitable means of defining severity in those who have had surgery. The Committee heard from the clinical specialists that the definition of severe as specified in 'Guidance on the use of infliximab for Crohn's disease' (NICE technology appraisal guidance 40) was appropriate; that is, normally corresponding to a CDAI score of 300 or more. However, the clinical specialists emphasised that the phrase 'normally corresponds to a CDAI score of 300 or more' should not be misinterpreted as a strict threshold for treatment because some people with severe disease may not meet this criterion as a result of their current or previous treatment. The Committee concluded that the definition of severe Crohn's disease should remain as specified in technology appraisal guidance 40, but emphasised that although this normally corresponds to a CDAI score of more than 300, this was not exclusively so and should be interpreted in the light of the specific clinical situation. They also acknowledged that the Harvey-Bradshaw Index is another useful measure of disease severity and that patients with a score of 8 to 9 or above are considered to have severe disease. The Committee therefore decided that either CDAI score or the Harvey-Bradshaw Index should be used to assess disease severity for the purpose of this technology appraisal guidance. The Committee noted that both infliximab and adalimumab were licensed for the treatment of severe active Crohn's disease, but the trials included people with moderate to severe Crohn's disease. The Committee noted that the results of the trials suggested that response to treatment did not differ between moderate and severe disease. The Committee was mindful of the limitations of the trial data, but considered that the analyses presented provided the most reasonable estimates of treatment effectiveness. In line with clinical experience, the clinical specialists considered infliximab and adalimumab to be equally effective treatments for Crohn's disease. Furthermore, in the absence of any direct comparative studies, the Committee was persuaded that infliximab and adalimumab could not be differentiated in terms of clinical effectiveness. The Committee discussed the different modes of treatment with infliximab and adalimumab in severe Crohn's disease, namely induction, episodic and maintenance treatment. The Committee heard from the clinical specialists that for people with severe Crohn's disease the use of episodic treatment was not clinically appropriate for the following reasons: The high potential for relapse meant that patients may be exposed to a rapid increase in their symptoms after each episode of treatment, and in reality the length of time between episodes would be very short. Episodic treatment was not favoured by clinicians and would be unlikely to be used in routine clinical practice because of concerns about the higher risk of developing antibodies to the drug and the potential for loss of effect. It was accepted that this was more of an issue with infliximab than adalimumab. Although early clinical trials of infliximab and adalimumab in moderate to severe Crohn's disease had used episodic therapy, the evidence from clinical practice now strongly favoured a longer-term approach to treatment with infliximab and adalimumab.The Committee discussed the definition of episodic treatment and maintenance treatment and concluded that these were not clearly defined. It was agreed that a 'planned course of treatment' was a clearer way of defining a longer-term approach to treatment for a specified period of time. The Committee discussed the cost-effectiveness analyses presented by the manufacturers and the Assessment Group, and the limitations of each evaluation, as noted in the DSU report. It considered the differences between the models in terms of their structure and inputs, even after reconciliation efforts by the DSU, and the effect these differences had on the resulting economic outcomes. It noted that the source of data used to estimate the distribution of patients between various health states was a key difference between the models. Furthermore, assumptions of constant utilities in the health states and of instantaneous transitions did not accurately reflect the course of the condition, especially the variation in health-related quality of life. The Committee was persuaded that it was not possible for the DSU to completely reconcile the models given the substantial differences between them. However, despite this limitation, the Committee decided that the collective body of evidence was sufficient to inform their decision on the cost-effectiveness of infliximab and adalimumab. The Committee agreed that, despite the limitations of the available evidence, the transition probabilities from remission to relapse with standard care (relapse rate) could be considerably higher in those people for whom infliximab and adalimumab is indicated than the transition probabilities used in the Assessment Group's model. The Committee considered the DSU's sensitivity analyses on the impact on the cost effectiveness of each treatment strategy when the relapse rates in the Assessment Group model were increased in line with published evidence, and those provided by the manufacturers. The Committee noted that the cost effectiveness of each treatment strategy was more favourable using the higher relapse rates. Because these rates may reflect more accurately the clinical situation for people with severe disease, it concluded that its decision should be informed by outcomes generated using higher relapse rates than those used in the Assessment Group model. The Committee noted that for episodic treatment of severe Crohn's disease (broadly defined as people having the opportunity to have another course of treatment if their disease initially responded to a short course of treatment but then relapsed) both infliximab and adalimumab were more effective and less costly than standard care in the analyses presented. However, in light of testimony from the clinical specialists (see section 4.3.5), the Committee considered that repeated induction or episodic treatment with infliximab or adalimumab should not be the preferred option for treating severe Crohn's disease. Therefore its recommendations should be based on the clinical and cost effectiveness of a planned course of treatment relative to standard care alone. The Committee noted that both infliximab and adalimumab appeared to be clinically and cost effective when used continuously for defined periods in people who responded to induction treatment. However, it noted the limitations in the evidence base relating to the duration of the clinical trials and the time horizons used in the economic models. The Committee concluded that there was considerable uncertainty about the clinical and cost effectiveness of both drugs over periods longer than 1 year. The Committee heard from the clinical specialists that they were concerned about the longer-term effectiveness and safety of infliximab and adalimumab. They also stated that there was evidence suggesting that it may be reasonable to try withdrawing treatment in people whose disease demonstrated a complete response. The Committee acknowledged the limitations of this evidence and noted that there may still be a significant risk of relapse after treatment is stopped, but that relapse would also occur in some patients who continued on treatment. The clinical specialists also noted that Crohn's disease usually fluctuated between periods of high and low activity. The Committee noted that for planned courses of treatment, the ICERs for adalimumab were lower than those for infliximab, when both were compared with standard care. Given the lack of head-to-head trials, the Committee was unable to comment reliably on which drug was superior in terms of clinical effectiveness, and therefore concluded that they could only be differentiated by their cost. The Committee also discussed evidence provided by the manufacturers and the DSU on administration and drug costs for infliximab and adalimumab, and noted that there was uncertainty over the true costs for each agent. The estimated annual cost of infliximab varied according to the assumption of average number of vials used, which was dictated by patient body weight and whether vials could be shared to avoid wastage. It was also noted that the induction dose for adalimumab could be either 80 mg followed by 40 mg at week 2 or 160 mg followed by 80 mg at week 2. The Committee also reviewed different sources of data on average patient body weight and considered the feasibility of vial sharing. The Committee concluded that infliximab and adalimumab should be recommended for a planned course of treatment for 12 months after induction for non-fistulising disease and that choice of treatment should be based on cost, taking into account any local discounting agreements and vial-sharing arrangements. The Committee considered the evidence on the use of infliximab in patients with fistulae. It heard from the clinical specialists that people with fistulae would not all be classified as having severe Crohn's disease. The clinical specialists also stated that in their experience, TNF inhibitors have the greatest benefit in patients with complex fistulae (for example, recto-vaginal fistulae), which are associated with significant impairment of quality of life. The Committee accepted that such complications may not be fully captured by the CDAI, but could contribute to clinical judgement of the definition of severe disease. The Committee therefore considered that infliximab was potentially cost effective in this situation. The Committee noted that the Assessment Group had not modelled the cost effectiveness of infliximab for fistulising disease separately because of the lack of a long-term standard care cohort study. The Committee considered the estimate of cost effectiveness provided by the manufacturer. It noted that the manufacturer had only provided a comparison of maintenance treatment with standard care, giving an ICER of £30,300 per QALY gained. Although this ICER was considered to be relatively high, the Committee considered the severity of the disease and noted that there were few treatment options available to these patients. The Committee therefore concluded that a planned course of treatment with infliximab for people with fistulising disease could be cost effective if the definition of severe disease was met. The Committee discussed the use of infliximab for the treatment of children and young people aged 6–17 years. The Committee noted that the trials were not placebo controlled. However, it acknowledged the difficulties of conducting clinical trials in children and young people and considered that it was plausible to generalise results from studies in adults to the paediatric population. It considered the cost-effectiveness estimates presented for children and young people and noted the Assessment Group's concerns over the data and analysis. It considered the lower weight of children and young people and the consequent lower infliximab drug costs. In addition, the Committee noted children and young people could potentially benefit more from treatment than adults, especially with regard to the potential lifelong effects on quality of life and avoiding potential toxicity from alternative therapies. Given these factors the Committee concluded that infliximab would be cost effective for the treatment of children and young people with severe Crohn's disease. The Appraisal Committee discussed the additional data submitted in response to the ACD published in November 2009 about stopping treatment with infliximab and adalimumab at 12 months. The Committee noted that patients in the study by Louis et al. (2009) had been in steroid-free remission for at least 6 months before treatment was stopped. It heard from clinical specialists that this was a highly selected subgroup of people with Crohn's disease, and that it was difficult to apply data from this study to all patients on treatment. The Committee heard from two patient experts about their fear of their treatment being stopped at 12 months regardless of need. The patient experts informed the Committee that they preferred to avoid taking drug treatments when it was not necessary but feared deterioration in their condition if they stopped treatment when their disease was still active. The Committee then heard from clinical specialists that people with active disease would be more likely to relapse even if they were no longer symptomatic and that because of the diverse nature of Crohn's disease it was difficult to define which patients should stop treatment and when. The Committee noted that the evidence supporting continued treatment after 1 year was limited despite some data from open-label extension studies for adalimumab, and accepted that the available evidence supported a trial withdrawal of treatment in people who have been in steroid-free remission for at least 6 months. However, the Committee was uncertain of particular subgroups that would be at risk of relapse after stopping treatment or who would benefit from continued treatment. They discussed available evidence of mucosal healing as a predictor of sustained clinical benefit after stopping treatment with infliximab, but were aware of issues accessing colonoscopy in clinical practice to confirm this. The clinical specialists considered it reasonable to review the need for biological treatment in patients who were in stable remission. The Committee therefore agreed that people who continue treatment with infliximab or adalimumab beyond 1 year should have their disease reassessed at least every 12 months to determine whether they still have active disease and if ongoing treatment is clinically appropriate. In addition, they agreed that people whose disease relapses after treatment is stopped should have the option to start treatment again. The Committee was concerned that there was little incentive to produce additional data on treatment discontinuation or long-term efficacy in future, and emphasised that a register of individuals who receive TNF inhibitors for the treatment of Crohn's disease may help to provide valuable information on long-term outcomes. Despite additional data on dose escalation for both infliximab and adalimumab from clinical trials and observational studies, the Committee remained uncertain about true treatment costs for infliximab and adalimumab and accepted that local arrangements would have an impact on relative costs.# Recommendations for further research Randomised controlled trials should be carried out that directly compare infliximab and adalimumab. Trials should be carried out of continuous treatment with infliximab and adalimumab that are designed to allow a true, unbiased comparison with standard care. Trials of continuous treatment with adalimumab should be carried out exploring less-frequent dosing regimens. Data should be collected on the effect of TNF inhibitors on the natural history of Crohn's disease, particularly the effect on relapse rates. Health-related quality-of-life information about people with Crohn's disease should be collected. Clinically meaningful instruments should be developed to help identify patients for whom treatment with infliximab and adalimumab would be suitable. A register should be set up to monitor people who receive TNF inhibitors for the treatment of Crohn's disease in order to obtain data on long-term outcomes and relapse rates after withdrawal.# Related NICE guidance Guidance on the use of infliximab for Crohn's disease. NICE technology appraisal guidance 40 (2002).# Review of guidance The guidance on this technology will be considered for review by the Guidance Executive in September 2011. NICE welcomes comment on this proposed date. The Guidance Executive will decide whether the technology should be reviewed based on information gathered by NICE, and in consultation with consultees and commentators. Andrew DillonChief ExecutiveMay 2010# Changes after publication February 2014: implementation section updated to clarify that infliximab and adalimumab are recommended as options for treating Crohn's disease. Additional minor maintenance update also carried out. March 2012: minor maintenance# About this guidance NICE technology appraisal guidance is about the use of new and existing medicines and treatments in the NHS in England and Wales. This guidance was developed using the NICE multiple technology appraisal process. It replaces NICE technology appraisal guidance 40 issued in April 2002. The review and re-appraisal of infliximab for the treatment of severe active or active fistulising Crohn's disease has resulted in a change in the guidance. Specifically, infliximab should now be given as a planned course of treatment until treatment failure (including the need for surgery) or for 12 months, whichever is shorter. Treatment should then only be continued if there is clear evidence of ongoing active disease. Adalimumab is now also recommended as another treatment option for people with severe active Crohn's disease. We have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available. Your responsibility This guidance represents the views of NICE and was arrived at after careful consideration of the evidence available. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. However, the guidance does not override the individual responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or guardian or carer. Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties. Copyright © National Institute for Health and Clinical Excellence 2010. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.	{'Guidance': "This guidance replaces 'NICE technology appraisal guidance 40' issued in April 2002.\n\nFor details, see 'About this guidance'.\n\nInfliximab and adalimumab, within their licensed indications, are recommended as treatment options for adults with severe active Crohn's disease (see 1.6) whose disease has not responded to conventional therapy (including immunosuppressive and/or corticosteroid treatments), or who are intolerant of or have contraindications to conventional therapy. Infliximab or adalimumab should be given as a planned course of treatment until treatment failure (including the need for surgery), or until 12\xa0months after the start of treatment, whichever is shorter. People should then have their disease reassessed (see 1.4) to determine whether ongoing treatment is still clinically appropriate.\n\nTreatment as described in 1.1 should normally be started with the less expensive drug (taking into account drug administration costs, required dose and product price per dose). This may need to be varied for individual patients because of differences in the method of administration and treatment schedules.\n\nInfliximab, within its licensed indication, is recommended as a treatment option for people with active fistulising Crohn's disease whose disease has not responded to conventional therapy (including antibiotics, drainage and immunosuppressive treatments), or who are intolerant of or have contraindications to conventional therapy. Infliximab should be given as a planned course of treatment until treatment failure (including the need for surgery) or until 12\xa0months after the start of treatment, whichever is shorter. People should then have their disease reassessed (see\xa01.4) to determine whether ongoing treatment is still clinically appropriate.\n\nTreatment with infliximab or adalimumab (see 1.1 and 1.3) should only be continued if there is clear evidence of ongoing active disease as determined by clinical symptoms, biological markers and investigation, including endoscopy if necessary. Specialists should discuss the risks and benefits of continued treatment with patients and consider a trial withdrawal from treatment for all patients who are in stable clinical remission. People who continue treatment with infliximab or adalimumab should have their disease reassessed at least every 12 months to determine whether ongoing treatment is still clinically appropriate. People whose disease relapses after treatment is stopped should have the option to start treatment again.\n\nInfliximab, within its licensed indication, is recommended for the treatment of people aged 6–17 years with severe active Crohn's disease whose disease has not responded to conventional therapy (including corticosteroids, immunomodulators and primary nutrition therapy), or who are intolerant of or have contraindications to conventional therapy. The need to continue treatment should be reviewed at least every 12 months.\n\nFor the purposes of this guidance, severe active Crohn's disease is defined as very poor general health and one or more symptoms such as weight loss, fever, severe abdominal pain and usually frequent (3–4 or more) diarrhoeal stools daily. People with severe active Crohn's disease may or may not develop new fistulae or have extra-intestinal manifestations of the disease. This clinical definition normally, but not exclusively, corresponds to a Crohn's Disease Activity Index (CDAI) score of 300 or more, or a Harvey-Bradshaw score of 8 to 9 or above.\n\nWhen using the CDAI and Harvey-Bradshaw Index, healthcare professionals should take into account any physical, sensory or learning disabilities, or communication difficulties that could affect the scores and make any adjustments they consider appropriate.\n\nTreatment with infliximab or adalimumab should only be started and reviewed by clinicians with experience of TNF inhibitors and of managing Crohn's disease.", 'Clinical need and practice': "Crohn's disease is a chronic inflammatory condition affecting the gastrointestinal tract (gut). It can affect any part of the gut from the mouth to the anus. The lining of the affected area becomes inflamed and may be ulcerated, and the wall of the intestine thickens. The clinical features of Crohn's disease vary and are determined partly by the site of the disease. Symptoms include diarrhoea, abdominal pain, weight loss, malaise, lethargy, anorexia, nausea, vomiting and fever.\n\nCrohn's disease can be complicated by the development of strictures (narrowing of the intestine), obstructions, fistulae and perianal disease. Fistulae – abnormal connections between areas of the intestine or adjacent organs – develop in 17–43% of people with Crohn's disease. Perianal disease includes fissures, fistulae and abscesses. Other complications of Crohn's disease include acute dilation, perforation and massive haemorrhage of the gut, and carcinoma of the small bowel or colon.\n\nPeople with Crohn's disease have acute 'flares' of the disease in between periods of remission or less active disease. These flares can affect any part of the gut. They may be defined by location (terminal ileal, colonic, ileocolonic, upper gastrointestinal), or by the pattern of the disease (inflammatory, fistulising or stricturing).\n\nThe prevalence of Crohn's disease in the UK is estimated to be about 50–100 per 100,000 people. It affects approximately 60,000\xa0people in the UK. The incidence of Crohn's disease is greatest in people aged between 15 and 30\xa0years. However, it may affect people of any age: 15% of people with the disease are older than 60\xa0years at diagnosis and 20–30% are younger than 20\xa0years. Mortality among people with Crohn's disease is only slightly higher than in the general population.\n\nCrohn's disease is not medically or surgically curable. Treatment aims to control manifestations of Crohn's disease to reduce symptoms, and to maintain or improve quality of life while minimising short- and long-term adverse effects.\n\nClinical management depends on disease activity, site, behaviour of disease (inflammatory, fistulising or stricturing), response to previous medications, side-effect profiles of medications and extra-intestinal manifestations. Because Crohn's disease is unpredictable, successful treatment focuses on inducing and maintaining clinical remission.\n\nCurrent treatment includes aminosalicylates, corticosteroids, immunosuppressants, TNF inhibitors, antibiotics, nutritional supplementation and dietary measures. Crohn's disease is typically treated in the short term (4–8\xa0weeks) with corticosteroids. In severe active disease, hospital admission and intravenous administration of corticosteroids may be required. There is evidence that Crohn's disease in some people, despite a good initial response, becomes resistant to corticosteroids. Other people may become dependent on corticosteroid treatment, relapsing once the dose is reduced or treatment is stopped. Azathioprine and 6-mercaptopurine are widely used in the management of active Crohn's disease.\n\nBetween 50 and 80% of people with Crohn's disease will require surgery at some stage. The main reasons for surgery are strictures causing obstructive symptoms, lack of response to medical therapy, and complications such as fistulae and perianal disease.\n\nThe CDAI is frequently used to assess disease severity. It is a composite of overall activity of Crohn's disease as assessed by clinicians, and has eight variables weighted according to their ability to predict disease activity. It gives a score ranging from 0 to over 600, based on a diary of symptoms kept by the patient for 1–7 days, and other measurements such as the patient's weight and haematocrit. A CDAI score of less than 150 is considered to be remission, a score greater than 220 is considered to define moderate to severe disease, and a score greater than 300 is considered to be severe disease. The paediatric CDAI (PCDAI) is an instrument similar to the CDAI but with less emphasis on subjectively reported symptoms and more emphasis on laboratory parameters of intestinal inflammation.\n\nThe Harvey-Bradshaw Index is another commonly used tool, which correlates well with CDAI. It is based on assessments of general wellbeing, abdominal pain, number of diarrhoeal stools per day, and the presence of abdominal mass and associated complications. Patients with a score of 8 to 9 or higher are considered to have severe disease.", 'The technologies': "# Infliximab\n\nInfliximab (Schering-Plough Ltd) is a chimeric human–murine monoclonal antibody that binds with high affinity to TNF-α and inhibits its functional activity. Infliximab has a UK marketing authorisation for the treatment of:\n\nsevere, active Crohn's disease in people whose disease has not responded despite a full and adequate course of therapy with a corticosteroid and/or an immunosuppressant, or who are intolerant to or have medical contraindications for such therapies\n\nfistulising, active Crohn's disease in people whose disease has not responded despite a full and adequate course of therapy with conventional treatment (including antibiotics, drainage and immunosuppressive therapy)\n\nsevere, active Crohn's disease in people aged 6–17\xa0years whose disease has not responded to conventional therapy, including a corticosteroid, an immunomodulator and primary nutrition therapy, or who are intolerant to or have contraindications for such therapies.\n\nThe most common adverse events reported during infliximab therapy include acute infusion-related reactions, infections and delayed hypersensitivity reactions. Infliximab is contraindicated in people with moderate or severe heart failure and active infections. Before treatment is started, people must be screened for active and inactive tuberculosis. The summary of product characteristics (SPC) specifies a number of uncommon but serious adverse events related to the immunomodulatory activity. For full details of side effects and contraindications, see the SPC.\n\nFor severe, active Crohn's disease, infliximab is given as a 5-mg/kg intravenous infusion over a 2-hour period followed by another 5-mg/kg infusion 2\xa0weeks after the first. If a person's disease does not respond after two doses, no additional treatment with infliximab should be given. In people whose disease responds, infliximab regimens include maintenance treatment (another 5-mg/kg infusion at 6\xa0weeks after the initial dose, followed by infusions every 8\xa0weeks) or re-administration, otherwise known as episodic treatment (an infusion of 5-mg/kg if signs and symptoms of the disease recur) in line with the marketing authorisation. In adults, dose escalation is an option for people whose disease has stopped responding. According to the SPC, continued therapy should be carefully reconsidered in patients who show no evidence of therapeutic benefit after dose adjustment.\n\nFor fistulising, active Crohn's disease, infliximab is given as a 5-mg/kg infusion over a 2-hour period followed by additional 5-mg/kg infusions at 2\xa0and 6\xa0weeks after the first. If a person's disease does not respond after three doses, no further treatment with infliximab should be given. In people whose disease responds, infliximab can be given as maintenance treatment (5-mg/kg infusions every 8\xa0weeks) or as re-administration treatment (5-mg/kg when signs and symptoms recur, followed by infusions of 5-mg/kg every 8\xa0weeks). In adults, dose escalation is an option for people whose disease has stopped responding.\n\nFor people aged 6–17 years, infliximab is given as a 5-mg/kg intravenous infusion followed by additional 5-mg/kg doses at 2\xa0and 6\xa0weeks after the first dose, then every 8\xa0weeks thereafter.\n\nA 100-mg vial of infliximab costs £419.62 (excluding VAT; 'British national formulary' [BNF], 58th edition). The drug cost differs between individuals because the dose is adjusted to each person's body weight. For example, if it is assumed that vials are not shared between patients, for a person weighing 73\xa0kg the cost per infusion would be £1678, corresponding to four 100-mg vials needed for a dose of 365\xa0mg. For a course of two infusions, with an assumed drug administration cost for each infusion of £258, the total cost is approximately £3872. The total cost of continuing therapy at a standard dosage for 12 months is approximately £12,584. Costs may also vary in different settings because of negotiated procurement discounts.\n\n# Adalimumab\n\nAdalimumab (Abbott Laboratories) is a recombinant human monoclonal antibody that binds specifically to TNF-α, blocking interaction with its cell-surface receptors and thereby limiting the promotion of inflammatory pathways. Adalimumab is indicated for the treatment of severe, active Crohn's disease in people whose disease has not responded despite full and adequate treatment with an immunosuppressant and/or corticosteroid, or who are intolerant to or have contraindications to such therapies. For induction therapy adalimumab should be given in combination with corticosteroids. Adalimumab can be given as monotherapy if a person is intolerant to corticosteroids or when continued treatment with corticosteroids is inappropriate.\n\nCommon adverse events associated with adalimumab include injection site reactions and infections. Before therapy is started, all patients must be screened for active and inactive tuberculosis. Adalimumab is contraindicated in patients with moderate to severe heart failure, active tuberculosis and other severe infections. For full details of side effects and contraindications, see the SPC.\n\nThe adalimumab induction treatment dose regimen for adults with severe Crohn's disease is 80\xa0mg via subcutaneous injection, followed by 40\xa0mg 2\xa0weeks later. If there is a need for a more rapid response to therapy, a dose of 160\xa0mg followed by 80\xa0mg 2\xa0weeks later can be used, though the risk of adverse events with this higher dose is greater during induction. After induction treatment the recommended dose is 40\xa0mg every other week. This can be increased to 40\xa0mg every week in people whose disease shows a decrease in response to treatment. According to the SPC, continued therapy should be carefully reconsidered in patients whose disease does not respond within 12 weeks of initiating treatment.\n\nAdalimumab costs £357.50 per 40-mg prefilled syringe (excluding VAT; BNF, 58th edition). Normal induction treatment costs approximately £1073 and the cost to continue treatment at a standard dosage for 1 year is £9295. Costs may vary in different settings because of negotiated procurement discounts.", 'Evidence and interpretation': "The Appraisal Committee (appendix A) considered evidence from a number of sources (appendix B).\n\n# Clinical effectiveness\n\nEleven randomised controlled trials (RCTs) that included licensed doses of infliximab and adalimumab met the criteria for inclusion in the assessment report (seven for infliximab and four for adalimumab). These trials covered short treatment regimens that aimed to induce remission in people with active Crohn's disease (induction regimens) and longer-term regular dosing regimens that aimed to prevent relapse in people who had already responded to an induction regimen (maintenance regimens). The RCTs included people with moderate to severe Crohn's disease. Seven studies wholly or predominantly included adults with non-fistulising disease, two trials included adults with fistulae and two studies were in children and young people.\n\nThe outcomes reported in the clinical trials were mainly based on the CDAI. The PCDAI was reported in the paediatric studies. The inflammatory bowel disease questionnaire (IBDQ), a health-related quality-of-life measure, was also reported in some studies.\n\nTwo placebo-controlled trials of induction regimens were identified for each of infliximab and adalimumab. Another study investigated infliximab induction treatment in children and young people with Crohn's disease, but there was no placebo arm in this study. One infliximab trial mainly included people with non-fistulising disease (n\xa0=\xa0108), and the other included people with fistulising disease only (n\xa0=\xa094). One of the studies of adalimumab induction treatment (CLASSIC\xa0I, n\xa0=\xa0299) included people with moderate to severe Crohn's disease (11% had fistulae at baseline) who had not previously received treatment with a TNF inhibitor. The second (GAIN, n\xa0=\xa0325) included people who had previously been treated with infliximab, but had either not responded to the treatment or had not tolerated it. The Assessment Group was unable to carry out an indirect comparison or meta-analysis because of heterogeneity between the trials.\n\nThe trial of infliximab that mainly included people with non-fistulising disease studied a single-dose regimen. Participants were randomised to infliximab 5\xa0mg/kg, 10\xa0mg/kg, 20\xa0mg/kg or placebo. Results were reported at 4\xa0weeks. Infliximab at the licensed dose of 5\xa0mg/kg achieved significant improvements in remission rate versus placebo. The rate ratio (RR) for remission (the rate of remission in the 5\xa0mg/kg group divided by the rate of remission in the placebo group; remission defined as CDAI score below 150) was 12.04 (95%\xa0confidence interval [CI] 1.70 to 85.44). There were also significantly greater rates of 70-point reductions in CDAI (referred to below as response\xa070) in the infliximab 5\xa0mg/kg group.\n\nThe study of infliximab induction treatment in fistulising disease compared infliximab at a dose of 5\xa0mg/kg or 10\xa0mg/kg with placebo. Follow-up extended to at least week\xa018. The primary outcome was a 50% reduction in the number of draining fistulae; the rate difference between the infliximab 5\xa0mg/kg and placebo groups was 0.42 (95%\xa0CI 0.19 to 0.64). The secondary outcome was complete absence of fistulae; the rate difference between the infliximab 5\xa0mg/kg and placebo groups was 0.42 (95%\xa0CI 0.21 to 0.63). Infliximab groups had statistically significant improvements in CDAI and PCDAI scores at week\xa02.\n\nThe studies of adalimumab as induction treatment used a regimen of an initial dose followed by a second, lower dose 2\xa0weeks later. In CLASSIC\xa0I, the participants were randomised to one of three dosing schedules (40\xa0mg/20\xa0mg, 80\xa0mg/40\xa0mg or 160\xa0mg/80\xa0mg) or placebo. Only the 80\xa0mg/40\xa0mg and 160\xa0mg/80\xa0mg doses were in line with the SPC. In the other study (GAIN) participants were randomised to 160\xa0mg followed by 80\xa0mg adalimumab or placebo. For the 160\xa0mg/80\xa0mg regimen versus placebo, both studies reported statistically significant improvements in the end points of remission (RR 2.92 and 2.96 for CLASSIC\xa0I and GAIN respectively), response\xa070 (RR 1.62 and 1.53 for CLASSIC\xa0I and GAIN respectively) and response\xa0100 (RR 1.95 and 1.55 for CLASSIC\xa0I and GAIN respectively). The results for the 80\xa0mg/40\xa0mg regimen did not achieve statistical significance against placebo for the endpoints of remission (RR\xa01.97, 95%\xa0CI 0.95 to 4.11) or response\xa0100 (RR 1.56, 95%\xa0CI 0.97 to 2.51).\n\nFour studies of maintenance treatment in adults that mainly included people with non-fistulising disease were identified for inclusion by the Assessment Group. For infliximab, two trials were identified. In one of these (ACCENT\xa0I, n\xa0=\xa0573) all patients received a single infusion of 5\xa0mg/kg infliximab and were then randomised to receive placebo, or infliximab at a dose of 5\xa0mg/kg at weeks\xa02 and\xa06 and then every 8\xa0weeks to week\xa054 (known as the 5\xa0mg/kg group), or infliximab 5\xa0mg/kg at weeks\xa02 and\xa06 and then 10\xa0mg/kg every 8\xa0weeks to week\xa054 (known as the 10\xa0mg/kg group). However, those whose disease initially responded but then worsened were allowed to cross over to treatment with a higher dose of infliximab at week\xa014. Those who crossed over from the placebo group were considered to have had episodic treatment, and those who crossed over from an active treatment arm were considered to have disease that did not respond for most analyses. The other infliximab trial (n\xa0=\xa073) recruited patients from one of the infliximab induction trials. Only those who responded to infliximab in the induction trial were eligible to enter this study. Participants were randomised to placebo or infliximab 10\xa0mg/kg at 8-week intervals (note that the dose recommended in the SPC is 5\xa0mg/kg every 8\xa0weeks). Follow-up was for 48\xa0weeks.\n\nResults for ACCENT\xa0I demonstrated that infliximab improved the point prevalence of remission at weeks\xa030 and\xa054. At week\xa054 the point prevalence of remission RR for the infliximab 5\xa0mg/kg group was 2.08 (95%\xa0CI 1.19 to 3.61), and the response\xa070 RR was 2.46 (95%\xa0CI 1.50 to 4.04).\n\nTwo studies (CHARM, n\xa0=\xa0778 and CLASSIC\xa0II, n\xa0=\xa055) examined adalimumab maintenance at a dose of 40\xa0mg either every other week or every week in people whose disease had already responded to an induction regimen. They mainly included people with non-fistulising disease. In both studies, patients were followed up for 56\xa0weeks, and the primary outcome was the proportion of patients in remission (at week\xa026 and 56 in CHARM and at week\xa056 in CLASSIC\xa0II). Patients were allowed to switch to open-label treatment if there was sustained non-response or a disease flare. In the CHARM trial, adalimumab every other week and weekly dosing schedules led to statistically significant improvements in the rate of remission at week\xa056 (RR versus placebo 3.06 [95%\xa0CI 1.94 to 4.84] for the every other week schedule, and 3.52 [95%\xa0CI 2.24 to 5.53] for the weekly schedule). In the CLASSIC\xa0II trial, the point estimate for remission RR versus placebo at week\xa056 was 1.78 (95%\xa0CI 1.01 to 3.13) for the every other week schedule and 1.88 (95%\xa0CI 1.08 to 3.27) for the weekly schedule.\n\nThe Assessment Group identified an additional study that investigated maintenance treatment with infliximab in fistulising disease (n\xa0=\xa0282). All participants received an induction course of three doses of infliximab 5\xa0mg/kg and then responders and non-responders were randomised at week\xa014 to infliximab 5\xa0mg/kg or placebo every 8\xa0weeks for five doses. Patients were followed up for 54\xa0weeks. After week\xa022 patients whose disease lost response could cross over to infliximab 5\xa0mg/kg or 10\xa0mg/kg. The primary outcome was time to loss of response (defined as a reappearance of a draining fistula, a change in therapy, a need for surgery, drop-out because of lack of efficacy, or worsening symptoms). Median time to loss of response after randomisation was 14\xa0weeks for the placebo group and more than 40\xa0weeks for the infliximab group.\n\nThe Assessment Group identified two trials that analysed infliximab in children and young people: one 12-week trial of induction treatment (n\xa0=\xa021) and one 54-week trial of maintenance treatment (n\xa0=\xa0103). Both trials included an arm that examined the licensed dose and neither trial included a placebo arm. The results presented suggested that both CDAI and PCDAI decreased and response improved with infliximab treatment. In the induction trial, infliximab 5\xa0mg/kg was associated with a 13% median improvement in PCDAI from baseline at 12\xa0weeks. For the groups receiving infliximab 1\xa0mg/kg and 10\xa0mg/kg the median improvements were 27% and 40% respectively. For the infliximab maintenance regimen a 27-point improvement in PCDAI was reported at week\xa054 for the treatment arms combined.\n\nIn addition to the data from clinical trials, new research evidence was submitted by consultees. The National Association for Colitis and Crohn's Disease (NACC) circulated a questionnaire to 320 of its members who had been offered or refused treatment with biological therapies. It received responses from 183 members who had Crohn's disease. The questionnaire included sections on characteristics, experiences of the treatment and condition and an EQ-5D questionnaire to assess quality of life before and after treatment. The main findings from the questionnaire were that the participants' experiences of biological treatment were generally positive and this was demonstrated in an overall improvement in the EQ-5D scores. This trend was repeated in people with fistulae and in seven people aged between 11 and 18\xa0years.\n\nFurther data about the effect of discontinuing treatment with infliximab and adalimumab at 12 months was submitted in response to the appraisal consultation document (ACD) published in November 2009. An abstract by Louis et al. (2009), which reported the STORI study ('Stop infliximab in patients with Crohn's disease') by the GETAID research group, described outcomes when continuous treatment with infliximab was stopped after a period of at least 12 months. Overall 45 out of 115 (39%) people with Crohn's disease relapsed following treatment discontinuation after a median follow-up of 12 months. It was noted that patients in the study had been in steroid-free remission for at least 6 months before infliximab was stopped. Data from a retrospective study by Armuzzi et al. (2009) was also submitted. This stated that 44% of people relapsed during a median follow-up of 13 months, after infliximab treatment was stopped following sustained clinical benefit. In addition, a survival analysis in this study identified mucosal healing as a predictor of sustained clinical benefit after stopping treatment with infliximab.\n\nIn response to the Committee's concerns about a lack of long-term data to support continued treatment, the manufacturer of adalimumab highlighted data from the ADHERE study (an open-label extension of the pivotal CHARM study) for patients on adalimumab treatment for 3 years. Remission rates were between 64% and 83% at week 108 depending on the analysis method used (clinical specialists predicted that the true value would be between these two figures). The clinical specialists confirmed that the evidence base would grow as a result of audits, registries and the development of alternative treatments but did not specify particular long-term studies.\n\nIn response to the ACD published in November 2009, both manufacturers submitted further data on dose escalation for infliximab and adalimumab. The Committee noted that the number of patients who require dose escalation with both agents was different in each study. Another consultee confirmed dose escalation with both drugs was widespread in clinical practice but that precise numbers were difficult to obtain. It was noted that in both the clinical trial setting and in clinical practice, many patients who receive adalimumab may have already been treated with infliximab. Clinical specialists also described an increasing tendency for higher induction doses of 160/80 mg of adalimumab being used in the UK as in the USA.\n\n# Cost effectiveness\n\nThe Assessment Group reviewed the cost-effectiveness data submitted by the manufacturers of infliximab and adalimumab. It also conducted a literature search for any published cost-effectiveness studies.\n\nThe Assessment Group identified four published economic analyses that examined infliximab in fistulising and non-fistulising Crohn's disease (no published economic studies were found for adalimumab). The studies used an epidemiological model constructed by Silverstein et al. (1999) that reported a 2-monthly transition matrix estimated from 20\xa0years of follow-up of a cohort of 174\xa0people with Crohn's disease. The published analyses also used health-related quality-of-life values from Canadian people with Crohn's disease. The analyses produced incremental cost-effectiveness ratios (ICERs) above £50,000 per QALY gained for non-fistulising disease and above £100,000 per QALY gained for fistulising disease.\n\nSchering-Plough carried out three analyses comparing infliximab with standard care in adults with severe active Crohn's disease, in fistulising disease and in children and young people. The analyses used a Markov model with states representing progression over a 5-year period. For fistulising disease the same basic model was expanded to include health states relating to fistulae. The model considered two infliximab dosing schedules: maintenance treatment and infliximab clinical discretion (ICD). ICD approximates episodic treatment: an induction dose of 5\xa0mg/kg at week\xa00, and 5\xa0mg/kg thereafter according to clinical discretion. The Assessment Group noted that the definition didn't guarantee episodic treatment or rule out maintenance treatment. Maintenance was modelled as 5\xa0mg/kg at weeks\xa00, 2 and 6 and every 8\xa0weeks thereafter. The base-case ICER for severe active Crohn's disease for maintenance treatment compared with standard care was £25,903 per QALY gained. For ICD treatment, infliximab dominated standard care (that is, infliximab was more effective and less expensive than standard care). When maintenance treatment was compared with ICD the ICER was £457,386 per QALY gained. In fistulising disease the ICER was £30,005 per QALY gained, and for paediatric patients the ICER was £13,891 per QALY gained, both for maintenance treatment compared with standard care. Sensitivity analysis suggested that the results were most sensitive to changes in the average weight used for patients. When this was increased from 60\xa0kg to 70\xa0kg, it caused the ICERs to increase to over £30,000 per QALY gained in all adult analyses.\n\nAbbott produced two economic models, one comparing the cost effectiveness of adalimumab as a maintenance treatment against standard care, and the other comparing infliximab and adalimumab as maintenance treatments. The model comparing adalimumab with standard care had a lifetime horizon with a baseline age of 37 and a life expectancy of 66\xa0years. The model was structured around states based on severity of disease and defined by CDAI score. Clinical data for adalimumab were derived from the CHARM trial, and data for the standard care arm were derived from the CLASSIC\xa0I trial. For the model comparing adalimumab with infliximab, data came from the published articles of ACCENT\xa0I.\n\nIn Abbott's model, the base-case ICER for adalimumab compared with standard care for moderate and severe Crohn's disease was £30,319 per QALY gained. For severe disease only, the ICER was £11,998 per QALY gained. In this model it was assumed that people stay on treatment for life. To explore the effect of this, the Assessment Group modelled a scenario in which people were assumed to stop treatment at the same rate as was seen in the 40\xa0mg every other week arm of the CHARM trial. At 56\xa0weeks these ICERs changed to £56,621 and £30,964 for moderate and severe, and severe-only Crohn's disease respectively. When the time horizon was increased from 56\xa0weeks to 4\xa0years this reduced the ICER for the moderate-and-severe group from £56,621 to £52,713 per QALY gained. If this was increased to a lifetime horizon, the ICER fell to £24,385 per QALY gained.\n\nAbbott argued that it could not access enough data on infliximab to carry out a full comparative economic analysis. Therefore it simplified the analysis to one that examined the proportions of remission and non-remission and the associated costs. The results of this analysis were that adalimumab was more efficacious in achieving remission and was associated with lower costs. The manufacturer concluded that adalimumab dominated infliximab.\n\nThe Assessment Group carried out analyses for courses of induction treatment given when required and scheduled maintenance treatment for moderate and severe Crohn's disease. In induction treatment patients received active treatment only when relapsing. The Assessment Group stated that this is comparable to episodic use. The Assessment Group constructed a four-stage Markov model based on the model by Silverstein et al., but included only four health states (out of an original seven): remission, relapse, surgery and post-surgery remission. The transition probabilities to model natural history were derived from the Silverstein data set. The treatments were then assumed to have an equivalent effect on the probability of remaining in remission or relapse for both moderate and severe Crohn's disease. A 1-year time horizon was used and the effect of increasing the time horizon was examined in the sensitivity analysis.\n\nIn response to comments on the assessment report the Assessment Group made alterations to its cost-effectiveness analysis. The Assessment Group used the ACCENT\xa0I and CHARM 6-week trial data for all the effectiveness estimates for infliximab and adalimumab. It also added a transitional state to allow transitions to standard care. The Assessment Group presented sensitivity analyses to explore the effect of increasing the relapse rate on the cost-effectiveness estimates. The results reported in sections\xa04.2.9 to 4.2.14 are based on the updated analysis.\n\nThe Assessment Group only presented ICERs for infliximab and adalimumab compared with standard care. Only the results for severe disease were presented because the drugs are not licensed for the treatment of moderate Crohn's disease. For induction treatment, both infliximab and adalimumab dominated standard care. For maintenance treatment in severe disease, the ICER for adalimumab relative to standard care was £7478 per QALY gained. However, because standard care is dominated by induction treatment, it is appropriate to compare maintenance treatment with induction treatment rather than with standard care. For this comparison the ICER was £4,980,000 per QALY gained. For infliximab maintenance treatment the ICER relative to standard care was £67,619 per QALY gained and the ICER relative to induction treatment was £5,030,000 per QALY gained.\n\nFollowing comments from consultees on the assumptions about relapse rates based on the model by Silverstein et al., the Assessment Group performed sensitivity analyses using various probabilities of relapsing from the remission state. This indicated that as the relapse rate increased, induction treatment became less cost effective, and maintenance treatment became more cost effective. When the probability of relapse was increased to 0.3 (a 51 times increase) the ICER for infliximab induction treatment in severe disease compared with standard care was £153,136 per QALY gained. For infliximab maintenance treatment compared with standard care the ICER was £43,744 per QALY gained. Using the same assumptions, maintenance treatment with adalimumab dominated standard care, and the ICER for adalimumab maintenance treatment compared with induction treatment was £37,007 per QALY gained.\n\nThe Assessment Group presented a threshold analysis for the use of infliximab in children and young people. The Assessment Group extrapolated the utilities, effectiveness and non-drug costs from the adult analyses to children. Only the drug costs associated with infliximab that were because of the lower body weight were changed. The Assessment Group carried out analyses at body weights of 20–40kg and 40–60kg. If it was assumed that infliximab improved a child's health to 'full' (a full QALY) the ICER for maintenance treatment in severe disease was £193,328 per QALY gained. For induction treatment, infliximab dominated standard care in children with severe Crohn's disease for all body weights.\n\nIn response to uncertainties raised by consultees and the Committee about the validity of the cost-effectiveness evidence, the Decision Support Unit (DSU) was commissioned to reconcile the economic models produced by the Assessment Group and the manufacturers. The DSU noted that the models were substantially different in terms of their structures and input parameters. However, one of the key causes for the differences in the cost-effectiveness estimates among the models was the relapse rate used. Given the importance of this parameter, the DSU carried out a systematic review to identify literature that specified the relapse rate of people having standard care with moderate to severe Crohn's disease who were already in remission. Four studies were identified that suggested that 4-week probabilities of relapse ranging from 7% to 14% in this population may be typical. This rate was noted to differ substantially from the relapse rate of 0.59% used in the Assessment Group model for initially severe disease, and from other relapse rates proposed by the manufacturers from their clinical trials.\n\nThe DSU sought to reconcile the differences between the Schering Plough and Assessment Group models by populating the Assessment Group model with input parameters from Schering Plough's analysis. The DSU noted that these changes did align the models to an extent, but there were still substantial differences in the results produced by each model because it was not possible to reconcile every element of the Markov process. The revised Assessment Group model was also run with parameters from the Abbott model. The DSU noted that the outcomes from the revised Assessment Group model were not to be considered as representative of the most plausible ICERs for each treatment scenario; rather the intention was to demonstrate the impact each parameter had on the ICERs, to highlight the areas of uncertainty and the caution that the Committee should exercise when considering the economic evidence.\n\nComments on the DSU report from consultees highlighted that the course of episodic treatment with infliximab used in the original Assessment Group model was not consistent with the marketing authorisation, and therefore the assumed cost of episodic treatment was incorrect. The DSU conducted additional analyses with the reconciled model using revised costs for episodic treatment with infliximab, and noted that this lowered the ICER.\n\nConsultees also highlighted that a publication by Bodger et\xa0al. (2009) compared the cost effectiveness of maintenance treatment with infliximab or adalimumab with standard care over a lifetime horizon in patients with moderate to severely active Crohn's disease. The publication suggested that after 1\xa0year of maintenance treatment with infliximab in initial responders, the ICER was £19,050 per QALY gained, and £7190 per QALY gained for 1\xa0year of maintenance treatment with adalimumab, both compared with standard care. After 2\xa0years of maintenance treatment, the ICERs increased to £21,300 per QALY gained and £10,310 per QALY gained for infliximab and adalimumab respectively, compared with standard care. The authors noted that outcomes were sensitive to the time horizon chosen for the analysis, and that neither infliximab nor adalimumab maintenance treatment was cost effective compared with standard care when the time horizon was shortened to match the base-case treatment duration.\n\nIn response to consultation on the ACD published in November 2009, consultees submitted further data on the annual treatment costs of infliximab and adalimumab. The data highlighted the variation in costs and the uncertainty about the true cost of infliximab and adalimumab. Further cost estimates were submitted by consultees incorporating varying levels of dose escalation, patient weight, administration cost, vial-sharing practice and local discounting arrangements.\n\n# Consideration of the evidence\n\nThe Appraisal Committee reviewed the data available on the clinical and cost effectiveness of infliximab and adalimumab, having considered evidence on the nature of Crohn's disease and the value placed on the benefits of infliximab and adalimumab by people with the condition, those who represent them, and clinical specialists. It also took into account the effective use of NHS resources and comments made during consultation on the previous appraisal consultation documents.\n\nThe Committee heard from clinical specialists and patient experts about the effects of severe active Crohn's disease. The clinical specialists stated that the majority of people with Crohn's disease were diagnosed under the age of 30, emphasising the chronic long-term nature of the condition. The Committee heard that Crohn's disease and its treatment (in particular corticosteroids) could severely impair growth in children and young people, especially during puberty. The Committee heard from the patient experts about the difficulties of living with Crohn's disease, the substantial disruptive effects that relapses have on everyday activities and the major impact on quality of life in general. Effective treatment and avoidance of relapses were considered of paramount importance by people with Crohn's disease.\n\nThe Committee considered the definition of severe Crohn's disease. It heard from clinical specialists and patient experts about the limitations of the CDAI in assessing the severity of a patient's condition. In particular, that the instrument takes into account the patient's prior treatment and may not be the most suitable means of defining severity in those who have had surgery. The Committee heard from the clinical specialists that the definition of severe as specified in 'Guidance on the use of infliximab for Crohn's disease' (NICE technology appraisal guidance 40) was appropriate; that is, normally corresponding to a CDAI score of 300 or more. However, the clinical specialists emphasised that the phrase 'normally corresponds to a CDAI score of 300 or more' should not be misinterpreted as a strict threshold for treatment because some people with severe disease may not meet this criterion as a result of their current or previous treatment. The Committee concluded that the definition of severe Crohn's disease should remain as specified in technology appraisal guidance 40, but emphasised that although this normally corresponds to a CDAI score of more than 300, this was not exclusively so and should be interpreted in the light of the specific clinical situation. They also acknowledged that the Harvey-Bradshaw Index is another useful measure of disease severity and that patients with a score of 8 to 9 or above are considered to have severe disease. The Committee therefore decided that either CDAI score or the Harvey-Bradshaw Index should be used to assess disease severity for the purpose of this technology appraisal guidance.\n\nThe Committee noted that both infliximab and adalimumab were licensed for the treatment of severe active Crohn's disease, but the trials included people with moderate to severe Crohn's disease. The Committee noted that the results of the trials suggested that response to treatment did not differ between moderate and severe disease. The Committee was mindful of the limitations of the trial data, but considered that the analyses presented provided the most reasonable estimates of treatment effectiveness. In line with clinical experience, the clinical specialists considered infliximab and adalimumab to be equally effective treatments for Crohn's disease. Furthermore, in the absence of any direct comparative studies, the Committee was persuaded that infliximab and adalimumab could not be differentiated in terms of clinical effectiveness.\n\nThe Committee discussed the different modes of treatment with infliximab and adalimumab in severe Crohn's disease, namely induction, episodic and maintenance treatment. The Committee heard from the clinical specialists that for people with severe Crohn's disease the use of episodic treatment was not clinically appropriate for the following reasons:\n\nThe high potential for relapse meant that patients may be exposed to a rapid increase in their symptoms after each episode of treatment, and in reality the length of time between episodes would be very short.\n\nEpisodic treatment was not favoured by clinicians and would be unlikely to be used in routine clinical practice because of concerns about the higher risk of developing antibodies to the drug and the potential for loss of effect. It was accepted that this was more of an issue with infliximab than adalimumab.\n\nAlthough early clinical trials of infliximab and adalimumab in moderate to severe Crohn's disease had used episodic therapy, the evidence from clinical practice now strongly favoured a longer-term approach to treatment with infliximab and adalimumab.The Committee discussed the definition of episodic treatment and maintenance treatment and concluded that these were not clearly defined. It was agreed that a 'planned course of treatment' was a clearer way of defining a longer-term approach to treatment for a specified period of time.\n\nThe Committee discussed the cost-effectiveness analyses presented by the manufacturers and the Assessment Group, and the limitations of each evaluation, as noted in the DSU report. It considered the differences between the models in terms of their structure and inputs, even after reconciliation efforts by the DSU, and the effect these differences had on the resulting economic outcomes. It noted that the source of data used to estimate the distribution of patients between various health states was a key difference between the models. Furthermore, assumptions of constant utilities in the health states and of instantaneous transitions did not accurately reflect the course of the condition, especially the variation in health-related quality of life. The Committee was persuaded that it was not possible for the DSU to completely reconcile the models given the substantial differences between them. However, despite this limitation, the Committee decided that the collective body of evidence was sufficient to inform their decision on the cost-effectiveness of infliximab and adalimumab.\n\nThe Committee agreed that, despite the limitations of the available evidence, the transition probabilities from remission to relapse with standard care (relapse rate) could be considerably higher in those people for whom infliximab and adalimumab is indicated than the transition probabilities used in the Assessment Group's model. The Committee considered the DSU's sensitivity analyses on the impact on the cost effectiveness of each treatment strategy when the relapse rates in the Assessment Group model were increased in line with published evidence, and those provided by the manufacturers. The Committee noted that the cost effectiveness of each treatment strategy was more favourable using the higher relapse rates. Because these rates may reflect more accurately the clinical situation for people with severe disease, it concluded that its decision should be informed by outcomes generated using higher relapse rates than those used in the Assessment Group model.\n\nThe Committee noted that for episodic treatment of severe Crohn's disease (broadly defined as people having the opportunity to have another course of treatment if their disease initially responded to a short course of treatment but then relapsed) both infliximab and adalimumab were more effective and less costly than standard care in the analyses presented. However, in light of testimony from the clinical specialists (see section\xa04.3.5), the Committee considered that repeated induction or episodic treatment with infliximab or adalimumab should not be the preferred option for treating severe Crohn's disease. Therefore its recommendations should be based on the clinical and cost effectiveness of a planned course of treatment relative to standard care alone.\n\nThe Committee noted that both infliximab and adalimumab appeared to be clinically and cost effective when used continuously for defined periods in people who responded to induction treatment. However, it noted the limitations in the evidence base relating to the duration of the clinical trials and the time horizons used in the economic models. The Committee concluded that there was considerable uncertainty about the clinical and cost effectiveness of both drugs over periods longer than 1 year.\n\nThe Committee heard from the clinical specialists that they were concerned about the longer-term effectiveness and safety of infliximab and adalimumab. They also stated that there was evidence suggesting that it may be reasonable to try withdrawing treatment in people whose disease demonstrated a complete response. The Committee acknowledged the limitations of this evidence and noted that there may still be a significant risk of relapse after treatment is stopped, but that relapse would also occur in some patients who continued on treatment. The clinical specialists also noted that Crohn's disease usually fluctuated between periods of high and low activity.\n\nThe Committee noted that for planned courses of treatment, the ICERs for adalimumab were lower than those for infliximab, when both were compared with standard care. Given the lack of head-to-head trials, the Committee was unable to comment reliably on which drug was superior in terms of clinical effectiveness, and therefore concluded that they could only be differentiated by their cost. The Committee also discussed evidence provided by the manufacturers and the DSU on administration and drug costs for infliximab and adalimumab, and noted that there was uncertainty over the true costs for each agent. The estimated annual cost of infliximab varied according to the assumption of average number of vials used, which was dictated by patient body weight and whether vials could be shared to avoid wastage. It was also noted that the induction dose for adalimumab could be either 80\xa0mg followed by 40\xa0mg at week 2 or 160\xa0mg followed by 80\xa0mg at week 2. The Committee also reviewed different sources of data on average patient body weight and considered the feasibility of vial sharing. The Committee concluded that infliximab and adalimumab should be recommended for a planned course of treatment for 12\xa0months after induction for non-fistulising disease and that choice of treatment should be based on cost, taking into account any local discounting agreements and vial-sharing arrangements.\n\nThe Committee considered the evidence on the use of infliximab in patients with fistulae. It heard from the clinical specialists that people with fistulae would not all be classified as having severe Crohn's disease. The clinical specialists also stated that in their experience, TNF inhibitors have the greatest benefit in patients with complex fistulae (for example, recto-vaginal fistulae), which are associated with significant impairment of quality of life. The Committee accepted that such complications may not be fully captured by the CDAI, but could contribute to clinical judgement of the definition of severe disease. The Committee therefore considered that infliximab was potentially cost effective in this situation.\n\nThe Committee noted that the Assessment Group had not modelled the cost effectiveness of infliximab for fistulising disease separately because of the lack of a long-term standard care cohort study. The Committee considered the estimate of cost effectiveness provided by the manufacturer. It noted that the manufacturer had only provided a comparison of maintenance treatment with standard care, giving an ICER of £30,300 per QALY gained. Although this ICER was considered to be relatively high, the Committee considered the severity of the disease and noted that there were few treatment options available to these patients. The Committee therefore concluded that a planned course of treatment with infliximab for people with fistulising disease could be cost effective if the definition of severe disease was met.\n\nThe Committee discussed the use of infliximab for the treatment of children and young people aged 6–17 years. The Committee noted that the trials were not placebo controlled. However, it acknowledged the difficulties of conducting clinical trials in children and young people and considered that it was plausible to generalise results from studies in adults to the paediatric population. It considered the cost-effectiveness estimates presented for children and young people and noted the Assessment Group's concerns over the data and analysis. It considered the lower weight of children and young people and the consequent lower infliximab drug costs. In addition, the Committee noted children and young people could potentially benefit more from treatment than adults, especially with regard to the potential lifelong effects on quality of life and avoiding potential toxicity from alternative therapies. Given these factors the Committee concluded that infliximab would be cost effective for the treatment of children and young people with severe Crohn's disease.\n\nThe Appraisal Committee discussed the additional data submitted in response to the ACD published in November 2009 about stopping treatment with infliximab and adalimumab at 12 months. The Committee noted that patients in the study by Louis et al. (2009) had been in steroid-free remission for at least 6 months before treatment was stopped. It heard from clinical specialists that this was a highly selected subgroup of people with Crohn's disease, and that it was difficult to apply data from this study to all patients on treatment. The Committee heard from two patient experts about their fear of their treatment being stopped at 12\xa0months regardless of need. The patient experts informed the Committee that they preferred to avoid taking drug treatments when it was not necessary but feared deterioration in their condition if they stopped treatment when their disease was still active. The Committee then heard from clinical specialists that people with active disease would be more likely to relapse even if they were no longer symptomatic and that because of the diverse nature of Crohn's disease it was difficult to define which patients should stop treatment and when. The Committee noted that the evidence supporting continued treatment after 1 year was limited despite some data from open-label extension studies for adalimumab, and accepted that the available evidence supported a trial withdrawal of treatment in people who have been in steroid-free remission for at least 6\xa0months. However, the Committee was uncertain of particular subgroups that would be at risk of relapse after stopping treatment or who would benefit from continued treatment. They discussed available evidence of mucosal healing as a predictor of sustained clinical benefit after stopping treatment with infliximab, but were aware of issues accessing colonoscopy in clinical practice to confirm this. The clinical specialists considered it reasonable to review the need for biological treatment in patients who were in stable remission. The Committee therefore agreed that people who continue treatment with infliximab or adalimumab beyond 1 year should have their disease reassessed at least every 12 months to determine whether they still have active disease and if ongoing treatment is clinically appropriate. In addition, they agreed that people whose disease relapses after treatment is stopped should have the option to start treatment again.\n\nThe Committee was concerned that there was little incentive to produce additional data on treatment discontinuation or long-term efficacy in future, and emphasised that a register of individuals who receive TNF inhibitors for the treatment of Crohn's disease may help to provide valuable information on long-term outcomes.\n\nDespite additional data on dose escalation for both infliximab and adalimumab from clinical trials and observational studies, the Committee remained uncertain about true treatment costs for infliximab and adalimumab and accepted that local arrangements would have an impact on relative costs.", 'Recommendations for further research ': "Randomised controlled trials should be carried out that directly compare infliximab and adalimumab.\n\nTrials should be carried out of continuous treatment with infliximab and adalimumab that are designed to allow a true, unbiased comparison with standard care.\n\nTrials of continuous treatment with adalimumab should be carried out exploring less-frequent dosing regimens.\n\nData should be collected on the effect of TNF inhibitors on the natural history of Crohn's disease, particularly the effect on relapse\xa0rates.\n\nHealth-related quality-of-life information about people with Crohn's disease should be collected.\n\nClinically meaningful instruments should be developed to help identify patients for whom treatment with infliximab and adalimumab would be suitable.\n\nA register should be set up to monitor people who receive TNF inhibitors for the treatment of Crohn's disease in order to obtain data on long-term outcomes and relapse rates after withdrawal.", 'Related NICE guidance': "Guidance on the use of infliximab for Crohn's disease. NICE technology appraisal guidance 40 (2002).", 'Review of guidance': 'The guidance on this technology will be considered for review by the Guidance Executive in September 2011. NICE welcomes comment on this proposed date. The Guidance Executive will decide whether the technology should be reviewed based on information gathered by NICE, and in consultation with consultees and commentators.\n\nAndrew DillonChief ExecutiveMay 2010', 'Changes after publication': "February 2014: implementation section updated to clarify that infliximab and adalimumab are recommended as options for treating Crohn's disease. Additional minor maintenance update also carried out.\n\nMarch 2012: minor maintenance", 'About this guidance': "NICE technology appraisal guidance is about the use of new and existing medicines and treatments in the NHS in England and Wales.\n\nThis guidance was developed using the NICE multiple technology appraisal process.\n\nIt replaces NICE technology appraisal guidance 40 issued in April 2002.\n\nThe review and re-appraisal of infliximab for the treatment of severe active or active fistulising Crohn's disease has resulted in a change in the guidance. Specifically, infliximab should now be given as a planned course of treatment until treatment failure (including the need for surgery) or for 12 months, whichever is shorter. Treatment should then only be continued if there is clear evidence of ongoing active disease. Adalimumab is now also recommended as another treatment option for people with severe active Crohn's disease.\n\nWe have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available.\n\nYour responsibility\n\nThis guidance represents the views of NICE and was arrived at after careful consideration of the evidence available. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. However, the guidance does not override the individual responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.\n\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.\n\nCopyright\n\n© National Institute for Health and Clinical Excellence 2010. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE."}	https://www.nice.org.uk/guidance/ta187	Evidence-based recommendations on infliximab (Remicade) and adalimumab (Humira) for treating severe active Crohn's disease in adults.
bd9d10f18f847e7c581e56997fa0853bf56898b6	nice	Limited macular translocation for wet age-related macular degeneration	Limited macular translocation for wet age-related macular degeneration # Guidance Current evidence on limited macular translocation for wet age-related macular degeneration (AMD) shows that this procedure is efficacious in only a proportion of patients and that there is a potential for serious adverse events. Therefore the procedure should only be used with special arrangements for clinical governance, consent and audit or research. Clinicians wishing to undertake limited macular translocation for wet AMD should take the following actions. Inform the clinical governance leads in their Trusts. Ensure that patients and their carers understand the uncertainty about the procedure's safety and efficacy and provide them with clear information about both this procedure and alternative treatments (see section 2.5.1). In addition, the use of NICE's information for patients ('Understanding NICE guidance') is recommended. Audit and review clinical outcomes of all patients having limited macular translocation for wet AMD (see section 3.1).# The procedure # Indications and current treatments AMD is the most common cause of blindness in developed countries. A small proportion of patients with AMD have wet AMD. Wet AMD is characterised by the abnormal growth of blood vessels in the choroid layer underneath the macular part of the retina. These vessels can threaten vision if they leak and cause scarring. Current treatments for wet AMD include laser photocoagulation, photodynamic therapy, intravitreal injections of antivascular endothelial growth factor agents and implantation of miniature lens systems. Patients with advanced disease may benefit from optical aids such as magnifying glasses. # Outline of the procedure The aim of limited macular translocation for wet AMD is to move the macula so that it lies over a healthier part of the choroid layer that is unaffected by neovascularisation. The technique was developed as a less invasive alternative to macular translocation with 360° retinotomy. Limited macular translocation involves making a short incision in the retina to allow fluid to be injected under the retina, so detaching it from the underlying choroid. The outer layers of the eye are then folded and secured with a stitch (sclera imbrication) so that the underlying choroid layer is moved slightly in relation to the macula. Sections 2.3 and 2.4 describe efficacy and safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview. # Efficacy A case series of 151 patients reported that 41% (35/86) of patients had best corrected visual acuity (BCVA) of 20/100 or better, and 40% (34/86) of patients had improved BCVA by 2 or more lines at 12-month follow-up (mean BCVA at baseline was 20/160). A non-randomised controlled study of 65 patients reported that mean improvement in BCVA was significantly greater following limited macular translocation (+0.5 lines) (n = 21) than following photodynamic therapy (–3.4 lines) (n = 20) at 12-month follow-up (p = 0.007). In the case series of 101 patients, 60% (52/86) of eyes achieved median foveal displacement of 1200 micrometres at 12-month follow-up (described as 'effective' translocation). A case series of 25 patients reported median foveal displacement of 1142 micrometres (described as 'successful' translocation) in 68% (17/25) of patients (follow-up not stated). In the non-randomised controlled study of 65 patients, recurrence of neovascularisation was reported in 13 eyes treated by limited macular translocation at mean follow-up of 4.8 months. The Specialist Advisers listed key efficacy outcomes as visual acuity, reading speed, quality of life and recurrence of the condition. # Safety The non-randomised controlled study of 65 patients reported that 38% of eyes treated by limited macular translocation (n = 36) experienced 1 or more postoperative complications (absolute figures not stated). A mean BCVA loss of 4.8 lines was reported for these eyes. In the non-randomised controlled study of 65 patients, retinal detachment due to a peripheral tear, and requiring additional surgery, was reported in 5 eyes among the 36 patients treated by limited macular translocation at a mean follow-up of 3.2 months. Postoperative retinal detachment occurred in 16% (25/153) of eyes in a case series of 151 patients at follow-up between 1 and 13 weeks, with 84% (21/25) of these requiring additional surgery. The frequency of retinal detachment decreased significantly in patients treated later in the series (p = 0.006). A retinal break (not otherwise described) was reported in 8% (13/153) of eyes in the case series of 151 patients. Intermittent or continuous diplopia after limited macular translocation was reported in 6% (14/250) of patients in a case series of 250 patients (management and follow-up not stated). Diplopia was reported in 1 patient in a case report of 2 patients (symptoms resolved without additional surgery by 5-month follow-up). The Specialist Advisers identified suprachoroidal haemorrhage as an adverse event reported in the literature. They listed anecdotal or observed adverse events as cataract and persistent retinal fold in the macular area. They considered theoretical events to include endophthalmitis. # Other comments The Committee noted that intravitreal injections of antivascular endothelial growth factor agents are more commonly used for the treatment of AMD than surgical techniques. For more information see 'Ranibizumab and pegaptanib for the treatment of age-related macular degeneration' (NICE technology appraisal guidance 155).# Further information This guidance requires that clinicians undertaking the procedure make special arrangements for audit. NICE has identified relevant audit criteria and developed audit support (which is for use at local discretion). For related NICE guidance see our website. # Information for patients NICE has produced information on this procedure for patients and carers ('Understanding NICE guidance'). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.# Other NICE recommendations on macular translocation NICE has also issued full guidance on Macular translocation with 360° retinotomy for wet age related macular degeneration (Interventional Procedures Guidance no 340). These replace the previous guidance on Macular translocation for age-related macular degeneration (Interventional Procedures Guidance no. 48, March 2004). If you wish to be updated to any developments with this procedure, you can express an interest via our website.# About this guidance NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland. This guidance was developed using the NICE interventional procedure guidance process. We have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available. Changes since publication January 2012: minor maintenance. Your responsibility This guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer. Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties. Copyright © National Institute for Health and Clinical Excellence 2010. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE. Contact NICE National Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT www.nice.org.uk nice@nice.org.uk	{'Guidance': "Current evidence on limited macular translocation for wet age-related macular degeneration (AMD) shows that this procedure is efficacious in only a proportion of patients and that there is a potential for serious adverse events. Therefore the procedure should only be used with special arrangements for clinical governance, consent and audit or research.\n\nClinicians wishing to undertake limited macular translocation for wet AMD should take the following actions.\n\nInform the clinical governance leads in their Trusts.\n\nEnsure that patients and their carers understand the uncertainty about the procedure's safety and efficacy and provide them with clear information about both this procedure and alternative treatments (see section 2.5.1). In addition, the use of NICE's information for patients ('Understanding NICE guidance') is recommended.\n\nAudit and review clinical outcomes of all patients having limited macular translocation for wet AMD (see section 3.1).", 'The procedure': "# Indications and current treatments\n\nAMD is the most common cause of blindness in developed countries. A small proportion of patients with AMD have wet AMD. Wet AMD is characterised by the abnormal growth of blood vessels in the choroid layer underneath the macular part of the retina. These vessels can threaten vision if they leak and cause scarring.\n\nCurrent treatments for wet AMD include laser photocoagulation, photodynamic therapy, intravitreal injections of antivascular endothelial growth factor agents and implantation of miniature lens systems. Patients with advanced disease may benefit from optical aids such as magnifying glasses.\n\n# Outline of the procedure\n\nThe aim of limited macular translocation for wet AMD is to move the macula so that it lies over a healthier part of the choroid layer that is unaffected by neovascularisation. The technique was developed as a less invasive alternative to macular translocation with 360° retinotomy.\n\nLimited macular translocation involves making a short incision in the retina to allow fluid to be injected under the retina, so detaching it from the underlying choroid. The outer layers of the eye are then folded and secured with a stitch (sclera imbrication) so that the underlying choroid layer is moved slightly in relation to the macula.\n\nSections 2.3 and 2.4 describe efficacy and safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview.\n\n# Efficacy\n\nA case series of 151 patients reported that 41% (35/86) of patients had best corrected visual acuity (BCVA) of 20/100 or better, and 40% (34/86) of patients had improved BCVA by 2 or more lines at 12-month follow-up (mean BCVA at baseline was 20/160). A non-randomised controlled study of 65 patients reported that mean improvement in BCVA was significantly greater following limited macular translocation (+0.5 lines) (n = 21) than following photodynamic therapy (–3.4 lines) (n = 20) at 12-month follow-up (p = 0.007).\n\nIn the case series of 101 patients, 60% (52/86) of eyes achieved median foveal displacement of 1200 micrometres at 12-month follow-up (described as 'effective' translocation). A case series of 25 patients reported median foveal displacement of 1142 micrometres (described as 'successful' translocation) in 68% (17/25) of patients (follow-up not stated).\n\nIn the non-randomised controlled study of 65 patients, recurrence of neovascularisation was reported in 13 eyes treated by limited macular translocation at mean follow-up of 4.8 months.\n\nThe Specialist Advisers listed key efficacy outcomes as visual acuity, reading speed, quality of life and recurrence of the condition.\n\n# Safety\n\nThe non-randomised controlled study of 65 patients reported that 38% of eyes treated by limited macular translocation (n = 36) experienced 1 or more postoperative complications (absolute figures not stated). A mean BCVA loss of 4.8 lines was reported for these eyes.\n\nIn the non-randomised controlled study of 65 patients, retinal detachment due to a peripheral tear, and requiring additional surgery, was reported in 5 eyes among the 36 patients treated by limited macular translocation at a mean follow-up of 3.2 months. Postoperative retinal detachment occurred in 16% (25/153) of eyes in a case series of 151 patients at follow-up between 1 and 13 weeks, with 84% (21/25) of these requiring additional surgery. The frequency of retinal detachment decreased significantly in patients treated later in the series (p = 0.006). A retinal break (not otherwise described) was reported in 8% (13/153) of eyes in the case series of 151 patients.\n\nIntermittent or continuous diplopia after limited macular translocation was reported in 6% (14/250) of patients in a case series of 250 patients (management and follow-up not stated). Diplopia was reported in 1 patient in a case report of 2 patients (symptoms resolved without additional surgery by 5-month follow-up).\n\nThe Specialist Advisers identified suprachoroidal haemorrhage as an adverse event reported in the literature. They listed anecdotal or observed adverse events as cataract and persistent retinal fold in the macular area. They considered theoretical events to include endophthalmitis.\n\n# Other comments\n\nThe Committee noted that intravitreal injections of antivascular endothelial growth factor agents are more commonly used for the treatment of AMD than surgical techniques. For more information see 'Ranibizumab and pegaptanib for the treatment of age-related macular degeneration' (NICE technology appraisal guidance 155).", 'Further information': "This guidance requires that clinicians undertaking the procedure make special arrangements for audit. NICE has identified relevant audit criteria and developed audit support (which is for use at local discretion).\n\nFor related NICE guidance see our website.\n\n# Information for patients\n\nNICE has produced information on this procedure for patients and carers ('Understanding NICE guidance'). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.", 'Other NICE recommendations on macular translocation': 'NICE has also issued full guidance on Macular translocation with 360° retinotomy for wet age related macular degeneration (Interventional Procedures Guidance no 340).\n\nThese replace the previous guidance on Macular translocation for age-related macular degeneration (Interventional Procedures Guidance no. 48, March 2004).\n\nIf you wish to be updated to any developments with this procedure, you can express an interest via our website.', 'About this guidance': 'NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland.\n\nThis guidance was developed using the NICE interventional procedure guidance process.\n\nWe have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available.\n\nChanges since publication\n\nJanuary 2012: minor maintenance.\n\nYour responsibility\n\nThis guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.\n\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.\n\nCopyright\n\n© National Institute for Health and Clinical Excellence 2010. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.\n\nContact NICE\n\nNational Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT\n\nwww.nice.org.uk\n \n nice@nice.org.uk\n 0845 033 7780'}	https://www.nice.org.uk/guidance/ipg339
db6f7f643aaeef6d3afec372d7eaf0a27393f040	nice	Macular translocation with 360° retinotomy for wet age-related macular degeneration	Macular translocation with 360° retinotomy for wet age-related macular degeneration # Guidance Current evidence on macular translocation with 360° retinotomy for wet age-related macular degeneration (AMD) shows that this procedure is efficacious in only a proportion of patients and that there is a potential for serious adverse events. Therefore the procedure should only be used with special arrangements for clinical governance, consent and audit or research. Clinicians wishing to undertake macular translocation with 360° retinotomy for wet AMD should take the following actions. Inform the clinical governance leads in their Trusts. Ensure that patients and their carers understand the uncertainty about the procedure's safety and efficacy and provide them with clear information about both this procedure and alternative treatments (see section 2.5.1). In addition, the use of NICE's information for patients ('Understanding NICE guidance') is recommended. Audit and review clinical outcomes of all patients having macular translocation with 360° retinotomy for wet AMD (see section 3.1).# The procedure # Indications and current treatments AMD is the most common cause of blindness in developed countries. A small proportion of patients with AMD have wet AMD. Wet AMD is characterised by the abnormal growth of blood vessels in the choroid layer underneath the macular part of the retina. These vessels can threaten vision if they leak and cause scarring. Current treatments for wet AMD include laser photocoagulation, photodynamic therapy (PDT), intravitreal injections of antivascular endothelial growth factor agents and implantation of miniature lens systems. Patients with advanced disease may benefit from optical aids such as magnifying glasses. # Outline of the procedure The aim of this procedure is to move the macula so that it lies over a healthier part of the choroid layer that is unaffected by neovascularisation. In macular translocation with 360° retinotomy for wet AMD, a vitrectomy is done and the retina is then detached from the back of the eye using an injection of saline solution. An incision is made around the entire perimeter of the retina so that it is freely mobile, and attached only at the optic disc. The abnormal choroidal vessels are removed and the retina is reattached with the macula rotated away from the original disease site. Once the retina is reattached the vitreous cavity is injected with silicone oil for tamponade. In a second operation approximately 1–2 months later, the whole globe is rotated in the opposite direction by dividing and reattaching the external ocular muscles in order to remove the resulting visual disturbance caused by the torsion, and the silicone oil is drained from the vitreous cavity. Sections 2.3 and 2.4 describe efficacy and safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview. # Efficacy A randomised controlled trial (RCT) of 50 patients treated by the procedure or PDT reported an increase of 3 lines or more of best corrected visual acuity (BCVA) in 28% (7/25) and 0% (0/25) of patients respectively at 24-month follow-up (p < 0.01). A case series of 50 patients reported 2-line or greater BCVA improvement in 66% (33/50), no improvement in 28% (14/50) and a loss of more than 2 lines in 6% (3/50) of patients at 21-month follow-up. A case series of 64 patients reported BCVA improvement of 1 line or more in 52% (32/61) and a loss of more than 3 lines in 11% (7/61) of patients at 12-month follow-up. A non-randomised controlled study of 24 patients reported that mean BCVA improved from 0.90 to 0.69 logMAR in 12 patients treated by the procedure (p = 0.09) and worsened from 0.87 to 1.38 logMAR in 12 patients treated by choroidal patch graft at 3-year follow-up (p < 0.001). The case series of 64 patients reported that median reading speed improved among 55 patients from 71 words per minute at baseline to 105 words per minute at 12-month follow-up (p < 0.001). The RCT of 50 patients reported no difference in quality-of-life scores between patients treated by the procedure or PDT for general vision (p = 0.27) at 24-month follow-up. The Specialist Advisers listed key efficacy outcomes as attached retina following surgery, functional outcomes of BCVA, and reading speed. # Safety Retinal detachment (requiring vitrectomy and endotamponade for reattachment) was reported in 24% (6/25) of patients treated by the procedure in the RCT of 50 patients. In case series of 90 and 64 patients, retinal detachment was reported in 19% (absolute figures not stated) and 8% (5/61) of patients respectively (12-month follow-up for both studies). In the non-randomised controlled study of 24 patients, residual torsion requiring a third procedure was reported in 17% (2/12) of patients treated by the procedure (timing of events not stated). Retinal slippage from the desired final location after translocation was reported in 3% (2/75) of eyes in the case series of 75 eyes (number of patients not stated). The Specialist Advisers stated that adverse events reported in the literature include proliferative vitreoretinopathy, macular oedema, diplopia and phthisis. They listed theoretical adverse events as recurrence of neovascularisation. # Other comments The Committee noted that intravitreal injections of antivascular endothelial growth factor agents are more commonly used for the treatment of AMD than surgical techniques. For more information see 'Ranibizumab and pegaptanib for the treatment of age-related macular degeneration' (NICE technology appraisal guidance 155).# Further information This guidance requires that clinicians undertaking the procedure make special arrangements for audit. NICE has identified relevant audit criteria and developed audit support (which is for use at local discretion). For related NICE guidance see our website. # Information for patients NICE has produced information on this procedure for patients and carers ('Understanding NICE guidance'). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.# Other NICE recommendations on macular translocation NICE has also issued full guidance on Limited macular translocation for wet age related macular degeneration (Interventional Procedures Guidance no. 339) These replace the previous guidance on Macular translocation for age-related macular degeneration (Interventional Procedures Guidance no. 48, March 2004). If you wish to be updated to any developments with this procedure, you can express an interest via our website.# About this guidance NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland. This guidance was developed using the NICE interventional procedure guidance process. We have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available. Changes since publication January 2012: minor maintenance. Your responsibility This guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer. Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties. Copyright © National Institute for Health and Clinical Excellence 2010. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE. Contact NICE National Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT www.nice.org.uk nice@nice.org.uk	{'Guidance': "Current evidence on macular translocation with 360° retinotomy for wet age-related macular degeneration (AMD) shows that this procedure is efficacious in only a proportion of patients and that there is a potential for serious adverse events. Therefore the procedure should only be used with special arrangements for clinical governance, consent and audit or research.\n\nClinicians wishing to undertake macular translocation with 360° retinotomy for wet AMD should take the following actions.\n\nInform the clinical governance leads in their Trusts.\n\nEnsure that patients and their carers understand the uncertainty about the procedure's safety and efficacy and provide them with clear information about both this procedure and alternative treatments (see section 2.5.1). In addition, the use of NICE's information for patients ('Understanding NICE guidance') is recommended.\n\nAudit and review clinical outcomes of all patients having macular translocation with 360° retinotomy for wet AMD (see section 3.1).", 'The procedure': "# Indications and current treatments\n\nAMD is the most common cause of blindness in developed countries. A small proportion of patients with AMD have wet AMD. Wet AMD is characterised by the abnormal growth of blood vessels in the choroid layer underneath the macular part of the retina. These vessels can threaten vision if they leak and cause scarring.\n\nCurrent treatments for wet AMD include laser photocoagulation, photodynamic therapy (PDT), intravitreal injections of antivascular endothelial growth factor agents and implantation of miniature lens systems. Patients with advanced disease may benefit from optical aids such as magnifying glasses.\n\n# Outline of the procedure\n\nThe aim of this procedure is to move the macula so that it lies over a healthier part of the choroid layer that is unaffected by neovascularisation.\n\nIn macular translocation with 360° retinotomy for wet AMD, a vitrectomy is done and the retina is then detached from the back of the eye using an injection of saline solution. An incision is made around the entire perimeter of the retina so that it is freely mobile, and attached only at the optic disc. The abnormal choroidal vessels are removed and the retina is reattached with the macula rotated away from the original disease site. Once the retina is reattached the vitreous cavity is injected with silicone oil for tamponade. In a second operation approximately 1–2 months later, the whole globe is rotated in the opposite direction by dividing and reattaching the external ocular muscles in order to remove the resulting visual disturbance caused by the torsion, and the silicone oil is drained from the vitreous cavity.\n\nSections 2.3 and 2.4 describe efficacy and safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview.\n\n# Efficacy\n\nA randomised controlled trial (RCT) of 50 patients treated by the procedure or PDT reported an increase of 3 lines or more of best corrected visual acuity (BCVA) in 28% (7/25) and 0% (0/25) of patients respectively at 24-month follow-up (p < 0.01). A case series of 50 patients reported 2-line or greater BCVA improvement in 66% (33/50), no improvement in 28% (14/50) and a loss of more than 2 lines in 6% (3/50) of patients at 21-month follow-up. A case series of 64 patients reported BCVA improvement of 1 line or more in 52% (32/61) and a loss of more than 3 lines in 11% (7/61) of patients at 12-month follow-up.\n\nA non-randomised controlled study of 24 patients reported that mean BCVA improved from 0.90 to 0.69 logMAR in 12 patients treated by the procedure (p = 0.09) and worsened from 0.87 to 1.38 logMAR in 12 patients treated by choroidal patch graft at 3-year follow-up (p < 0.001).\n\nThe case series of 64 patients reported that median reading speed improved among 55 patients from 71 words per minute at baseline to 105 words per minute at 12-month follow-up (p < 0.001).\n\nThe RCT of 50 patients reported no difference in quality-of-life scores between patients treated by the procedure or PDT for general vision (p = 0.27) at 24-month follow-up.\n\nThe Specialist Advisers listed key efficacy outcomes as attached retina following surgery, functional outcomes of BCVA, and reading speed.\n\n# Safety\n\nRetinal detachment (requiring vitrectomy and endotamponade for reattachment) was reported in 24% (6/25) of patients treated by the procedure in the RCT of 50 patients. In case series of 90 and 64 patients, retinal detachment was reported in 19% (absolute figures not stated) and 8% (5/61) of patients respectively (12-month follow-up for both studies).\n\nIn the non-randomised controlled study of 24 patients, residual torsion requiring a third procedure was reported in 17% (2/12) of patients treated by the procedure (timing of events not stated).\n\nRetinal slippage from the desired final location after translocation was reported in 3% (2/75) of eyes in the case series of 75 eyes (number of patients not stated).\n\nThe Specialist Advisers stated that adverse events reported in the literature include proliferative vitreoretinopathy, macular oedema, diplopia and phthisis. They listed theoretical adverse events as recurrence of neovascularisation.\n\n# Other comments\n\nThe Committee noted that intravitreal injections of antivascular endothelial growth factor agents are more commonly used for the treatment of AMD than surgical techniques. For more information see 'Ranibizumab and pegaptanib for the treatment of age-related macular degeneration' (NICE technology appraisal guidance 155).", 'Further information': "This guidance requires that clinicians undertaking the procedure make special arrangements for audit. NICE has identified relevant audit criteria and developed audit support (which is for use at local discretion).\n\nFor related NICE guidance see our website.\n\n# Information for patients\n\nNICE has produced information on this procedure for patients and carers ('Understanding NICE guidance'). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.", 'Other NICE recommendations on macular translocation': 'NICE has also issued full guidance on Limited macular translocation for wet age related macular degeneration (Interventional Procedures Guidance no. 339)\n\nThese replace the previous guidance on Macular translocation for age-related macular degeneration (Interventional Procedures Guidance no. 48, March 2004).\n\nIf you wish to be updated to any developments with this procedure, you can express an interest via our website.', 'About this guidance': 'NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland.\n\nThis guidance was developed using the NICE interventional procedure guidance process.\n\nWe have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available.\n\nChanges since publication\n\nJanuary 2012: minor maintenance.\n\nYour responsibility\n\nThis guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.\n\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.\n\nCopyright\n\n© National Institute for Health and Clinical Excellence 2010. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.\n\nContact NICE\n\nNational Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT\n\nwww.nice.org.uk\n \n nice@nice.org.uk\n 0845 033 7780'}	https://www.nice.org.uk/guidance/ipg340
b4bf20cb02ef01d41c4efbc0f25a6a3e25f4f60f	nice	Prosthetic intervertebral disc replacement in the cervical spine	Prosthetic intervertebral disc replacement in the cervical spine # Guidance This guidance replaces the previous guidance on Prosthetic intervertebral disc replacement in the cervical spine (Interventional Procedures Guidance no. 143, 2005). Current evidence on the efficacy of prosthetic intervertebral disc replacement in the cervical spine shows that this procedure is as least as efficacious as fusion in the short term and may result in a reduced need for revision surgery in the long term. The evidence raises no particular safety issues that are not already known in relation to fusion procedures. Therefore this procedure may be used provided that normal arrangements are in place for clinical governance, consent and audit. This procedure should only be carried out in specialist units where surgery of the cervical spine is undertaken regularly. NICE encourages further research into prosthetic intervertebral disc replacement in the cervical spine. Research outcomes should include long-term data on preservation of mobility, occurrence of adjacent segment disease and the avoidance of revision surgery.# The procedure # Indications and current treatments Degenerative cervical disc disease may present with symptoms of pain and stiffness in the neck, and pain, paraesthesia, numbness or weakness of the limbs. Conservative treatment options include rest, analgesic medication, physical therapy and local injections. In patients who are refractory to conservative treatment or at risk of permanent neurological damage, decompression of nerve roots or the spinal cord by cervical discectomy may be offered, with or without vertebral body fusion using a bone graft or cage. # Outline of the procedure Prosthetic intervertebral discs are implants that can be inserted between the vertebrae as an alternative to fusion using bone grafts or cages. They are designed with the aim of preserving the mobility of the diseased intravertebral segment, and therefore reducing the risk of adjacent segment degeneration in the long term. With the patient under general anaesthesia and in the supine position, the anterior cervical spine is exposed. After standard decompression of the neural elements, and partial or full removal of the damaged disc, the artificial disc prosthesis is placed into the intervertebral space. More than one disc can be replaced during the same procedure. Various devices can be used for this procedure. Sections 2.3 and 2.4 describe efficacy and safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview. # Efficacy A randomised controlled trial (RCT) of 541 patients reported that improvement from baseline in mean Neck Disability Index (NDI) score (10-item questionnaire scored out of 100; higher scores indicate greater disability) was significantly greater in patients treated with prosthetic cervical disc insertion (55.7 to 20.7 points) compared with fusion (56.4 to 26.8 points) at 3-month follow-up (p = 0.004), but this difference was not significant at 6-, 12- or 24-month follow-up. An RCT of 463 patients reported a greater improvement from baseline in mean NDI score in patients treated with a prosthetic cervical disc (51.4 to 16.2 points) than in those treated by fusion (50.2 to 19.2 points) at 24-month follow-up (p = 0.025). A case series of 54 patients, who received 77 prosthetic cervical discs between them, reported no heterotopic ossification in 34% (26/77) of implants, bridging ossification but with preservation of prosthesis movement in 10% (8/77), and complete fusion of the level in 9% (7/77) at 1-year follow-up. RCTs of 541, 463 and 209 patients all reported that baseline quality of life measurements (using Short Form-36 physical and mental health components) improved significantly at 24-month follow-up in patients treated by either prosthetic cervical disc insertion or fusion, but that differences between groups were not statistically significant (absolute figures not stated). The Specialist Advisers listed key efficacy outcomes as NDI score, arm and neck pain score measured by visual analogue scale, Short Form-36 score, technical success and revision rate, range of movement and reduction in rate of adjacent level disease after 5 to 10 years. # Safety Revision surgery was required in 0% (0/276) of patients treated with a prosthetic cervical disc and 2% (5/265) of patients treated by fusion at 2-year follow-up in the RCT of 541 patients (p = 0.028). The rate of supplemental fixation in the neck (not otherwise defined) requiring additional surgery was significantly lower among patients treated with a prosthetic disc (0% ) than those treated by fusion (3% ) (p = 0.003). Cerebrospinal fluid leak during decompression surgery occurred in 2% (1/43) of patients treated with prosthetic cervical discs at 2 levels in a non-randomised controlled trial of 146 patients (subsequent management and sequelae not described). A case report described fracture of the posterior central parts of the caudal C6 and the cranial C7 vertebrae during the procedure. Bleeding occurred during the procedure, caused by bony fragments avulsed from the fracture compressing the posterior longitudinal ligament and the thecal sac (bleeding controlled and disc inserted without further complication). The Specialist Advisers listed possible adverse events as implant migration or loosening, paraplegia, disc extrusion following trauma, segmental kyphosis and inadequate decompression. They considered theoretical adverse events to include infection, fusion of prosthesis, need for explantation surgery, disc debris causing inflammatory response, wear to the disc and osteolysis.# Further information For related NICE guidance see our website. # Information for patients NICE has produced information on this procedure for patients and carers ('Understanding NICE guidance'). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.# About this guidance NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland. This guidance was developed using the NICE interventional procedure guidance process. It updates and replaces NICE interventional procedure guidance 143. We have produced a summary of this guidance for patients and carers. Information about the evidence it is based on is also available. If you wish to be updated to any developments with this procedure, you can express an interest via our website. Changes since publication January 2012: minor maintenance. Your responsibility This guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer. Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties. Copyright © National Institute for Health and Clinical Excellence 2010. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE. Contact NICE National Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT www.nice.org.uk nice@nice.org.uk	{'Guidance': 'This guidance replaces the previous guidance on Prosthetic intervertebral disc replacement in the cervical spine (Interventional Procedures Guidance no. 143, 2005).\n\nCurrent evidence on the efficacy of prosthetic intervertebral disc replacement in the cervical spine shows that this procedure is as least as efficacious as fusion in the short term and may result in a reduced need for revision surgery in the long term. The evidence raises no particular safety issues that are not already known in relation to fusion procedures. Therefore this procedure may be used provided that normal arrangements are in place for clinical governance, consent and audit.\n\nThis procedure should only be carried out in specialist units where surgery of the cervical spine is undertaken regularly.\n\nNICE encourages further research into prosthetic intervertebral disc replacement in the cervical spine. Research outcomes should include long-term data on preservation of mobility, occurrence of adjacent segment disease and the avoidance of revision surgery.', 'The procedure': '# Indications and current treatments\n\nDegenerative cervical disc disease may present with symptoms of pain and stiffness in the neck, and pain, paraesthesia, numbness or weakness of the limbs.\n\nConservative treatment options include rest, analgesic medication, physical therapy and local injections. In patients who are refractory to conservative treatment or at risk of permanent neurological damage, decompression of nerve roots or the spinal cord by cervical discectomy may be offered, with or without vertebral body fusion using a bone graft or cage.\n\n# Outline of the procedure\n\nProsthetic intervertebral discs are implants that can be inserted between the vertebrae as an alternative to fusion using bone grafts or cages. They are designed with the aim of preserving the mobility of the diseased intravertebral segment, and therefore reducing the risk of adjacent segment degeneration in the long term.\n\nWith the patient under general anaesthesia and in the supine position, the anterior cervical spine is exposed. After standard decompression of the neural elements, and partial or full removal of the damaged disc, the artificial disc prosthesis is placed into the intervertebral space. More than one disc can be replaced during the same procedure.\n\nVarious devices can be used for this procedure.\n\nSections 2.3 and 2.4 describe efficacy and safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview.\n\n# Efficacy\n\nA randomised controlled trial (RCT) of 541 patients reported that improvement from baseline in mean Neck Disability Index (NDI) score (10-item questionnaire scored out of 100; higher scores indicate greater disability) was significantly greater in patients treated with prosthetic cervical disc insertion (55.7 to 20.7 points) compared with fusion (56.4 to 26.8 points) at 3-month follow-up (p = 0.004), but this difference was not significant at 6-, 12- or 24-month follow-up.\n\nAn RCT of 463 patients reported a greater improvement from baseline in mean NDI score in patients treated with a prosthetic cervical disc (51.4 to 16.2 points) than in those treated by fusion (50.2 to 19.2 points) at 24-month follow-up (p = 0.025).\n\nA case series of 54 patients, who received 77 prosthetic cervical discs between them, reported no heterotopic ossification in 34% (26/77) of implants, bridging ossification but with preservation of prosthesis movement in 10% (8/77), and complete fusion of the level in 9% (7/77) at 1-year follow-up.\n\nRCTs of 541, 463 and 209 patients all reported that baseline quality of life measurements (using Short Form-36 physical and mental health components) improved significantly at 24-month follow-up in patients treated by either prosthetic cervical disc insertion or fusion, but that differences between groups were not statistically significant (absolute figures not stated).\n\nThe Specialist Advisers listed key efficacy outcomes as NDI score, arm and neck pain score measured by visual analogue scale, Short Form-36 score, technical success and revision rate, range of movement and reduction in rate of adjacent level disease after 5 to 10 years.\n\n# Safety\n\nRevision surgery was required in 0% (0/276) of patients treated with a prosthetic cervical disc and 2% (5/265) of patients treated by fusion at 2-year follow-up in the RCT of 541 patients (p = 0.028). The rate of supplemental fixation in the neck (not otherwise defined) requiring additional surgery was significantly lower among patients treated with a prosthetic disc (0% [0/276]) than those treated by fusion (3% [9/265]) (p = 0.003).\n\nCerebrospinal fluid leak during decompression surgery occurred in 2% (1/43) of patients treated with prosthetic cervical discs at 2 levels in a non-randomised controlled trial of 146 patients (subsequent management and sequelae not described).\n\nA case report described fracture of the posterior central parts of the caudal C6 and the cranial C7 vertebrae during the procedure. Bleeding occurred during the procedure, caused by bony fragments avulsed from the fracture compressing the posterior longitudinal ligament and the thecal sac (bleeding controlled and disc inserted without further complication).\n\nThe Specialist Advisers listed possible adverse events as implant migration or loosening, paraplegia, disc extrusion following trauma, segmental kyphosis and inadequate decompression. They considered theoretical adverse events to include infection, fusion of prosthesis, need for explantation surgery, disc debris causing inflammatory response, wear to the disc and osteolysis.', 'Further information': "For related NICE guidance see our website.\n\n# Information for patients\n\nNICE has produced information on this procedure for patients and carers ('Understanding NICE guidance'). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.", 'About this guidance': 'NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland.\n\nThis guidance was developed using the NICE interventional procedure guidance process.\n\nIt updates and replaces NICE interventional procedure guidance 143.\n\nWe have produced a summary of this guidance for patients and carers. Information about the evidence it is based on is also available.\n\nIf you wish to be updated to any developments with this procedure, you can express an interest via our website.\n\nChanges since publication\n\nJanuary 2012: minor maintenance.\n\nYour responsibility\n\nThis guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.\n\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.\n\nCopyright\n\n© National Institute for Health and Clinical Excellence 2010. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.\n\nContact NICE\n\nNational Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT\n\nwww.nice.org.uk\n \n nice@nice.org.uk\n 0845 033 7780'}	https://www.nice.org.uk/guidance/ipg341
6681ceb1d3e5ad6a2f05d329604b761c2da554bb	nice	Haemorrhoidal artery ligation	Haemorrhoidal artery ligation # Guidance Current evidence on haemorrhoidal artery ligation shows that this procedure is an efficacious alternative to conventional haemorrhoidectomy or stapled haemorrhoidopexy in the short and medium term, and that there are no major safety concerns. Therefore this procedure may be used provided that normal arrangements are in place for clinical governance, consent and audit.# The procedure # Indications and current treatments Haemorrhoids (piles) occur when the vascular anal cushions become enlarged. They may cause bleeding, itching or discomfort (grade I) and, if large, may prolapse out of the rectum. Haemorrhoids that prolapse may reduce (return into the anal canal) spontaneously after defaecation (grade II); they may need to be reduced digitally (grade III); or they may not be reducible, remaining continually prolapsed (grade IV). Grade I or II haemorrhoids may be treated by diet modification and topical applications. Interventional treatments include rubber band ligation and sclerosant injections. Treatments for grade III and IV haemorrhoids include surgical excision of the haemorrhoids (haemorrhoidectomy) or stapled haemorrhoidopexy. # Outline of the procedure Haemorrhoidal artery ligation reduces the blood flow to haemorrhoids, with the aim of reducing discomfort and bleeding. It also aims to achieve some shrinkage of haemorrhoids but adjunctive treatment is required for large prolapsing haemorrhoids. The procedure is usually performed with the patient under general anaesthesia, and is normally carried out after an enema. Using a proctoscope, the haemorrhoidal arteries are ligated with sutures (above the dentate line) to remove the flow of blood to the haemorrhoids. A Doppler probe may be used to help locate the haemorrhoidal arteries. For larger prolapsing haemorrhoids, an adjunctive mucosal plication procedure is done. The prolapsing mucosa is plicated up to the level of the dentate line where it is fixed by ligation of the plicating sutures (haemorrhoidopexy). Sections 2.3 and 2.4 describe efficacy and safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview. # Efficacy In a systematic review of 17 studies with a total of 1996 patients, a subset of 6 studies with a follow-up of 1 year or more (850 patients treated by the procedure) reported bleeding, pain on defaecation, and prolapse in 10% (49/507), 9% (18/206) and 11% (46/427) of patients respectively. A subset of 9 studies with a follow-up of less than 1 year (855 patients treated by the procedure) reported bleeding and prolapse in 6% (40/638) and 8% (50/638) of patients respectively. The proportion of patients with preoperative bleeding, pain and prolapse ranged from 45% to 100%, 12% to 83% and 12% to100% respectively across the studies. A randomised controlled trial (RCT) of 41 patients treated by the procedure or stapled haemorrhoidopexy reported symptom resolution in 78% (18/23) and 83% (15/18) of patients respectively at 6-week follow-up (p = not significant). A case series of 616 patients treated by the procedure without Doppler guidance reported symptom resolution at 4-week follow-up in 96%, 98% and 96% of patients who had presented with bleeding, prolapse and pain on defaecation respectively (absolute figures not stated). In the same study, among 523 patients with 1-year follow-up, mean patient satisfaction score was 8.2 on a 10-point visual analogue scale (VAS). A case series of 330 patients reported resolution of symptoms at a mean follow-up of 46 months in 93% (132/142) of patients who presented with bleeding and 92% (110/119) of patients who presented with prolapse. The Specialist Advisers listed key efficacy outcomes as less postoperative pain than other treatments, resolution of haemorrhoids, and relief of symptoms such as bleeding, prolapse, swelling, pain, soreness and itching in the short and long term. # Safety Postoperative haemorrhage was reported in 3 of 1996 patients treated by the procedure in the systematic review (2 required blood transfusion and 1 developed coagulopathy, not otherwise described). Bleeding requiring readmission was reported in 4 patients in the case series of 616 patients (timing of events not stated). Immediate and delayed bleeding was reported in 4 and 3 patients respectively in the case series of 330 patients (1 case of immediate bleeding was due to laceration of a rectal polyp; 1 case of delayed bleeding required a further operation to stop the bleeding). Submucosal haematoma was reported in 1% (4/330) of patients in the case series of 330 patients (not otherwise described). Postoperative haemorrhoid thrombosis was reported in 18 and 5 patients in the case series of 507 and 330 patients respectively (follow-up not stated). In a case series of 100 patients, thrombosis of residual haemorrhoids was reported in 3 patients at 4-, 7- and 17-month follow-up (patients had grade III haemorrhoids; 2 treated by thrombectomy, 1 treated by haemorrhoidectomy). Postoperative fistula formation was reported in 1 patient in the case series of 507 patients (1-year follow-up). Postoperative fissure was reported in 11 and 2 patients in the case series of 507 and 330 patients respectively (not otherwise described). Acute fissure (successfully managed by conservative treatment) was reported in 3 patients at 9-, 10- and 15-day follow-up and anal fissure was reported in 2 patients at 8- and 11-month follow-up in the case series of 100 patients (not otherwise described). The RCT of 41 patients treated by haemorrhoidal artery ligation or stapled haemorrhoidopexy reported postoperative pain on a VAS (higher score indicates more pain; range not defined) as 1.6 and 3.2 respectively at 7-day follow-up (p < 0.001) and 0.2 and 1.0 respectively at 21-day follow-up (p = 0.06). The Specialist Advisers considered theoretical adverse events to include infection, rectal perforation, pelvic abscess, anal stenosis, acute and chronic pain and faecal incontinence.# Further information For related NICE guidance see our website. # Information for patients NICE has produced information on this procedure for patients and carers ('Understanding NICE guidance'). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.# About this guidance NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland. This guidance was developed using the NICE interventional procedure guidance process. We have produced a summary of this guidance for patients and carers. Information about the evidence it is based on is also available. Changes since publication January 2012: minor maintenance. Your responsibility This guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer. Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties. Copyright © National Institute for Health and Clinical Excellence 2010. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE. Contact NICE National Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT www.nice.org.uk nice@nice.org.uk	{'Guidance': 'Current evidence on haemorrhoidal artery ligation shows that this procedure is an efficacious alternative to conventional haemorrhoidectomy or stapled haemorrhoidopexy in the short and medium term, and that there are no major safety concerns. Therefore this procedure may be used provided that normal arrangements are in place for clinical governance, consent and audit.', 'The procedure': '# Indications and current treatments\n\nHaemorrhoids (piles) occur when the vascular anal cushions become enlarged. They may cause bleeding, itching or discomfort (grade I) and, if large, may prolapse out of the rectum. Haemorrhoids that prolapse may reduce (return into the anal canal) spontaneously after defaecation (grade II); they may need to be reduced digitally (grade III); or they may not be reducible, remaining continually prolapsed (grade IV).\n\nGrade I or II haemorrhoids may be treated by diet modification and topical applications. Interventional treatments include rubber band ligation and sclerosant injections. Treatments for grade III and IV haemorrhoids include surgical excision of the haemorrhoids (haemorrhoidectomy) or stapled haemorrhoidopexy.\n\n# Outline of the procedure\n\nHaemorrhoidal artery ligation reduces the blood flow to haemorrhoids, with the aim of reducing discomfort and bleeding. It also aims to achieve some shrinkage of haemorrhoids but adjunctive treatment is required for large prolapsing haemorrhoids.\n\nThe procedure is usually performed with the patient under general anaesthesia, and is normally carried out after an enema. Using a proctoscope, the haemorrhoidal arteries are ligated with sutures (above the dentate line) to remove the flow of blood to the haemorrhoids. A Doppler probe may be used to help locate the haemorrhoidal arteries. For larger prolapsing haemorrhoids, an adjunctive mucosal plication procedure is done. The prolapsing mucosa is plicated up to the level of the dentate line where it is fixed by ligation of the plicating sutures (haemorrhoidopexy).\n\nSections 2.3 and 2.4 describe efficacy and safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview.\n\n# Efficacy\n\nIn a systematic review of 17 studies with a total of 1996 patients, a subset of 6 studies with a follow-up of 1 year or more (850 patients treated by the procedure) reported bleeding, pain on defaecation, and prolapse in 10% (49/507), 9% (18/206) and 11% (46/427) of patients respectively. A subset of 9 studies with a follow-up of less than 1 year (855 patients treated by the procedure) reported bleeding and prolapse in 6% (40/638) and 8% (50/638) of patients respectively. The proportion of patients with preoperative bleeding, pain and prolapse ranged from 45% to 100%, 12% to 83% and 12% to100% respectively across the studies.\n\nA randomised controlled trial (RCT) of 41 patients treated by the procedure or stapled haemorrhoidopexy reported symptom resolution in 78% (18/23) and 83% (15/18) of patients respectively at 6-week follow-up (p = not significant).\n\nA case series of 616 patients treated by the procedure without Doppler guidance reported symptom resolution at 4-week follow-up in 96%, 98% and 96% of patients who had presented with bleeding, prolapse and pain on defaecation respectively (absolute figures not stated). In the same study, among 523 patients with 1-year follow-up, mean patient satisfaction score was 8.2 on a 10-point visual analogue scale (VAS). A case series of 330 patients reported resolution of symptoms at a mean follow-up of 46 months in 93% (132/142) of patients who presented with bleeding and 92% (110/119) of patients who presented with prolapse.\n\nThe Specialist Advisers listed key efficacy outcomes as less postoperative pain than other treatments, resolution of haemorrhoids, and relief of symptoms such as bleeding, prolapse, swelling, pain, soreness and itching in the short and long term.\n\n# Safety\n\nPostoperative haemorrhage was reported in 3 of 1996 patients treated by the procedure in the systematic review (2 required blood transfusion and 1 developed coagulopathy, not otherwise described). Bleeding requiring readmission was reported in 4 patients in the case series of 616 patients (timing of events not stated). Immediate and delayed bleeding was reported in 4 and 3 patients respectively in the case series of 330 patients (1 case of immediate bleeding was due to laceration of a rectal polyp; 1 case of delayed bleeding required a further operation to stop the bleeding). Submucosal haematoma was reported in 1% (4/330) of patients in the case series of 330 patients (not otherwise described).\n\nPostoperative haemorrhoid thrombosis was reported in 18 and 5 patients in the case series of 507 and 330 patients respectively (follow-up not stated). In a case series of 100 patients, thrombosis of residual haemorrhoids was reported in 3 patients at 4-, 7- and 17-month follow-up (patients had grade III haemorrhoids; 2 treated by thrombectomy, 1 treated by haemorrhoidectomy).\n\nPostoperative fistula formation was reported in 1 patient in the case series of 507 patients (1-year follow-up).\n\nPostoperative fissure was reported in 11 and 2 patients in the case series of 507 and 330 patients respectively (not otherwise described). Acute fissure (successfully managed by conservative treatment) was reported in 3 patients at 9-, 10- and 15-day follow-up and anal fissure was reported in 2 patients at 8- and 11-month follow-up in the case series of 100 patients (not otherwise described).\n\nThe RCT of 41 patients treated by haemorrhoidal artery ligation or stapled haemorrhoidopexy reported postoperative pain on a VAS (higher score indicates more pain; range not defined) as 1.6 and 3.2 respectively at 7-day follow-up (p < 0.001) and 0.2 and 1.0 respectively at 21-day follow-up (p = 0.06).\n\nThe Specialist Advisers considered theoretical adverse events to include infection, rectal perforation, pelvic abscess, anal stenosis, acute and chronic pain and faecal incontinence.', 'Further information': "For related NICE guidance see our website.\n\n# Information for patients\n\nNICE has produced information on this procedure for patients and carers ('Understanding NICE guidance'). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.", 'About this guidance': 'NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland.\n\nThis guidance was developed using the NICE interventional procedure guidance process.\n\nWe have produced a summary of this guidance for patients and carers. Information about the evidence it is based on is also available.\n\nChanges since publication\n\nJanuary 2012: minor maintenance.\n\nYour responsibility\n\nThis guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.\n\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.\n\nCopyright\n\n© National Institute for Health and Clinical Excellence 2010. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.\n\nContact NICE\n\nNational Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT\n\nwww.nice.org.uk\n \n nice@nice.org.uk\n 0845 033 7780'}	https://www.nice.org.uk/guidance/ipg342
1a1933011aacf287660b41a92a6b94a7826ba4c8	nice	Endobronchial ultrasound-guided transbronchial biopsy for peripheral lung lesions	Endobronchial ultrasound-guided transbronchial biopsy for peripheral lung lesions # Guidance Current evidence on the efficacy of endobronchial ultrasound-guided transbronchial biopsy (EBUS–TBB) for peripheral lung lesions supports the efficacy of the procedure in producing a high diagnostic yield. With regard to safety, there is an incidence of false negative results in malignant disease, so negative or inconclusive specimens should be further investigated using other biopsy techniques. The procedure may be used provided that normal arrangements are in place for clinical governance, consent and audit. This procedure should only be carried out by a bronchoscopist who has had specific training and mentoring in the technique.# The procedure # Indications and current treatments In this guidance, 'peripheral lung lesions' describes lung lesions that cannot be visualised using conventional bronchoscopy because they do not protrude into the bronchial tree. This guidance is concerned only with the diagnosis of such lesions, and not with their treatment. Patients with peripheral lung lesions are often asymptomatic and the abnormality is detected incidentally on chest X-ray or computed tomography (CT) scanning. Symptoms of cough, haemoptysis and breathlessness may be present, but are more often associated with endobronchial tumours that are accessible to standard bronchoscopic biopsy. Current biopsy techniques include blind transbronchial lung biopsy, image-guided percutaneous lung biopsy, or (thoracoscopic or open) surgical biopsy. # Outline of the procedure The procedure can be undertaken with the patient under general anaesthesia or under local anaesthesia with or without sedation. The lesion is identified by prior CT, positron emission tomography (PET) or conventional chest X-ray imaging. A flexible fibreoptic bronchoscope with a radial mini-probe or catheter is inserted through the nose or mouth, and advanced towards the peripheral lung lesion using endobronchial ultrasound (EBUS) guidance. Once the bronchoscope is in the appropriate location, the ultrasound mini-probe or catheter is withdrawn and biopsy forceps or needles are introduced into the working channel to obtain a histological sample of the target lesion, with or without fluoroscopic guidance. Use of a guide sheath can help to keep the bronchoscope in place during the removal of the probe and insertion of biopsy instruments. Sections 2.3 and 2.4 describe efficacy and safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview. # Efficacy A randomised controlled trial (RCT) of 293 patients investigated by TBB with or without EBUS guidance reported a diagnostic yield of 79% (48/61) for malignant lesions and 69% (18/26) for benign lesions in the EBUS–TBB group compared with 55% (46/83) and 44% (16/36) in the TBB-alone group (without EBUS guidance). An RCT of 202 patients investigated by either EBUS–TBB plus bronchial washing (BW) or EBUS transbronchial needle aspiration (TBNA) plus TBB plus BW, reported diagnostic yields of 61% (57/94) and 78% (69/88) respectively (p = 0.015). Without EBUS guidance, the diagnostic yield was 63% (55/88) for TBNA, 49% (89/182) for TBB (p = 0.049 compared with TBNA) and 20% (36/182) for BW (p < 0.001 compared with TBNA). An RCT of 120 patients investigated by EBUS–TBB, or electromagnetic navigation bronchoscopy (ENB)–TBB, or a combination of EBUS/ENB–TBB reported diagnostic yields of 69% (27/39), 59% (23/39) and 88% (35/40) respectively (p = 0.02 for comparisons between the groups). A non-randomised comparative study of 261 diagnostic procedures using EBUS–TBB (using a guide sheath ) or percutaneous CT-guided fine needle aspiration (CT–FNA) reported sensitivity values of 66% (93/140) and 64% (77/121) respectively (significance not stated). The Specialist Advisers listed key efficacy outcomes as diagnostic yield, sensitivity, specificity, positive and negative predictive values, avoidance of CT-guided procedures (that is, reducing radiation exposure for the patient) and patient acceptability. # Safety The RCT of 120 patients reported pneumothorax in 5% (2/39) of the EBUS–TBB group, 5% (2/39) of the ENB–TBB group and 8% (3/40) of the combined EBUS/ENB–TBB group; 4 patients were treated with chest drain insertion and 1 was managed with aspiration and observation. The other 2 patients were managed by observation and supplemental oxygen. Pneumothorax was reported in 1% (2/140) of patients in the EBUS–GS transbronchial lung biopsy group compared with 22% (27/121) of patients in the percutaneous CT–FNA group (p < 0.01) in the non-randomised comparative study of 261 procedures. Pneumothorax was reported in 3% (3/119) of patients in the TBB-alone group compared with none of the patients in the EBUS–TBB group in the RCT of 293 patients. Pneumothorax determined by chest radiograph taken 1 to 2 hours after the procedure was reported in 2% (2/88) of patients in the EBUS–TBNA plus TBB plus BW group and 2% (2/94) of patients in the EBUS–TBB plus BW group in the RCT of 202 patients. The RCT of 293 patients reported bleeding in none of the patients in the EBUS-TBB group compared with 6% (7/119) of patients in the TBB-alone group. The RCT of 202 patients reported bleeding in 5% (4/88) of patients in the EBUS–TBNA plus TBB plus BW group compared with 2% (2/94) of patients in the EBUS–TBB plus BW group. The Specialist Advisers listed adverse events reported in the literature as pneumothorax and haemorrhage. They listed a theoretical adverse event as false negative rate. # Other comments The Committee noted the risk of false negative results using this procedure. Any negative or inconclusive findings should be investigated using other biopsy procedures.# Further information For related NICE guidance see www.nice.org.uk # Information for patients NICE has produced information on this procedure for patients and carers ('Understanding NICE guidance'). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.	{'Guidance': 'Current evidence on the efficacy of endobronchial ultrasound-guided transbronchial biopsy (EBUS–TBB) for peripheral lung lesions supports the efficacy of the procedure in producing a high diagnostic yield. With regard to safety, there is an incidence of false negative results in malignant disease, so negative or inconclusive specimens should be further investigated using other biopsy techniques. The procedure may be used provided that normal arrangements are in place for clinical governance, consent and audit.\n\nThis procedure should only be carried out by a bronchoscopist who has had specific training and mentoring in the technique.', 'The procedure': "# Indications and current treatments\n\nIn this guidance, 'peripheral lung lesions' describes lung lesions that cannot be visualised using conventional bronchoscopy because they do not protrude into the bronchial tree. This guidance is concerned only with the diagnosis of such lesions, and not with their treatment.\n\nPatients with peripheral lung lesions are often asymptomatic and the abnormality is detected incidentally on chest X-ray or computed tomography (CT) scanning. Symptoms of cough, haemoptysis and breathlessness may be present, but are more often associated with endobronchial tumours that are accessible to standard bronchoscopic biopsy.\n\nCurrent biopsy techniques include blind transbronchial lung biopsy, image-guided percutaneous lung biopsy, or (thoracoscopic or open) surgical biopsy.\n\n# Outline of the procedure\n\nThe procedure can be undertaken with the patient under general anaesthesia or under local anaesthesia with or without sedation. The lesion is identified by prior CT, positron emission tomography (PET) or conventional chest X-ray imaging. A flexible fibreoptic bronchoscope with a radial mini-probe or catheter is inserted through the nose or mouth, and advanced towards the peripheral lung lesion using endobronchial ultrasound (EBUS) guidance. Once the bronchoscope is in the appropriate location, the ultrasound mini-probe or catheter is withdrawn and biopsy forceps or needles are introduced into the working channel to obtain a histological sample of the target lesion, with or without fluoroscopic guidance. Use of a guide sheath can help to keep the bronchoscope in place during the removal of the probe and insertion of biopsy instruments.\n\nSections 2.3 and 2.4 describe efficacy and safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview.\n\n# Efficacy\n\nA randomised controlled trial (RCT) of 293 patients investigated by TBB with or without EBUS guidance reported a diagnostic yield of 79% (48/61) for malignant lesions and 69% (18/26) for benign lesions in the EBUS–TBB group compared with 55% (46/83) and 44% (16/36) in the TBB-alone group (without EBUS guidance).\n\nAn RCT of 202 patients investigated by either EBUS–TBB plus bronchial washing (BW) or EBUS transbronchial needle aspiration (TBNA) plus TBB plus BW, reported diagnostic yields of 61% (57/94) and 78% (69/88) respectively (p = 0.015). Without EBUS guidance, the diagnostic yield was 63% (55/88) for TBNA, 49% (89/182) for TBB (p = 0.049 compared with TBNA) and 20% (36/182) for BW (p < 0.001 compared with TBNA).\n\nAn RCT of 120 patients investigated by EBUS–TBB, or electromagnetic navigation bronchoscopy (ENB)–TBB, or a combination of EBUS/ENB–TBB reported diagnostic yields of 69% (27/39), 59% (23/39) and 88% (35/40) respectively (p = 0.02 for comparisons between the groups).\n\nA non-randomised comparative study of 261 diagnostic procedures using EBUS–TBB (using a guide sheath [GS]) or percutaneous CT-guided fine needle aspiration (CT–FNA) reported sensitivity values of 66% (93/140) and 64% (77/121) respectively (significance not stated).\n\nThe Specialist Advisers listed key efficacy outcomes as diagnostic yield, sensitivity, specificity, positive and negative predictive values, avoidance of CT-guided procedures (that is, reducing radiation exposure for the patient) and patient acceptability.\n\n# Safety\n\nThe RCT of 120 patients reported pneumothorax in 5% (2/39) of the EBUS–TBB group, 5% (2/39) of the ENB–TBB group and 8% (3/40) of the combined EBUS/ENB–TBB group; 4 patients were treated with chest drain insertion and 1 was managed with aspiration and observation. The other 2 patients were managed by observation and supplemental oxygen.\n\nPneumothorax was reported in 1% (2/140) of patients in the EBUS–GS transbronchial lung biopsy group compared with 22% (27/121) of patients in the percutaneous CT–FNA group (p < 0.01) in the non-randomised comparative study of 261 procedures.\n\nPneumothorax was reported in 3% (3/119) of patients in the TBB-alone group compared with none of the patients in the EBUS–TBB group in the RCT of 293 patients. Pneumothorax determined by chest radiograph taken 1 to 2 hours after the procedure was reported in 2% (2/88) of patients in the EBUS–TBNA plus TBB plus BW group and 2% (2/94) of patients in the EBUS–TBB plus BW group in the RCT of 202 patients.\n\nThe RCT of 293 patients reported bleeding in none of the patients in the EBUS-TBB group compared with 6% (7/119) of patients in the TBB-alone group. The RCT of 202 patients reported bleeding in 5% (4/88) of patients in the EBUS–TBNA plus TBB plus BW group compared with 2% (2/94) of patients in the EBUS–TBB plus BW group.\n\nThe Specialist Advisers listed adverse events reported in the literature as pneumothorax and haemorrhage. They listed a theoretical adverse event as false negative rate.\n\n# Other comments\n\nThe Committee noted the risk of false negative results using this procedure. Any negative or inconclusive findings should be investigated using other biopsy procedures.", 'Further information': "For related NICE guidance see www.nice.org.uk\n\n# Information for patients\n\nNICE has produced information on this procedure for patients and carers ('Understanding NICE guidance'). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind."}	https://www.nice.org.uk/guidance/ipg337
d251f56a2f3fb3f86700327dbd215d24202985e7	nice	Arteriovenous crossing sheathotomy for branch retinal vein occlusion	Arteriovenous crossing sheathotomy for branch retinal vein occlusion # Guidance This document replaces previous guidance on arteriovenous sheathotomy for branch retinal vein occlusion (interventional procedure guidance 72). Current evidence on the efficacy and safety of arteriovenous crossing sheathotomy for branch retinal vein occlusion (BRVO) is inadequate in quantity and quality. Therefore, this procedure should only be used in the context of research. Research should take the form of controlled trials and should clearly define patient selection, the timing of treatment in relation to venous occlusion, and details of other treatment modalities used. NICE may review the procedure upon publication of further evidence.# The procedure # Indications and current treatments Branch retinal vein occlusions typically occur at arteriovenous crossings, where the artery and vein share a common membranous sheath. Degenerative changes can cause hardening of the retinal arteries which can lead to compression of companion retinal veins. This compression obstructs blood flow in the vein, leading to thrombosis, macular oedema and decreased visual acuity. The natural history of BRVO is variable. It is usually managed by observation, and decisions about intervention are based on several factors, including the development of neovascularisation and the persistence of macular oedema and reduced visual acuity. Current treatments include grid laser photocoagulation of the macula, intravitreal injection of triamcinolone or an anti-vascular endothelial growth factor agent, or surgery in the form of pars plana vitrectomy (surgical removal of the vitreous) without sheathotomy. # Outline of the procedure Arteriovenous crossing sheathotomy for BRVO involves cutting the sheath surrounding the artery and the vein and separating them at the site where they cross, with the aim of restoring venous drainage. The procedure may be carried out with the patient under general or local anaesthesia. A pars plana vitrectomy is usually performed before identification of the affected arteriovenous crossing and incision of the membranous sheath. A blade is used to separate adhesions holding the artery to the vein and the artery is then lifted away from the vein. Sections 2.3 and 2.4 describe efficacy and safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview. # Efficacy In a randomised controlled trial (RCT) of 40 patients treated by intravitreal injection or sheathotomy, mean improvement in best corrected visual acuity (BCVA) score (measured on the early treatment diabetic retinopathy study scores chart by the number of letters patients could read from the chart, with correction for individual refractive errors) was greater in the intravitreal injection group (12.2 ± 12.3) than in the sheathotomy group (4.4 ± 8.9) at 1-month follow-up (p = 0.026). Improvements in outcome scores were not significantly different between the groups at any other follow-up interval, up to 6 months. An RCT of 36 patients treated by sheathotomy or vitrectomy reported that both groups showed significant improvement in BCVA from baseline, but there was no significant difference between the groups at 31-month follow-up (0.014 logMAR and 0.08 logMAR respectively) (p = 0.25). A non-randomised controlled study of 68 patients reported a change in mean BCVA in patients treated by sheathotomy (from 0.16 ± 0.12 to 0.35 ± 0.25) and in those who declined surgery (from 0.23 ± 0.12 to 0.22 ± 0.16) at 6-week follow-up (significance not stated). A non-randomised controlled study of 40 patients reported that the mean number of lines of BCVA gained at 14-month follow-up in patients treated by sheathotomy (4.55 lines) was significantly greater than in patients in the control group who were followed up to 19 months (either no surgery or grid laser photocoagulation) (1.55 lines) (p = 0.023). A non-randomised controlled study of 36 patients reported that there was no significant difference in the mean change in BCVA from baseline in the sheathotomy group (0.29 logMAR ± 0.35) compared with the group treated by vitrectomy alone (0.30 logMAR ± 0.22) at 1-year follow-up (p = 0.71). A case series of 60 patients treated by sheathotomy for BRVO with macular oedema reported recurrence of macular oedema in 3% (2/60) of patients at 12- to 16-month follow-up. The Specialist Advisers listed key efficacy outcomes as improved blood flow (on fluorescein angiography), resolution of macular oedema and/or reduced macular thickness, and improvement in BCVA. # Safety Intraoperative haemorrhage caused by retinal vascular damage (controlled by increasing intraocular pressure by high pressure perfusion) was reported in 6% (1/18) of patients in the sheathotomy group of the RCT of 36 patients. Vitreous haemorrhage which resolved spontaneously was reported in 10% (2/20) of patients in the sheathotomy group of the non-randomised controlled study of 36 patients (timing of event and follow-up not stated). Cataract development was reported in 15% (3/20) of patients in the non-randomised controlled study of 40 patients (sheathotomy group), and in 10% (2/20) of patients in the sheathotomy group compared with 6% (1/16) of patients in the vitrectomy group of the nonrandomised controlled study of 36 patients (significance and follow-ups not stated). The RCT of 40 patients reported that the mean increase in grade of cataracts was not significantly different between patients treated by sheathotomy or by intravitreal injection (p = 0.382) (absolute figures and length of follow-up not stated). The non-randomised controlled study of 68 patients reported that 2% (1/43) of patients in the sheathotomy group and 36% (9/25) of patients in the no surgery group lost 2 or more BCVA lines at 6-week follow-up. The Specialist Advisers listed adverse events reported in the literature as arterial or venous haemorrhage and retinal detachment. They cited recurrent BRVO as an anecdotal adverse event, and considered theoretical adverse events to include endophthalmitis and/or ophthalmitis, and glaucoma. In particular, there was a concern that sheathotomy used in combination with vitrectomy may confer additional risks without evidence of additional benefit.# Further information # Information for patients NICE has produced information on this procedure for patients and carers ('Understanding NICE guidance'). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind. A large print version is also available.# About this guidance NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland. This guidance was developed using the NICE interventional procedures guidance process. It updates and replaces NICE interventional procedure guidance 72. We have produced a summary of this guidance for patients and carers. Your responsibility This guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer. Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties. Copyright © National Institute for Health and Clinical Excellence 2010. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE. Contact NICE National Institute for Health and Clinical Excellence Level 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT www.nice.org.uk nice@nice.org.uk	{'Guidance': 'This document replaces previous guidance on arteriovenous sheathotomy for branch retinal vein occlusion (interventional procedure guidance 72).\n\nCurrent evidence on the efficacy and safety of arteriovenous crossing sheathotomy for branch retinal vein occlusion (BRVO) is inadequate in quantity and quality. Therefore, this procedure should only be used in the context of research.\n\nResearch should take the form of controlled trials and should clearly define patient selection, the timing of treatment in relation to venous occlusion, and details of other treatment modalities used. NICE may review the procedure upon publication of further evidence.', 'The procedure': '# Indications and current treatments\n\nBranch retinal vein occlusions typically occur at arteriovenous crossings, where the artery and vein share a common membranous sheath. Degenerative changes can cause hardening of the retinal arteries which can lead to compression of companion retinal veins. This compression obstructs blood flow in the vein, leading to thrombosis, macular oedema and decreased visual acuity.\n\nThe natural history of BRVO is variable. It is usually managed by observation, and decisions about intervention are based on several factors, including the development of neovascularisation and the persistence of macular oedema and reduced visual acuity. Current treatments include grid laser photocoagulation of the macula, intravitreal injection of triamcinolone or an anti-vascular endothelial growth factor agent, or surgery in the form of pars plana vitrectomy (surgical removal of the vitreous) without sheathotomy.\n\n# Outline of the procedure\n\nArteriovenous crossing sheathotomy for BRVO involves cutting the sheath surrounding the artery and the vein and separating them at the site where they cross, with the aim of restoring venous drainage.\n\nThe procedure may be carried out with the patient under general or local anaesthesia. A pars plana vitrectomy is usually performed before identification of the affected arteriovenous crossing and incision of the membranous sheath. A blade is used to separate adhesions holding the artery to the vein and the artery is then lifted away from the vein.\n\nSections 2.3 and 2.4 describe efficacy and safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview.\n\n# Efficacy\n\nIn a randomised controlled trial (RCT) of 40 patients treated by intravitreal injection or sheathotomy, mean improvement in best corrected visual acuity (BCVA) score (measured on the early treatment diabetic retinopathy study scores chart by the number of letters patients could read from the chart, with correction for individual refractive errors) was greater in the intravitreal injection group (12.2 ± 12.3) than in the sheathotomy group (4.4 ± 8.9) at 1-month follow-up (p = 0.026). Improvements in outcome scores were not significantly different between the groups at any other follow-up interval, up to 6 months. An RCT of 36 patients treated by sheathotomy or vitrectomy reported that both groups showed significant improvement in BCVA from baseline, but there was no significant difference between the groups at 31-month follow-up (0.014 logMAR and 0.08 logMAR respectively) (p = 0.25).\n\nA non-randomised controlled study of 68 patients reported a change in mean BCVA in patients treated by sheathotomy (from 0.16 ± 0.12 to 0.35 ± 0.25) and in those who declined surgery (from 0.23 ± 0.12 to 0.22 ± 0.16) at 6-week follow-up (significance not stated).\n\nA non-randomised controlled study of 40 patients reported that the mean number of lines of BCVA gained at 14-month follow-up in patients treated by sheathotomy (4.55 lines) was significantly greater than in patients in the control group who were followed up to 19 months (either no surgery or grid laser photocoagulation) (1.55 lines) (p = 0.023).\n\nA non-randomised controlled study of 36 patients reported that there was no significant difference in the mean change in BCVA from baseline in the sheathotomy group (0.29 logMAR ± 0.35) compared with the group treated by vitrectomy alone (0.30 logMAR ± 0.22) at 1-year follow-up (p = 0.71).\n\nA case series of 60 patients treated by sheathotomy for BRVO with macular oedema reported recurrence of macular oedema in 3% (2/60) of patients at 12- to 16-month follow-up.\n\nThe Specialist Advisers listed key efficacy outcomes as improved blood flow (on fluorescein angiography), resolution of macular oedema and/or reduced macular thickness, and improvement in BCVA.\n\n# Safety\n\nIntraoperative haemorrhage caused by retinal vascular damage (controlled by increasing intraocular pressure by high pressure perfusion) was reported in 6% (1/18) of patients in the sheathotomy group of the RCT of 36 patients. Vitreous haemorrhage which resolved spontaneously was reported in 10% (2/20) of patients in the sheathotomy group of the non-randomised controlled study of 36 patients (timing of event and follow-up not stated).\n\nCataract development was reported in 15% (3/20) of patients in the non-randomised controlled study of 40 patients (sheathotomy group), and in 10% (2/20) of patients in the sheathotomy group compared with 6% (1/16) of patients in the vitrectomy group of the nonrandomised controlled study of 36 patients (significance and follow-ups not stated). The RCT of 40 patients reported that the mean increase in grade of cataracts was not significantly different between patients treated by sheathotomy or by intravitreal injection (p = 0.382) (absolute figures and length of follow-up not stated).\n\nThe non-randomised controlled study of 68 patients reported that 2% (1/43) of patients in the sheathotomy group and 36% (9/25) of patients in the no surgery group lost 2 or more BCVA lines at 6-week follow-up.\n\nThe Specialist Advisers listed adverse events reported in the literature as arterial or venous haemorrhage and retinal detachment. They cited recurrent BRVO as an anecdotal adverse event, and considered theoretical adverse events to include endophthalmitis and/or ophthalmitis, and glaucoma. In particular, there was a concern that sheathotomy used in combination with vitrectomy may confer additional risks without evidence of additional benefit.', 'Further information': "# Information for patients\n\nNICE has produced information on this procedure for patients and carers ('Understanding NICE guidance'). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind. A large print version is also available.", 'About this guidance': 'NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland.\n\nThis guidance was developed using the NICE interventional procedures guidance process.\n\nIt updates and replaces NICE interventional procedure guidance 72.\n\nWe have produced a summary of this guidance for patients and carers.\n\nYour responsibility\n\nThis guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.\n\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.\n\nCopyright\n\n© National Institute for Health and Clinical Excellence 2010. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.\n\nContact NICE\n\nNational Institute for Health and Clinical Excellence\n\nLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT\n\nwww.nice.org.uk\n\nnice@nice.org.uk\n\n033 7780'}	https://www.nice.org.uk/guidance/ipg334
3dcae797c28dc46c8e19b3e638498e55ce55c1dc	nice	Endoscopic submucosal dissection of lower gastrointestinal lesions	Endoscopic submucosal dissection of lower gastrointestinal lesions # Guidance Current evidence on endoscopic submucosal dissection (ESD) of lower gastrointestinal lesions shows that it is efficacious, but evidence on long-term survival when used to treat malignant lesions is limited in quantity. There are some concerns about safety with regard to the risk of perforation and bleeding. Therefore, this procedure should only be used with special arrangements for clinical governance, consent and audit or research. Clinicians wishing to undertake ESD of lower gastrointestinal lesions should take the following actions. Inform the clinical governance leads in their Trusts. Ensure that patients understand the uncertainty about the procedure's safety and efficacy in relation to the risks of perforation and bleeding, and that conversion to open surgery may be necessary. Patients should be provided with clear written information. In addition, the use of NICE's information for patients ('Understanding NICE guidance') is recommended. Audit and review clinical outcomes of all patients having ESD of lower gastrointestinal lesions (see section 3.1). Endoscopic submucosal dissection of lower gastrointestinal lesions is a technically challenging procedure and should only be carried out by clinicians with specific training in the technique. The Joint Advisory Group on Gastrointestinal Endoscopy intends to prepare training standards on this procedure. Patient selection should be carried out either by a colorectal surgeon or by both a colorectal surgeon and an endoscopist who are experienced in this technique. NICE encourages further research into ESD of lower gastrointestinal lesions. There should be clear documentation of the incidence of complications including perforation, haemorrhage and need for open surgery (with the reasons for this), rates of complete resection, and long-term outcomes including local recurrence and survival.# The procedure # Indications and current treatments Colorectal lesions may be benign, premalignant or malignant. Patients may be asymptomatic or may present with blood in the stool, change in bowel habit, abdominal pain or unexplained weight loss. Lower gastrointestinal lesions may be investigated radiologically and/or endoscopically. Treatment normally involves resection of the lesions, which may be performed endoscopically or surgically. Current management of small colorectal lesions usually involves snare polypectomy or endoscopic mucosal resection (EMR). EMR usually removes lesions in small pieces, while ESD aims to resect lesions intact. # Outline of the procedure In ESD, an electrocautery knife is used to resect the lesion in one piece (en bloc), aiming to reduce the risk of recurrence and to allow a more accurate histopathological assessment. The procedure is performed with the patient under sedation (usually) or general anaesthesia. Lesions are visualised at colonoscopy and the submucosa injected with fluid to raise the lesion. A circumferential mucosal incision is made initially around the lesion with the electrocautery knife. Submucosal dissection is then performed under endoscopic visualisation, parallel to the muscle layer. Diathermy coagulation is used to achieve haemostasis, but endoscopic clips may also be required to control bleeding and/or treat small perforations. Sections 2.3 and 2.4 describe efficacy and safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview. # Efficacy A systematic review of 14 studies including 1314 patients reported rates of en bloc lesion resection of 85% and complete cure (en bloc resection with histologically clear margins) of 75% (follow-up not stated). A non-randomised comparative study of 536 lesions (number of patients not stated) reported higher rates of en bloc resection in patients treated by ESD (99%, 463/468) compared with those treated by 'simplified' ESD using a snare (91%, 40/44) and those treated by small incision EMR (83%, 20/24) (p < 0.004 for both comparisons with ESD). Case series of 400 (405 lesions) and 278 (292 lesions) patients, reported en bloc resection rates of 87% (352/405) and 90% (263/292) of lesions respectively. Case series of 278, 42 and 35 patients reported en bloc resection with completely free margins in 15% (44/292) of lesions, and 74% (31/42) and 63% (22/35) of patients respectively. The case series of 278 patients reported recurrent rectal intramucosal cancer in 3% (1/38) of lesions with incomplete resection that were followed-up for a median of 36 months (cancer was successfully removed). The Specialist Advisers listed key efficacy outcomes as one-piece resection rate, complete resection rate with clear margins, endoscopic cure rate, clinical cure rate and avoidance of bowel resection. # Safety The non-randomised comparative study of 536 lesions reported perforation in 1% (7/468), 5% (2/44) and 0% (0/24) of patients treated by ESD, 'simplified' ESD using a snare, and small incision EMR respectively (no further details provided). The case series of 400 patients reported colonic wall perforation in 3% (14/405) of patients: all were detected intraprocedurally; all were managed successfully with endoscopic clips insertion; and 1 required surgical repair. In a case series of 186 patients (200 lesions) a perforation rate of 6% (12/200) was reported: 11 of the perforations were detected intraprocedurally and 1 was detected 2 days later (requiring surgical repair). The case series of 186 patients reported rectal bleeding, prompting emergency colonoscopy for application of endoscopic clips in 1% (2/200) of lesions. One bleed occurred on the day of the procedure and the other occurred 10 days later. Acute intestinal obstruction 18 hours after the procedure was reported in a case report of 1 patient (treated by aggressive fluid resuscitation and colonoscopic decompression). The Specialist Advisers considered theoretical adverse events to include conversion of a curable cancer to an incurable cancer because of perforation.# Further information This guidance requires that clinicians undertaking the procedure make special arrangements for audit. NICE has identified relevant audit criteria and developed audit support (which is for use at local discretion) for this guidance. For related NICE guidance see www.nice.org.uk # Information for patients NICE has produced information on this procedure for patients and carers ('Understanding NICE guidance'). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.# About this guidance NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland. This guidance was developed using the NICE interventional procedures guidance process. We have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available. Your responsibility This guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer. Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties. Copyright © National Institute for Health and Clinical Excellence 2010. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE. Contact NICE National Institute for Health and Clinical Excellence Level 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT www.nice.org.uk nice@nice.org.uk	{'Guidance': "Current evidence on endoscopic submucosal dissection (ESD) of lower gastrointestinal lesions shows that it is efficacious, but evidence on long-term survival when used to treat malignant lesions is limited in quantity. There are some concerns about safety with regard to the risk of perforation and bleeding. Therefore, this procedure should only be used with special arrangements for clinical governance, consent and audit or research.\n\nClinicians wishing to undertake ESD of lower gastrointestinal lesions should take the following actions.\n\nInform the clinical governance leads in their Trusts.\n\nEnsure that patients understand the uncertainty about the procedure's safety and efficacy in relation to the risks of perforation and bleeding, and that conversion to open surgery may be necessary. Patients should be provided with clear written information. In addition, the use of NICE's information for patients ('Understanding NICE guidance') is recommended.\n\nAudit and review clinical outcomes of all patients having ESD of lower gastrointestinal lesions (see section 3.1).\n\nEndoscopic submucosal dissection of lower gastrointestinal lesions is a technically challenging procedure and should only be carried out by clinicians with specific training in the technique. The Joint Advisory Group on Gastrointestinal Endoscopy intends to prepare training standards on this procedure.\n\nPatient selection should be carried out either by a colorectal surgeon or by both a colorectal surgeon and an endoscopist who are experienced in this technique.\n\nNICE encourages further research into ESD of lower gastrointestinal lesions. There should be clear documentation of the incidence of complications including perforation, haemorrhage and need for open surgery (with the reasons for this), rates of complete resection, and long-term outcomes including local recurrence and survival.", 'The procedure': "# Indications and current treatments\n\nColorectal lesions may be benign, premalignant or malignant. Patients may be asymptomatic or may present with blood in the stool, change in bowel habit, abdominal pain or unexplained weight loss.\n\nLower gastrointestinal lesions may be investigated radiologically and/or endoscopically. Treatment normally involves resection of the lesions, which may be performed endoscopically or surgically. Current management of small colorectal lesions usually involves snare polypectomy or endoscopic mucosal resection (EMR). EMR usually removes lesions in small pieces, while ESD aims to resect lesions intact.\n\n# Outline of the procedure\n\nIn ESD, an electrocautery knife is used to resect the lesion in one piece (en bloc), aiming to reduce the risk of recurrence and to allow a more accurate histopathological assessment.\n\nThe procedure is performed with the patient under sedation (usually) or general anaesthesia. Lesions are visualised at colonoscopy and the submucosa injected with fluid to raise the lesion.\n\nA circumferential mucosal incision is made initially around the lesion with the electrocautery knife. Submucosal dissection is then performed under endoscopic visualisation, parallel to the muscle layer. Diathermy coagulation is used to achieve haemostasis, but endoscopic clips may also be required to control bleeding and/or treat small perforations.\n\nSections 2.3 and 2.4 describe efficacy and safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview.\n\n# Efficacy\n\nA systematic review of 14 studies including 1314 patients reported rates of en bloc lesion resection of 85% and complete cure (en bloc resection with histologically clear margins) of 75% (follow-up not stated).\n\nA non-randomised comparative study of 536 lesions (number of patients not stated) reported higher rates of en bloc resection in patients treated by ESD (99%, 463/468) compared with those treated by 'simplified' ESD using a snare (91%, 40/44) and those treated by small incision EMR (83%, 20/24) (p < 0.004 for both comparisons with ESD).\n\nCase series of 400 (405 lesions) and 278 (292 lesions) patients, reported en bloc resection rates of 87% (352/405) and 90% (263/292) of lesions respectively. Case series of 278, 42 and 35 patients reported en bloc resection with completely free margins in 15% (44/292) of lesions, and 74% (31/42) and 63% (22/35) of patients respectively.\n\nThe case series of 278 patients reported recurrent rectal intramucosal cancer in 3% (1/38) of lesions with incomplete resection that were followed-up for a median of 36 months (cancer was successfully removed).\n\nThe Specialist Advisers listed key efficacy outcomes as one-piece resection rate, complete resection rate with clear margins, endoscopic cure rate, clinical cure rate and avoidance of bowel resection.\n\n# Safety\n\nThe non-randomised comparative study of 536 lesions reported perforation in 1% (7/468), 5% (2/44) and 0% (0/24) of patients treated by ESD, 'simplified' ESD using a snare, and small incision EMR respectively (no further details provided). The case series of 400 patients reported colonic wall perforation in 3% (14/405) of patients: all were detected intraprocedurally; all were managed successfully with endoscopic clips insertion; and 1 required surgical repair. In a case series of 186 patients (200 lesions) a perforation rate of 6% (12/200) was reported: 11 of the perforations were detected intraprocedurally and 1 was detected 2 days later (requiring surgical repair).\n\nThe case series of 186 patients reported rectal bleeding, prompting emergency colonoscopy for application of endoscopic clips in 1% (2/200) of lesions. One bleed occurred on the day of the procedure and the other occurred 10 days later.\n\nAcute intestinal obstruction 18 hours after the procedure was reported in a case report of 1 patient (treated by aggressive fluid resuscitation and colonoscopic decompression).\n\nThe Specialist Advisers considered theoretical adverse events to include conversion of a curable cancer to an incurable cancer because of perforation.", 'Further information': "This guidance requires that clinicians undertaking the procedure make special arrangements for audit. NICE has identified relevant audit criteria and developed audit support (which is for use at local discretion) for this guidance.\n\nFor related NICE guidance see www.nice.org.uk\n\n# Information for patients\n\nNICE has produced information on this procedure for patients and carers ('Understanding NICE guidance'). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.", 'About this guidance': 'NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland.\n\nThis guidance was developed using the NICE interventional procedures guidance process.\n\nWe have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available.\n\nYour responsibility\n\nThis guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.\n\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.\n\nCopyright\n\n© National Institute for Health and Clinical Excellence 2010. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.\n\nContact NICE\n\nNational Institute for Health and Clinical Excellence\n\nLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT\n\nwww.nice.org.uk\n\nnice@nice.org.uk\n\n033 7780'}	https://www.nice.org.uk/guidance/ipg335
9e28183716fb1c5e45dccab8e1adcc29abb96b90	nice	Transcatheter endovascular closure of perimembranous ventricular septal defect	Transcatheter endovascular closure of perimembranous ventricular septal defect # Guidance This guidance replaces previous guidance on endovascular closure of perimembranous ventricular septal defect (interventional procedure guidance 172). Current evidence on the safety and efficacy of transcatheter endovascular closure of perimembranous ventricular septal defect (VSD) is adequate to support the use of this procedure provided that normal arrangements are in place for clinical governance, consent and audit. Patient selection is important, especially in children and in asymptomatic patients, and should be carried out by a multidisciplinary team including an interventional cardiologist and a cardiac surgeon with specific expertise in the management of congenital heart disease. When carried out on children, this procedure should only be undertaken in specialist paediatric cardiology units. For patients of all ages, this procedure should only be undertaken by cardiologists trained in the technique, including the management of complications. There should be access to emergency cardiac surgery by a surgeon experienced in the treatment of congenital heart disease. Clinicians should enter details about all patients undergoing transcatheter endovascular closure of perimembranous VSD onto the UK Central Cardiac Audit Database. NICE encourages publication of further long-term follow-up data, specifically on the occurrence of heart block compared with open surgery.# The procedure # Indications and current treatments Ventricular septal defect is the persistence of one or more holes in the septum that separates the left and right ventricles of the heart. VSD is the most common congenital heart defect. Left untreated, VSD may be associated with congestive heart failure, pulmonary vascular disease and an increased risk of infective endocarditis. The cause of congenital VSD is unknown. Most infants have small VSDs that are asymptomatic and that usually close spontaneously after birth. However, if a VSD is large, surgical closure may be recommended. In adults, a VSD may be acquired as a complication of a myocardial infarction or trauma. These are generally muscular VSDs and therefore not addressed in this guidance. # Outline of the procedure In transcatheter endovascular closure of perimembranous VSD, a guidewire is introduced into the femoral artery and vein in the groin, to establish an arteriovenous wire loop. A delivery sheath is advanced over the wire across the VSD, via the right or left side of the heart. Echocardiographic and fluoroscopic guidance are used to guide the occluder device as it is advanced through the delivery sheath and expanded to close the defect. Sections 2.3 and 2.4 describe efficacy and safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview. # Efficacy A non-randomised comparative study of 2178 patients reported immediately successful closure rates of 99.8% (850/852) in patients treated by the procedure and 100% in patients treated by surgical closure (difference reported as 'not significant'). Case series of 430, 412, 210 and 186 patients reported final follow-up closure rates of 83% (absolute figures not stated), 97% (398/412), 97% (200/206) and 98% (175/178) respectively at follow-ups ranging from 1 postoperative day to 1 year. In the same case series, immediate closure rates of 40% (absolute figures not stated), 93% (382/412), 35% (72/206) and 92% (172/186) were reported respectively. In the non-randomised comparative study of 2178 patients treated by the procedure or surgical closure, residual shunts were reported in 0.5% (4/852) and 0.6% (8/1326) of patients respectively (difference reported as 'not significant'). The Specialist Advisers listed key efficacy outcomes as successful closure of VSD, symptomatic improvement post procedure, abolition of left-to-right interventricular blood flow and reduction in left ventricular diastolic diameter. # Safety The case series of 430 patients reported that 1 patient with multiple VSDs died during the procedure from cardiac arrest after a second occluder was implanted. A prospective register of 160 patients treated by the procedure reported 3 postoperative deaths: 1 after additional surgery for complications that occurred during the procedure (timing of event not stated), 1 at 476 postoperative days and 1 at 536 postoperative days. Device embolisation rates of 1% (4/430), 2% (2/100) and 4% (2/54) were reported in case series of 430, 100 and 65 patients respectively. In the case series of 430 patients, all devices were retrieved (1 by open surgery). The non-randomised study of 2178 patients reported failure of occlusion associated with tricuspid regurgitation in 1 patient treated by the procedure who subsequently required cardiac surgery under cardiopulmonary bypass. The same study reported third-degree atrioventricular (AV) block in 1 patient treated by the procedure; this patient needed cardiac surgery under cardiopulmonary bypass 3 days after the procedure. In addition, second-degree AV block was reported in 2 patients treated by the procedure but this changed to first-degree AV block at 4 and 5 days respectively. Case series of 430, 186, 182 and 100 patients reported the occurrence of complete AV block in 4% (16/430), 1% (2/186), 1% (1/182) and 2% (2/100) of patients respectively. Of these 21 patients, 2 had surgery, 12 were fitted with a permanent pacemaker, 1 was fitted with a temporary pacemaker and 6 were managed medically. The non-randomised comparative study of 2178 patients reported left bundle branch block in 0.4% (3/852) of patients treated by the procedure. The Specialist Advisers listed theoretical adverse events as device displacement/misplacement, cardiac tamponade, interference with the mitral or aortic valve (specifically including aortic incompetence), venous bleeding, the need to convert to open surgery, and alteration to the morphology of the heart which may become more pronounced with growth. # Other comments The Committee noted that there is a lack of evidence comparing the incidence of heart block following this procedure with that following open surgery for VSD.# Further information For related NICE guidance see our website. # Information for patients NICE has produced information on this procedure for patients and carers ('Understanding NICE guidance'). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.# About this guidance NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland. This guidance was developed using the NICE interventional procedure guidance process. It updates and replaces NICE interventional procedure guidance 172. We have produced a summary of this guidance for patients and carers. Information about the evidence it is based on are is also available. Changes since publication May 2012: minor maintenance. Your responsibility This guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer. Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties. Copyright © National Institute for Health and Clinical Excellence 2010. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE. Contact NICE National Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT www.nice.org.uk nice@nice.org.uk	{'Guidance': 'This guidance replaces previous guidance on endovascular closure of perimembranous ventricular septal defect (interventional procedure guidance 172).\n\nCurrent evidence on the safety and efficacy of transcatheter endovascular closure of perimembranous ventricular septal defect (VSD) is adequate to support the use of this procedure provided that normal arrangements are in place for clinical governance, consent and audit.\n\nPatient selection is important, especially in children and in asymptomatic patients, and should be carried out by a multidisciplinary team including an interventional cardiologist and a cardiac surgeon with specific expertise in the management of congenital heart disease.\n\nWhen carried out on children, this procedure should only be undertaken in specialist paediatric cardiology units. For patients of all ages, this procedure should only be undertaken by cardiologists trained in the technique, including the management of complications. There should be access to emergency cardiac surgery by a surgeon experienced in the treatment of congenital heart disease.\n\nClinicians should enter details about all patients undergoing transcatheter endovascular closure of perimembranous VSD onto the UK Central Cardiac Audit Database.\n\nNICE encourages publication of further long-term follow-up data, specifically on the occurrence of heart block compared with open surgery.', 'The procedure': "# Indications and current treatments\n\nVentricular septal defect is the persistence of one or more holes in the septum that separates the left and right ventricles of the heart. VSD is the most common congenital heart defect. Left untreated, VSD may be associated with congestive heart failure, pulmonary vascular disease and an increased risk of infective endocarditis.\n\nThe cause of congenital VSD is unknown. Most infants have small VSDs that are asymptomatic and that usually close spontaneously after birth. However, if a VSD is large, surgical closure may be recommended.\n\nIn adults, a VSD may be acquired as a complication of a myocardial infarction or trauma. These are generally muscular VSDs and therefore not addressed in this guidance.\n\n# Outline of the procedure\n\nIn transcatheter endovascular closure of perimembranous VSD, a guidewire is introduced into the femoral artery and vein in the groin, to establish an arteriovenous wire loop. A delivery sheath is advanced over the wire across the VSD, via the right or left side of the heart. Echocardiographic and fluoroscopic guidance are used to guide the occluder device as it is advanced through the delivery sheath and expanded to close the defect.\n\nSections 2.3 and 2.4 describe efficacy and safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview.\n\n# Efficacy\n\nA non-randomised comparative study of 2178 patients reported immediately successful closure rates of 99.8% (850/852) in patients treated by the procedure and 100% in patients treated by surgical closure (difference reported as 'not significant').\n\nCase series of 430, 412, 210 and 186 patients reported final follow-up closure rates of 83% (absolute figures not stated), 97% (398/412), 97% (200/206) and 98% (175/178) respectively at follow-ups ranging from 1 postoperative day to 1 year. In the same case series, immediate closure rates of 40% (absolute figures not stated), 93% (382/412), 35% (72/206) and 92% (172/186) were reported respectively.\n\nIn the non-randomised comparative study of 2178 patients treated by the procedure or surgical closure, residual shunts were reported in 0.5% (4/852) and 0.6% (8/1326) of patients respectively (difference reported as 'not significant').\n\nThe Specialist Advisers listed key efficacy outcomes as successful closure of VSD, symptomatic improvement post procedure, abolition of left-to-right interventricular blood flow and reduction in left ventricular diastolic diameter.\n\n# Safety\n\nThe case series of 430 patients reported that 1 patient with multiple VSDs died during the procedure from cardiac arrest after a second occluder was implanted. A prospective register of 160 patients treated by the procedure reported 3 postoperative deaths: 1 after additional surgery for complications that occurred during the procedure (timing of event not stated), 1 at 476 postoperative days and 1 at 536 postoperative days.\n\nDevice embolisation rates of 1% (4/430), 2% (2/100) and 4% (2/54) were reported in case series of 430, 100 and 65 patients respectively. In the case series of 430 patients, all devices were retrieved (1 by open surgery).\n\nThe non-randomised study of 2178 patients reported failure of occlusion associated with tricuspid regurgitation in 1 patient treated by the procedure who subsequently required cardiac surgery under cardiopulmonary bypass.\n\nThe same study reported third-degree atrioventricular (AV) block in 1 patient treated by the procedure; this patient needed cardiac surgery under cardiopulmonary bypass 3 days after the procedure. In addition, second-degree AV block was reported in 2 patients treated by the procedure but this changed to first-degree AV block at 4 and 5 days respectively.\n\nCase series of 430, 186, 182 and 100 patients reported the occurrence of complete AV block in 4% (16/430), 1% (2/186), 1% (1/182) and 2% (2/100) of patients respectively. Of these 21 patients, 2 had surgery, 12 were fitted with a permanent pacemaker, 1 was fitted with a temporary pacemaker and 6 were managed medically.\n\nThe non-randomised comparative study of 2178 patients reported left bundle branch block in 0.4% (3/852) of patients treated by the procedure.\n\nThe Specialist Advisers listed theoretical adverse events as device displacement/misplacement, cardiac tamponade, interference with the mitral or aortic valve (specifically including aortic incompetence), venous bleeding, the need to convert to open surgery, and alteration to the morphology of the heart which may become more pronounced with growth.\n\n# Other comments\n\nThe Committee noted that there is a lack of evidence comparing the incidence of heart block following this procedure with that following open surgery for VSD.", 'Further information': "For related NICE guidance see our website.\n\n# Information for patients\n\nNICE has produced information on this procedure for patients and carers ('Understanding NICE guidance'). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.", 'About this guidance': 'NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland.\n\nThis guidance was developed using the NICE interventional procedure guidance process.\n\nIt updates and replaces NICE interventional procedure guidance 172.\n\nWe have produced a summary of this guidance for patients and carers. Information about the evidence it is based on are is also available.\n\nChanges since publication\n\nMay 2012: minor maintenance.\n\nYour responsibility\n\nThis guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.\n\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.\n\nCopyright\n\n© National Institute for Health and Clinical Excellence 2010. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.\n\nContact NICE\n\nNational Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT\n\nwww.nice.org.uk\n \n nice@nice.org.uk\n 0845 033 7780'}	https://www.nice.org.uk/guidance/ipg336
22c875891b276042bf7f74023198e8bf89d202ad	nice	Guidance on the use of glycoprotein IIb/IIIa inhibitors in the treatment of acute coronary syndromes	Guidance on the use of glycoprotein IIb/IIIa inhibitors in the treatment of acute coronary syndromes Evidence-based recommendations on glycoprotein IIb/IIIa inhibitors (abciximab, eptifibatide, tirofiban) for treating acute coronary syndromes in adults. # Guidance This guidance replaces 'Glycoprotein IIb/IIIa inhibitors in the treatment of acute coronary syndromes' (Technology Appraisal Guidance No 12) issued in September 2000. This guidance has been partially updated by 'Unstable angina and NSTEMI' (NICE clinical guideline 94) as shown below. This recommendation no longer stands. This recommendation has been updated and replaced by recommendation 1.3.9 in NICE clinical guideline 94. This recommendation has been updated and replaced by recommendation 1.3.9 in NICE clinical guideline 94. This recommendation has been updated and replaced by recommendations 1.2.1 and 1.2.2 in NICE clinical guideline 94. This recommendation no longer stands. This recommendation has been updated and replaced by recommendation 1.3.10 in NICE clinical guideline 94. It is recommended that a GP IIb/IIIa inhibitor is considered as an adjunct to PCI for all patients with diabetes undergoing elective PCI, and for those patients undergoing complex procedures (for example, multi-vessel PCI, insertion of multiple stents, vein graft PCI or PCI for bifurcation lesions); currently only abciximab is licensed as an adjunct to PCI. In procedurally uncomplicated, elective PCI, where the risk of adverse sequelae is low, use of a GP IIb/IIIa inhibitor is not recommended unless unexpected immediate complications occur. GP IIb/IIIa inhibitors are not currently licensed in the UK for use as an adjunct to thrombolytic therapy in ST-segment-elevation MI.# Clinical need and practice Coronary heart disease (CHD) is the most common cause of death in the UK. It is a progressive disease. The first presenting symptom is often stable angina (pain in the chest on exertion), which may progress to an acute coronary syndrome (ACS). ACSs encompass a range of symptoms with broadly similar underlying causes. They include ischaemic cardiac chest pain of recent origin in the categories: non-ST-segment-elevation ACS, including unstable angina and non-ST-segment-elevation myocardial infarction (NSTEMI) myocardial infarction (MI) with ST-segment-elevation (an acute MI, also known as STEMI). Unstable angina covers a range of clinical states falling between stable angina and acute MI, including angina at rest lasting more than 20 minutes, increasing angina and angina occurring more than 24 hours after an acute MI. NSTEMI (also known as non-Q-wave MI) is the term used when the cardiac markers (troponins and creatine kinase ) are elevated to ranges that indicate that MI has occurred, but a Q-wave does not develop on ECG tracings. This profile is thought to indicate damage to the heart muscle that does not extend through the full thickness of the myocardium. NSTEMI therefore represents a subgroup of patients with non- ST-elevation ACS at high risk of a subsequent event. In 1998, the overall prevalence of CHD in England was estimated to be 7.1% in men and 4.6% in women. Prevalence increases with age. It is difficult to estimate the incidence of ACS in England and Wales. The Hospital Episode Statistics for 2000/01 detail 148,000 episodes of angina pectoris in England, with 83,000 of these specified as unstable angina. However, there are variations in the coding of this condition, and it has been suggested that these figures are conservative. Recently, the incidence of unstable angina has been estimated at 226 cases per 100,000 population, which equates to approximately 120,000 cases in England and Wales per annum. In 1999, in England and Wales, there were over 115,000 deaths caused by CHD. Although CHD-associated mortality rates are falling by about 4% per year in the UK, this does not reflect a fall in incidence of the disease. In addition, improvements in rates of death from CHD have not been uniform across all social classes; death rates among unskilled men are three times greater than those among professional men. The main aim in the short-term management of non-STsegment- elevation ACS is to control pain and prevent progression to full-thickness MI (STEMI) and/or death. The first steps in the management pathway involve bed rest and medical treatment including antiplatelet therapy (aspirin), anticoagulants (heparin and low-molecular-weight heparin ), vasodilators (nitrates), calcium-channel blockers and beta-blockers. Revascularisation, when necessary, is by means of PCI, usually with stent implantation, or by CABG. Certain patients with unstable angina are at high risk of progression to MI or death. The British Cardiac Society guidelines say that certain circumstances are associated with an increased risk of early adverse outcome – these include: age above 65 years; co-morbidity, especially diabetes; prolonged (>15 minutes) cardiac pain at rest; ischaemic ECG ST-segment depression on admission or during symptoms; ECG T-wave inversion (associated with a intermediate risk, lying between that associated with ST-segment depression and normal ECG); evidence of impairment of left ventricular function (either pre-existing or during MI); and elevated C-reactive protein. In addition, those with raised levels of cardiac troponin are considered to be at high risk of an event. Despite the use of standard therapy (antiplatelet agents and anticoagulants), the rate of adverse outcomes (such as death, non-fatal re-infarction, refractory angina or readmission for unstable angina) at 6 months after presenting with unstable angina is about 30%. In guidance issued in September 2000, the National Institute for Clinical Excellence recommended the intravenous use of glycoprotein IIb/IIIa (GP IIb/IIIa) inhibitors, in addition to aspirin and low (adjusted) dose unfractionated heparin, for patients with unstable angina at high risk of death or further MI. The Institute's guidance recommended intravenous administration of GP IIb/IIIa inhibitors to patients undergoing acute or elective PCI.# The technology # Abciximab (ReoPro) Abciximab is a monoclonal antibody that targets the GP IIb/IIIa receptor on the surface of platelets. Abciximab is indicated as an adjunct to aspirin and heparin for the prevention of ischaemic complications in patients undergoing PCI. It is also indicated for the short-term (1 month) reduction of risk of MI in patients who have unstable angina that is not responding to full conventional therapy and who are to undergo PCI. Abciximab is administered intravenously at an initial bolus dose of 250 μg/kg body weight followed by a maintenance dose of 0.125 μg/kg/min (maximum 10 μg/min) over 12 to 36 hours. As with the other GP IIb/IIIa inhibitors, the side effects of abciximab (including bleeding and thrombocytopenia) are related to its pharmacological effects. For full details of side effects and contraindications, see the Summary of Product Characteristics. The cost of abciximab is £280.00 (net) for a 10-mg vial (British National Formulary, 43rd edition). For a 70-kg person, the cost per course ranges from £840 to £1120, depending on the duration of treatment (costs rounded to full vials). # Eptifibatide (Integrilin) Eptifibatide is a synthetic cyclic heptapeptide and is one of the small-molecule GP IIb/IIIa inhibitors. It reversibly inhibits platelet aggregation by preventing the binding of fibrinogen and other adhesive ligands to the GP IIb/IIIa receptor. Eptifibatide is indicated for the prevention of early MI in patients presenting with unstable angina or non-Q-wave MI (NSTEMI) who have had chest pain within the last 24 hours and who have ECG changes and/or elevated cardiac enzymes. It is administered intravenously at an initial bolus dose of 180 μg/kg followed by a maintenance dose of 2.0 μg/kg/min for up to 72 hours (up to 96 hours if the patient has a PCI during treatment). As with the other GP IIb/IIIa inhibitors, the side effects of eptifibatide (including bleeding and thrombocytopenia) are related to its pharmacological effects. For full details of side effects and contraindications, see the Summary of Product Characteristics. The cost of eptifibatide is £15.54 (net) for a 20-mg vial and £48.84 (net) for a 75-mg vial (British National Formulary, 43rd edition). For a 70-kg person, the cost per course ranges from £455 to £553, depending on the duration of treatment (costs rounded to full vials). # Tirofiban (Aggrastat) Tirofiban is a non-peptidal antagonist of the GP IIb/IIIa receptor and is one of the small-molecule GP IIb/IIIa inhibitors. It prevents fibrinogen from binding to the GP IIb/IIIa receptor, thus blocking platelet aggregation. Tirofiban is indicated for the prevention of early MI in patients presenting with unstable angina or NSTEMI who have had chest pain within the last 12 hours and who have ECG changes and/or elevated cardiac enzymes. It is administered intravenously at an initial dose of 0.4 μg/kg/min for 30 minutes followed by a maintenance dose of 0.1 μg/kg/min for at least 48 hours, up to a maximum duration of treatment of 108 hours. As with the other GP IIb/IIIa inhibitors, the side effects of tirofiban (including bleeding and thrombocytopenia) are related to its pharmacological effects. For full details of side effects and contraindications, see the Summary of Product Characteristics. The cost of tirofiban is £146.11 (net) for a 12.5-mg vial (British National Formulary, 43rd edition). For a 70-kg person, the cost per course ranges from £292 to £584, depending on the duration of treatment (costs rounded to full vials).# Evidence and interpretation The Appraisal Committee considered evidence from a number of sources (see Appendix B). Each indication was considered separately. # Clinical effectiveness ## GP IIb/IIIa inhibitors for the medical management of ACSs The Assessment Group found one new study (GUSTO IV), in addition to four studies from the previous appraisal that are relevant to this review. All were classified as randomised controlled trials (RCTs) that included patients with unstable angina or NSTEMI, but the definitions of the participants varied between trials. Two studies looked at eptifibatide, two at tirofiban and one at abciximab; all these studies compared treatment with placebo or no treatment. On the whole, the studies were well conducted. Outcome measures included death, MI, need for revascularisation and adverse events associated with use of the trial drugs. Differences between trials precluded pooling results in the Assessment Report. In nearly all studies involving the small-molecule GP IIb/IIIa inhibitors (eptifibatide and tirofiban), the rates of death and MI were reduced in the treatment groups compared with the comparator group; however, the difference was not always statistically significant. In all of the trials, the risk of bleeding was greater in the groups receiving a GP IIb/IIIa inhibitor than in the comparator group, but the difference was not always statistically significant. In the GUSTO-IV trial of abciximab, the results demonstrated neither benefit nor trends of benefit in the primary outcomes of death and MI at 30 days. The Assessment Group concluded that the effects of GP IIb/IIIa inhibitors were small compared with those of other interventions in ACS, for example aspirin. Subgroup analyses showed that GP IIb/IIIa inhibitors may be particularly effective in troponin-positive patients. A recently published meta-analysis seen by the Committee (the Boersma study) analysed the data for various subgroups and suggested that, in those not routinely scheduled for early PCI, the rate of cardiac complications is reduced following the administration of GP IIb/IIIa inhibitors. The submissions for this appraisal from consultees (manufacturers/sponsors and professional and patient/carer groups) contained no clinical evidence on the use of GP IIb/IIIa inhibitors for the medical management of ACS that had not already been included in the Assessment Report. The clinical experts were asked about the evidence for medical management in those not going on to have a PCI during GP IIb/IIIa inhibitor administration, which is frequently the scenario in current UK practice. They stated that current evidence-based good practice is to investigate, by means of coronary angiography, with a view to early revascularisation, all of those patients presenting with ACS deemed to be at high enough risk to merit a GP IIb/IIIa inhibitor. They were also asked to comment on the importance of various risk factors used to identify high-risk ACS patients. They considered that an elevated troponin result often confirms the high-risk status of an individual, but that increased troponin should not be thought of as the only indicator of high risk and that other clinical factors have to be taken into account. ## GP IIb/IIIa inhibitors as an adjunct to PCI The Assessment Group found five new trials (PRICE, ADMIRAL, TACTICS-TIMI, TARGET and ESPRIT), in addition to 12 studies from the previous appraisal that are relevant to this review. Fourteen trials compared treatment with placebo or no treatment – ten of these involved abciximab, three involved eptifibatide and one involved tirofiban. There were two head-to-head trials, one of abciximab and eptifibatide and one of abciximab and tirofiban. One further trial compared invasive and conservative treatment, with all participants receiving tirofiban. The definition of participants both within and between trials was broad, from patients undergoing elective PCI to those who had acute PCI after MI. All trials were classified as RCTs, and many of them were large (with at least 1000 participants). Outcomes measured included death, non-fatal MI, the need for PCI or CABG after the current procedure, and adverse events. Again the results of the trials were not pooled for the Assessment Report because of heterogeneity, which included differences between studies in the inclusion criteria for patients undergoing the procedure. Only one trial showed the use of a GP IIb/IIIa inhibitor to be associated with a significant reduction in the mortality rate at 30 days; another trial showed significant reduction in the mortality rate at 6 months. The use of a GP IIb/IIIa inhibitor was associated with a reduction in the rate of revascularisation at 30 days and at 6 months in studies in which this was measured, but the difference was statistically significant in one trial only. However, with composite outcomes (usually a combination of death, subsequent MI and revascularisation), the great majority of trials showed a statistically significant benefit of treatment with a GP IIb/IIIa inhibitor. There were more minor and major bleeds in the treatment groups in all studies, but the increased rates were not always statistically significant. There was little evidence of benefit for subgroups. The only new data submitted on the use of GP IIb/IIIa inhibitors during PCI were longer-term data from two trials (ESPRIT and EPIC), some re-analysis of the existing data, and data from a recent UK audit presented by the British Cardiac Society and Royal College of Physicians (London). The clinical experts were asked to comment on the use of GP IIb/IIIa inhibitors as an adjunct during elective PCI. Their view was that elective single-vessel PCI in a low-risk patient carries a very small absolute risk of complications. Consequently, the use of GP IIb/IIIa inhibitors in such low-risk patients was generally considered unlikely to confer any clinically significant additional benefit; GP IIb/IIIa inhibitors should only be used in these circumstances if unexpected complications occur. Conversely, the use of GP IIb/IIIa inhibitors as an adjunct to PCI was considered beneficial in patients with evidence of recent ACS, in patients with diabetes and in patients undergoing potentially complex PCI, which might include multivessel disease, the use of multiple stents, PCI of a vein graft or PCI of bifurcation lesions. # Cost effectiveness ## GP IIb/IIIa inhibitors for the medical management of ACSs The Assessment Group found no additional cost-effectiveness studies beyond the seven included in the previous appraisal of GP IIb/IIIa inhibitors. None of these studies was UK-based. Since management of ACS in the UK differs from that in other developed countries, particularly in regard to the rate of PCI, the results were not considered to be applicable to the UK. Economic models for tirofiban and eptifibatide were submitted by the manufacturers for the original appraisal. The eptifibatide manufacturer's model was based on a prospective economic evaluation conducted as part of the PURSUIT trial. Based on the subgroup of patients from Western Europe (12% of the total patients), the cost per life-year gained for eptifibatide was estimated as £8179 to £11,079. Although lifetime survival duration was modelled, no extrapolation of costs over the patients' lifetime was attempted and it is not clear how this would impact on the results. The tirofiban manufacturer's model reported that 22% of the cost of tirofiban is offset by savings due to the reduction in events. The lack of a standardised outcome measure makes it difficult to interpret these results in relation to other treatments. The absolute reduction in event rates associated with tirofiban was not adjusted for UK-specific baseline-event rates. ## Use as an adjunct to PCI A further six economic studies in the literature were identified in addition to the 17 studies included in the original appraisal, but none of these fully reflects current UK practice and the long-term costs and consequences. The original appraisal also considered the manufacturer's submission for abciximab. In the manufacturer's model for abciximab, for patients undergoing urgent and elective PCIs in a UK setting, estimates of cost per quality-adjusted life year (QALY) ranged from £6941 to £9053 based on the EPILOG trial and from £3949 to £5151 based on the EPISTENT trial. These estimates must be interpreted with caution for the following reasons: the baseline risk of events is different in the UK from that in the trials; the assumption that patients surviving the first year will live for a further 15 years ignores variability of prognosis; and it may not be valid to assume that costs do not differ between treatment options over a period of 2 to 15 years. ## Assessment Group model The Assessment Group developed a UK-specific model to look at the optimal use and timing of use of GP IIb/IIIa inhibitors in ACS patients. The model estimated health outcomes in terms of QALYs and had a lifetime time horizon. Four treatment strategies for GP IIb/IIIa inhibitors were compared: a GP IIb/IIIa inhibitor used as part of initial management, with treatment begun immediately in all ACS patients at the time they were identified a GP IIb/IIIa inhibitor started only after making a decision to carry out PCI a GP IIb/IIIa inhibitor used as an adjunct to PCI, started up to 1 hour before the procedure no use of GP IIb/IIIa inhibitors.An additional analysis looked at initial management in high-risk ACS patients only (defined as those with at least one of three factors: age > 70 years, diabetes, ST-depression). Initially, baseline event rates were calculated based on PRAIS-UK/Leeds audit data. Since PCI rates here may be lower than in current practice, an alternative analysis using the Boersma meta-analysis was performed. The model applied relative risks from all available trials and from the Boersma data. All analyses showed that use of GP IIb/IIIa inhibitors in initial management was the preferred strategy. Depending on the assumptions used, estimates of cost per QALY ranged from £4605 to £11,671. However, the most cost-effective option was initial medical management in the subgroup of high-risk patients only, with cost per QALY estimated at £3966. The additional benefit of use in all patients compared to use in high-risk patients alone was gained at a cost per QALY of £91,000. When using GP IIb/IIIa inhibitors as an adjunct to PCI was compared with not using them, the base-case cost per QALY was £25,811; this was reduced to £11,160 if baseline event rates based on Boersma data were applied. In summary, the Assessment Report model, which is the closest representation of current UK practice available, indicates that the most cost-effective strategy is for GP IIb/IIIa inhibitors to be used as part of the initial medical management of high-risk ACS patients, irrespective of whether angiography with a view to PCI is performed. Although early angiography with a view to PCI is considered to be of benefit in the initial management of high-risk ACS patients, this was not assessed in the model and is not within the scope of the present guidance. The model suggests that the cost effectiveness of GP IIb/IIIa inhibitors is not dependent on whether a PCI is performed; therefore their administration does not need to be delayed until a decision is made to carry out PCI. The use of GP IIb/IIIa inhibitors as an adjunct during PCI only is also less cost effective than their use in initial medical management. # Consideration of the evidence The Committee considered the evidence available and the viewpoints expressed by the experts on the current management of ACS patients in the UK. It was emphasised that this appraisal related solely to the use of the GP IIb/IIIa inhibitors in the management of ACS, and that it did not extend to the role of PCI or the management of ACS in general. Historically, PCI rates have been lower in the UK than in the countries where the majority of the published trials of the GP IIb/IIIa inhibitors in ACS have been carried out. The Committee took this into account when considering the validity of these trials in relation to current UK practice, together with evidence from the experts suggesting that PCI rates in the UK are now rising by approximately 20% per annum. The Committee considered that the Assessment Group model provided the best estimates of cost effectiveness for the UK and, on the balance of clinical and cost effectiveness, the Committee concluded that use of GP IIb/IIIa inhibitors for initial medical management in high-risk patients was the preferred treatment strategy. The current licensed indications for the GP IIb/IIIa inhibitors are for use with aspirin and unfractionated heparin. However, the Committee recognised that LMWH is used widely in the management of ACS in place of unfractionated heparin, and was aware of the ongoing trials using GP IIb/IIIa inhibitors in conjunction with LMWH. If GP IIb/IIIa inhibitors are to be used as part of medical management in high-risk patients, the Committee thought that it was important that treatment should be initiated as soon as possible. This proves problematic if raised troponin alone is used to identify high-risk status, as the earliest that raised troponin levels can be accurately detected is 6 to 12 hours after the onset of chest pain. The Committee considered that, in the presence of sufficient high-risk factors (described in 1.4), GP IIb/IIIa inhibitor treatment should be initiated without delaying to confirm high-risk status with a positive cardiac troponin test. The Committee considered that those ACS patients undergoing PCI should be treated with a GP IIb/IIIa inhibitor. In situations where this is not covered by initial medical management, the Committee thought that the administration of a GP IIb/IIIa inhibitor would still be appropriate. No clinical trial evidence is available on a strategy that involves a second administration of a GP IIb/IIIa inhibitor (that is, after initial medical management) for a delayed PCI. At the same time, the Committee considered that, for clinically stable patients without diabetes who are undergoing procedurally uncomplicated, routine, elective single-vessel PCI, GP IIb/IIIa inhibitors may not be necessary and therefore should not be recommended for routine use unless unexpected immediate complications occur. The low risk of adverse events during such PCI procedures is demonstrated by UK audit data submitted by the British Cardiac Society and Royal College of Physicians (London).# Recommendations for further research All of the trials currently available looked at the GP IIb/IIIa inhibitors in conjunction with heparin, in line with their licensed indications. There is an ongoing trial (A-Z trial) looking at the use of tirofiban in conjunction with LMWH; INTERACT, another ongoing trial, is looking at a combination of eptifibatide with a LMWH (enoxaparin). As LMWH is widely used instead of standard heparin, the results of these trials are awaited with interest. The effects of GP IIb/IIIa inhibitors in current UK practice should be investigated in carefully designed research to assess their benefits in non-ST-segment-elevation ACS in patients who are not scheduled for PCI. Research should be carried out to investigate the efficacy of GP IIb/IIIa inhibitors in subgroups such as women. A recently published meta-analysis of patient-level data has suggested that GP IIb/IIIa inhibitors may have no benefit in the medical management of ACS in women. The results of the CURE trial may lead to a consideration of the use of clopidogrel for the management of patients with ACS. Research to establish the relative roles of the GP IIb/IIIa inhibitors and clopidogrel in the short-term management of patients with ACS will be necessary. Research is needed to establish the statistical relationship between clinical risk factors and troponin levels, so as to assess the value added by the troponin result in the determination of risk level.# Implications for the NHS Replacement of the September 2000 guidance with this revised guidance is not anticipated to increase costs to the NHS. Fewer patients undergoing elective PCI will receive GP IIb/IIIa inhibitors, which may result in some cost savings. Under the previous guidance it was assumed that a positive troponin test would be used to identify high risk and that therefore approximately one-third of people admitted with ACS would receive a GP IIb/IIIa inhibitor. The prevalence of the risk factors described in 1.4 among people admitted with ACS is unknown, but assuming a similar proportion will be identified as being at high risk as would have been identified using the troponin result, the impact of this section of the guidance remains unchanged. The British Cardiovascular Intervention Society audit recorded 30,916 PCIs in NHS centres during 2000. However, since there are only limited data as to the case-mix of patients undergoing these procedures estimation of budget impact cannot be made.# Related guidance The Institute issued the original guidance on the use of GP IIb/IIIa inhibitors in September 2000: National Institute for Clinical Excellence (2000) The use of glycoprotein IIb/IIIa inhibitors in the treatment of acute coronary syndromes. NICE Technology Appraisal Guidance No. 12. London: National Institute for Clinical Excellence. The Institute issued guidance on the use of coronary artery stents in April 2000: National Institute for Clinical Excellence (2000). The use of coronary artery stents in ischaemic heart disease. NICE Technology Appraisal Guidance No. 4. London: National Institute for Clinical Excellence. # Review of guidance The review date for a technology appraisal refers to the month and year in which the Guidance Executive will consider any new evidence on the technology, in the form of an updated assessment report, and decide whether the technology should be referred to the Appraisal Committee for review. Information on the review of the guidance on this technology is available on the NICE website. Andrew DillonChief ExecutiveSeptember 2002# Appendix C. The use of glycoprotein IIb/IIIa inhibitors in the treatment of acute coronary syndromes (review of existing guidance) 'Understanding NICE Guidance', a summary of this guidance for patients and carers can be found on our website.# Appendix D. Detail on criteria for audit of the use of glycoprotein IIb/IIIa inhibitors in the treatment of acute coronary syndromes # Possible objectives for the audit An audit on the appropriateness of the use of GP IIb/IIIa inhibitors could be carried out to ensure the following. Small-molecule GP IIb/IIIa inhibitors are provided as part of initial medical management for patients with unstable angina or with NSTEMI who are at high risk of subsequent MI or death. A GP IIb/IIIa inhibitor (abciximab) is provided as an adjunct for patients at high risk for whom PCI is recommended but delayed beyond the initial medical management phase. A GP IIb/IIIa inhibitor (abciximab) is considered as an adjunct to PCI for all patients with diabetes who are undergoing elective PCI or for those patients undergoing complex procedures. A GP IIb/IIIa inhibitor (abciximab) is not provided for patients who are undergoing procedurally uncomplicated, elective PCI. # Possible patients to be included in the audit An audit on the first objective above could be carried out on all patients presenting with unstable angina or NSTEMI over a suitable time period given the total number of patients with these conditions treated in 6 months or 1 year. If clinical coding is reliable, the patients can be identified through clinical or procedure codes. If clinical coding for these conditions is not entirely reliable, it may be necessary to retrieve cases of patients who are coded as unstable angina and those coded as myocardial infarction and screen these cases to find patients with NSTEMI. An audit on the other objectives could be carried out using all patients booked and on the waiting list for PCI over a suitable time period given the total number of PCIs carried out in 6 months or 1 year. # Measures that can be used as a basis for the audit Criterion Standard Exception Definition of Terms . A patient in any one of the following groups receives a GP IIb/IIIa inhibitor: a. The patient has unstable angina and is at high risk b. The patient has NSTEMI and is at high risk. % of patients with unstable angina or NSTEMI who are at high risk. None Clinicians will have to agree locally how the initial medical management phase is identified for audit purposes. High risk = of subsequent MI or death as determined by clinician judgement based on risk factors such as: clinical history (including age, previous MI, previous PCI or CABG); clinical signs including continuing pain despite initial treatment; and clinical investigations such as ECG changes, particularly dynamic or unstable patterns indicating myocardial ischaemia, haemodynamic changes and raised cardiac troponin level, if available at the appropriate time. Clinicians will have to agree locally on how high risk is documented for audit purposes. In this approach, the audit involves finding the patients in the audit group who are at high risk and determining if all those patients had a GP IIb/IIIa inhibitor. Another way to audit appropriateness of the use of GP IIb/IIIa inhibitors in initial medical management is first to find patients in the audit group who have had small-molecule GP IIb/IIIa inhibitors in the initial medical management phase, then to screen those cases to see if the patient was at high risk. The measures that could be used in an audit of appropriateness of the use of a GP IIb/IIIa inhibitor (abciximab) as an adjunct to PCI are as set out below: Criterion Standard Exception Definition of Terms . A GP IIb/IIIa inhibitor (abciximab) is provided for the patient who is at high risk and is recommended for PCI but the PCI is delayed beyond the initial medical management phase. % of patients who are at high risk and are scheduled for a PCI but the PCI is delayed beyond the initial medical management phase. None See above for a definition of high risk. . A GP IIb/IIIa inhibitor (abciximab) is considered for the patient who has diabetes and is undergoing an elective PCI. % of patients who have diabetes and are undergoing an elective PCI. None Clinicians will have to agree locally on what constitutes evidence that the treatment was considered for audit purposes. . A GP IIb/IIIa inhibitor (abciximab) is considered for the patient who is undergoing a complex procedure. % of patients who are undergoing a complex procedure. None Examples of complex procedures = multi-vessel PCI, insertion of multiple stents, vein graft PCI, PCI for bifurcation lesions. Clinicians will have to agree locally on what constitutes evidence that the treatment was considered for audit purposes. . A GP IIb/IIIa inhibitor (abciximab) is not provided for a patient who is undergoing a procedurally uncomplicated, routine elective PCI. % of patients who are undergoing an uncomplicated routine elective PCI. A. An unexpected immediate complication occurs. Another way to audit the appropriateness of the use of a GP IIb/IIIa inhibitor (abciximab) as an adjunct to PCI is to screen all patients scheduled for or who have undergone PCI to find out whether, if a GP IIb/IIIa inhibitor (abciximab) was administered, the patient met the criteria listed in measures 1-3 above. # Calculation of compliance with the measure Compliance with each measure described in the table is calculated as follows: Number of patients whose care is consistent with the criterion plus the number of patients who meet any exception Number of patients to whom the measure applies X 100 Clinicians should review the findings of measurement, identify if practice can be improved, agree on a plan to achieve any desired improvement and repeat the measurement of actual practice to confirm that the desired improvement is being achieved.# Changes after publication March 2014: minor maintenance March 2012: minor maintenance March 2010: This guidance has been partially updated by 'Unstable angina and NSTEMI' (NICE clinical guideline 94). The Institute reviews each piece of guidance it issues. The review and re-appraisal of the glycoprotein IIb/IIIa inhibitors in the treatment of acute coronary syndromes (ACS) has resulted in a revision of the definition of high-risk patients in relation to the use of these agents in initial medical management of ACS, and in a clarification of the recommendation on the use of a glycoprotein IIb/IIIa inhibitor as an adjunct to percutaneous coronary intervention.# About this guidance NICE technology appraisal guidance is about the use of new and existing medicines and treatments in the NHS in England and Wales. This guidance replaces 'Glycoprotein IIb/IIIa inhibitors in the treatment of acute coronary syndromes' (Technology Appraisal Guidance No 12) issued in September 2000. We have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available. Your responsibility This guidance represents the views of NICE and was arrived at after careful consideration of the evidence available. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. However, the guidance does not override the individual responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or guardian or carer. Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties. Copyright © National Institute for Health and Clinical Excellence 2002. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.	{'Guidance': "This guidance replaces 'Glycoprotein IIb/IIIa inhibitors in the treatment of acute coronary syndromes' (Technology Appraisal Guidance No 12) issued in September 2000.\n\nThis guidance has been partially updated by 'Unstable angina and NSTEMI' (NICE clinical guideline 94) as shown below.\n\nThis recommendation no longer stands.\n\nThis recommendation has been updated and replaced by recommendation 1.3.9 in NICE clinical guideline 94.\n\nThis recommendation has been updated and replaced by recommendation 1.3.9 in NICE clinical guideline 94.\n\nThis recommendation has been updated and replaced by recommendations 1.2.1 and 1.2.2 in NICE clinical guideline 94.\n\nThis recommendation no longer stands.\n\nThis recommendation has been updated and replaced by recommendation 1.3.10 in NICE clinical guideline 94.\n\nIt is recommended that a GP IIb/IIIa inhibitor is considered as an adjunct to PCI for all patients with diabetes undergoing elective PCI, and for those patients undergoing complex procedures (for example, multi-vessel PCI, insertion of multiple stents, vein graft PCI or PCI for bifurcation lesions); currently only abciximab is licensed as an adjunct to PCI. In procedurally uncomplicated, elective PCI, where the risk of adverse sequelae is low, use of a GP IIb/IIIa inhibitor is not recommended unless unexpected immediate complications occur.\n\nGP IIb/IIIa inhibitors are not currently licensed in the UK for use as an adjunct to thrombolytic therapy in ST-segment-elevation MI.", 'Clinical need and practice': "Coronary heart disease (CHD) is the most common cause of death in the UK. It is a progressive disease. The first presenting symptom is often stable angina (pain in the chest on exertion), which may progress to an acute coronary syndrome (ACS). ACSs encompass a range of symptoms with broadly similar underlying causes. They include ischaemic cardiac chest pain of recent origin in the categories:\n\nnon-ST-segment-elevation ACS, including unstable angina and non-ST-segment-elevation myocardial infarction (NSTEMI)\n\nmyocardial infarction (MI) with ST-segment-elevation (an acute MI, also known as STEMI).\n\nUnstable angina covers a range of clinical states falling between stable angina and acute MI, including angina at rest lasting more than 20 minutes, increasing angina and angina occurring more than 24 hours after an acute MI.\n\nNSTEMI (also known as non-Q-wave MI) is the term used when the cardiac markers (troponins and creatine kinase [CK]) are elevated to ranges that indicate that MI has occurred, but a Q-wave does not develop on ECG tracings. This profile is thought to indicate damage to the heart muscle that does not extend through the full thickness of the myocardium. NSTEMI therefore represents a subgroup of patients with non- ST-elevation ACS at high risk of a subsequent event.\n\nIn 1998, the overall prevalence of CHD in England was estimated to be 7.1% in men and 4.6% in women. Prevalence increases with age. It is difficult to estimate the incidence of ACS in England and Wales. The Hospital Episode Statistics for 2000/01 detail 148,000 episodes of angina pectoris in England, with 83,000 of these specified as unstable angina. However, there are variations in the coding of this condition, and it has been suggested that these figures are conservative. Recently, the incidence of unstable angina has been estimated at 226 cases per 100,000 population, which equates to approximately 120,000 cases in England and Wales per annum.\n\nIn 1999, in England and Wales, there were over 115,000 deaths caused by CHD. Although CHD-associated mortality rates are falling by about 4% per year in the UK, this does not reflect a fall in incidence of the disease. In addition, improvements in rates of death from CHD have not been uniform across all social classes; death rates among unskilled men are three times greater than those among professional men.\n\nThe main aim in the short-term management of non-STsegment- elevation ACS is to control pain and prevent progression to full-thickness MI (STEMI) and/or death. The first steps in the management pathway involve bed rest and medical treatment including antiplatelet therapy (aspirin), anticoagulants (heparin and low-molecular-weight heparin [LMWH]), vasodilators (nitrates), calcium-channel blockers and beta-blockers. Revascularisation, when necessary, is by means of PCI, usually with stent implantation, or by CABG.\n\nCertain patients with unstable angina are at high risk of progression to MI or death. The British Cardiac Society guidelines say that certain circumstances are associated with an increased risk of early adverse outcome – these include: age above 65 years; co-morbidity, especially diabetes; prolonged (>15 minutes) cardiac pain at rest; ischaemic ECG ST-segment depression on admission or during symptoms; ECG T-wave inversion (associated with a intermediate risk, lying between that associated with ST-segment depression and normal ECG); evidence of impairment of left ventricular function (either pre-existing or during MI); and elevated C-reactive protein. In addition, those with raised levels of cardiac troponin are considered to be at high risk of an event.\n\nDespite the use of standard therapy (antiplatelet agents and anticoagulants), the rate of adverse outcomes (such as death, non-fatal re-infarction, refractory angina or readmission for unstable angina) at 6 months after presenting with unstable angina is about 30%.\n\nIn guidance issued in September 2000, the National Institute for Clinical Excellence recommended the intravenous use of glycoprotein IIb/IIIa (GP IIb/IIIa) inhibitors, in addition to aspirin and low (adjusted) dose unfractionated heparin, for patients with unstable angina at high risk of death or further MI. The Institute's guidance recommended intravenous administration of GP IIb/IIIa inhibitors to patients undergoing acute or elective PCI.", 'The technology': '# Abciximab (ReoPro)\n\nAbciximab is a monoclonal antibody that targets the GP IIb/IIIa receptor on the surface of platelets.\n\nAbciximab is indicated as an adjunct to aspirin and heparin for the prevention of ischaemic complications in patients undergoing PCI. It is also indicated for the short-term (1 month) reduction of risk of MI in patients who have unstable angina that is not responding to full conventional therapy and who are to undergo PCI. Abciximab is administered intravenously at an initial bolus dose of 250 μg/kg body weight followed by a maintenance dose of 0.125 μg/kg/min (maximum 10 μg/min) over 12 to 36 hours.\n\nAs with the other GP IIb/IIIa inhibitors, the side effects of abciximab (including bleeding and thrombocytopenia) are related to its pharmacological effects. For full details of side effects and contraindications, see the Summary of Product Characteristics.\n\nThe cost of abciximab is £280.00 (net) for a 10-mg vial (British National Formulary, 43rd edition). For a 70-kg person, the cost per course ranges from £840 to £1120, depending on the duration of treatment (costs rounded to full vials).\n\n# Eptifibatide (Integrilin)\n\nEptifibatide is a synthetic cyclic heptapeptide and is one of the small-molecule GP IIb/IIIa inhibitors. It reversibly inhibits platelet aggregation by preventing the binding of fibrinogen and other adhesive ligands to the GP IIb/IIIa receptor.\n\nEptifibatide is indicated for the prevention of early MI in patients presenting with unstable angina or non-Q-wave MI (NSTEMI) who have had chest pain within the last 24 hours and who have ECG changes and/or elevated cardiac enzymes. It is administered intravenously at an initial bolus dose of 180 μg/kg followed by a maintenance dose of 2.0 μg/kg/min for up to 72 hours (up to 96 hours if the patient has a PCI during treatment).\n\nAs with the other GP IIb/IIIa inhibitors, the side effects of eptifibatide (including bleeding and thrombocytopenia) are related to its pharmacological effects. For full details of side effects and contraindications, see the Summary of Product Characteristics.\n\nThe cost of eptifibatide is £15.54 (net) for a 20-mg vial and £48.84 (net) for a 75-mg vial (British National Formulary, 43rd edition). For a 70-kg person, the cost per course ranges from £455 to £553, depending on the duration of treatment (costs rounded to full vials).\n\n# Tirofiban (Aggrastat)\n\nTirofiban is a non-peptidal antagonist of the GP IIb/IIIa receptor and is one of the small-molecule GP IIb/IIIa inhibitors. It prevents fibrinogen from binding to the GP IIb/IIIa receptor, thus blocking platelet aggregation.\n\nTirofiban is indicated for the prevention of early MI in patients presenting with unstable angina or NSTEMI who have had chest pain within the last 12 hours and who have ECG changes and/or elevated cardiac enzymes. It is administered intravenously at an initial dose of 0.4 μg/kg/min for 30 minutes followed by a maintenance dose of 0.1 μg/kg/min for at least 48 hours, up to a maximum duration of treatment of 108 hours.\n\nAs with the other GP IIb/IIIa inhibitors, the side effects of tirofiban (including bleeding and thrombocytopenia) are related to its pharmacological effects. For full details of side effects and contraindications, see the Summary of Product Characteristics.\n\nThe cost of tirofiban is £146.11 (net) for a 12.5-mg vial (British National Formulary, 43rd edition). For a 70-kg person, the cost per course ranges from £292 to £584, depending on the duration of treatment (costs rounded to full vials).', 'Evidence and interpretation ': "The Appraisal Committee considered evidence from a number of sources (see Appendix B). Each indication was considered separately.\n\n# Clinical effectiveness\n\n## GP IIb/IIIa inhibitors for the medical management of ACSs\n\nThe Assessment Group found one new study (GUSTO IV), in addition to four studies from the previous appraisal that are relevant to this review. All were classified as randomised controlled trials (RCTs) that included patients with unstable angina or NSTEMI, but the definitions of the participants varied between trials. Two studies looked at eptifibatide, two at tirofiban and one at abciximab; all these studies compared treatment with placebo or no treatment. On the whole, the studies were well conducted. Outcome measures included death, MI, need for revascularisation and adverse events associated with use of the trial drugs. Differences between trials precluded pooling results in the Assessment Report.\n\nIn nearly all studies involving the small-molecule GP IIb/IIIa inhibitors (eptifibatide and tirofiban), the rates of death and MI were reduced in the treatment groups compared with the comparator group; however, the difference was not always statistically significant. In all of the trials, the risk of bleeding was greater in the groups receiving a GP IIb/IIIa inhibitor than in the comparator group, but the difference was not always statistically significant.\n\nIn the GUSTO-IV trial of abciximab, the results demonstrated neither benefit nor trends of benefit in the primary outcomes of death and MI at 30 days.\n\nThe Assessment Group concluded that the effects of GP IIb/IIIa inhibitors were small compared with those of other interventions in ACS, for example aspirin. Subgroup analyses showed that GP IIb/IIIa inhibitors may be particularly effective in troponin-positive patients. A recently published meta-analysis seen by the Committee (the Boersma study) analysed the data for various subgroups and suggested that, in those not routinely scheduled for early PCI, the rate of cardiac complications is reduced following the administration of GP IIb/IIIa inhibitors.\n\nThe submissions for this appraisal from consultees (manufacturers/sponsors and professional and patient/carer groups) contained no clinical evidence on the use of GP IIb/IIIa inhibitors for the medical management of ACS that had not already been included in the Assessment Report.\n\nThe clinical experts were asked about the evidence for medical management in those not going on to have a PCI during GP IIb/IIIa inhibitor administration, which is frequently the scenario in current UK practice. They stated that current evidence-based good practice is to investigate, by means of coronary angiography, with a view to early revascularisation, all of those patients presenting with ACS deemed to be at high enough risk to merit a GP IIb/IIIa inhibitor.\n\nThey were also asked to comment on the importance of various risk factors used to identify high-risk ACS patients. They considered that an elevated troponin result often confirms the high-risk status of an individual, but that increased troponin should not be thought of as the only indicator of high risk and that other clinical factors have to be taken into account.\n\n## GP IIb/IIIa inhibitors as an adjunct to PCI\n\nThe Assessment Group found five new trials (PRICE, ADMIRAL, TACTICS-TIMI, TARGET and ESPRIT), in addition to 12 studies from the previous appraisal that are relevant to this review. Fourteen trials compared treatment with placebo or no treatment – ten of these involved abciximab, three involved eptifibatide and one involved tirofiban. There were two head-to-head trials, one of abciximab and eptifibatide and one of abciximab and tirofiban. One further trial compared invasive and conservative treatment, with all participants receiving tirofiban. The definition of participants both within and between trials was broad, from patients undergoing elective PCI to those who had acute PCI after MI. All trials were classified as RCTs, and many of them were large (with at least 1000 participants). Outcomes measured included death, non-fatal MI, the need for PCI or CABG after the current procedure, and adverse events.\n\nAgain the results of the trials were not pooled for the Assessment Report because of heterogeneity, which included differences between studies in the inclusion criteria for patients undergoing the procedure. Only one trial showed the use of a GP IIb/IIIa inhibitor to be associated with a significant reduction in the mortality rate at 30 days; another trial showed significant reduction in the mortality rate at 6 months. The use of a GP IIb/IIIa inhibitor was associated with a reduction in the rate of revascularisation at 30 days and at 6 months in studies in which this was measured, but the difference was statistically significant in one trial only.\n\nHowever, with composite outcomes (usually a combination of death, subsequent MI and revascularisation), the great majority of trials showed a statistically significant benefit of treatment with a GP IIb/IIIa inhibitor. There were more minor and major bleeds in the treatment groups in all studies, but the increased rates were not always statistically significant. There was little evidence of benefit for subgroups.\n\nThe only new data submitted on the use of GP IIb/IIIa inhibitors during PCI were longer-term data from two trials (ESPRIT and EPIC), some re-analysis of the existing data, and data from a recent UK audit presented by the British Cardiac Society and Royal College of Physicians (London).\n\nThe clinical experts were asked to comment on the use of GP IIb/IIIa inhibitors as an adjunct during elective PCI. Their view was that elective single-vessel PCI in a low-risk patient carries a very small absolute risk of complications. Consequently, the use of GP IIb/IIIa inhibitors in such low-risk patients was generally considered unlikely to confer any clinically significant additional benefit; GP IIb/IIIa inhibitors should only be used in these circumstances if unexpected complications occur. Conversely, the use of GP IIb/IIIa inhibitors as an adjunct to PCI was considered beneficial in patients with evidence of recent ACS, in patients with diabetes and in patients undergoing potentially complex PCI, which might include multivessel disease, the use of multiple stents, PCI of a vein graft or PCI of bifurcation lesions.\n\n# Cost effectiveness\n\n## GP IIb/IIIa inhibitors for the medical management of ACSs\n\nThe Assessment Group found no additional cost-effectiveness studies beyond the seven included in the previous appraisal of GP IIb/IIIa inhibitors. None of these studies was UK-based. Since management of ACS in the UK differs from that in other developed countries, particularly in regard to the rate of PCI, the results were not considered to be applicable to the UK. Economic models for tirofiban and eptifibatide were submitted by the manufacturers for the original appraisal.\n\nThe eptifibatide manufacturer's model was based on a prospective economic evaluation conducted as part of the PURSUIT trial. Based on the subgroup of patients from Western Europe (12% of the total patients), the cost per life-year gained for eptifibatide was estimated as £8179 to £11,079. Although lifetime survival duration was modelled, no extrapolation of costs over the patients' lifetime was attempted and it is not clear how this would impact on the results.\n\nThe tirofiban manufacturer's model reported that 22% of the cost of tirofiban is offset by savings due to the reduction in events. The lack of a standardised outcome measure makes it difficult to interpret these results in relation to other treatments. The absolute reduction in event rates associated with tirofiban was not adjusted for UK-specific baseline-event rates.\n\n## Use as an adjunct to PCI\n\nA further six economic studies in the literature were identified in addition to the 17 studies included in the original appraisal, but none of these fully reflects current UK practice and the long-term costs and consequences. The original appraisal also considered the manufacturer's submission for abciximab.\n\nIn the manufacturer's model for abciximab, for patients undergoing urgent and elective PCIs in a UK setting, estimates of cost per quality-adjusted life year (QALY) ranged from £6941 to £9053 based on the EPILOG trial and from £3949 to £5151 based on the EPISTENT trial. These estimates must be interpreted with caution for the following reasons: the baseline risk of events is different in the UK from that in the trials; the assumption that patients surviving the first year will live for a further 15 years ignores variability of prognosis; and it may not be valid to assume that costs do not differ between treatment options over a period of 2 to 15 years.\n\n## Assessment Group model\n\nThe Assessment Group developed a UK-specific model to look at the optimal use and timing of use of GP IIb/IIIa inhibitors in ACS patients. The model estimated health outcomes in terms of QALYs and had a lifetime time horizon. Four treatment strategies for GP IIb/IIIa inhibitors were compared:\n\na GP IIb/IIIa inhibitor used as part of initial management, with treatment begun immediately in all ACS patients at the time they were identified\n\na GP IIb/IIIa inhibitor started only after making a decision to carry out PCI\n\na GP IIb/IIIa inhibitor used as an adjunct to PCI, started up to 1 hour before the procedure\n\nno use of GP IIb/IIIa inhibitors.An additional analysis looked at initial management in high-risk ACS patients only (defined as those with at least one of three factors: age > 70 years, diabetes, ST-depression). Initially, baseline event rates were calculated based on PRAIS-UK/Leeds audit data. Since PCI rates here may be lower than in current practice, an alternative analysis using the Boersma meta-analysis was performed. The model applied relative risks from all available trials and from the Boersma data. All analyses showed that use of GP IIb/IIIa inhibitors in initial management was the preferred strategy. Depending on the assumptions used, estimates of cost per QALY ranged from £4605 to £11,671. However, the most cost-effective option was initial medical management in the subgroup of high-risk patients only, with cost per QALY estimated at £3966. The additional benefit of use in all patients compared to use in high-risk patients alone was gained at a cost per QALY of £91,000. When using GP IIb/IIIa inhibitors as an adjunct to PCI was compared with not using them, the base-case cost per QALY was £25,811; this was reduced to £11,160 if baseline event rates based on Boersma data were applied.\n\nIn summary, the Assessment Report model, which is the closest representation of current UK practice available, indicates that the most cost-effective strategy is for GP IIb/IIIa inhibitors to be used as part of the initial medical management of high-risk ACS patients, irrespective of whether angiography with a view to PCI is performed. Although early angiography with a view to PCI is considered to be of benefit in the initial management of high-risk ACS patients, this was not assessed in the model and is not within the scope of the present guidance. The model suggests that the cost effectiveness of GP IIb/IIIa inhibitors is not dependent on whether a PCI is performed; therefore their administration does not need to be delayed until a decision is made to carry out PCI. The use of GP IIb/IIIa inhibitors as an adjunct during PCI only is also less cost effective than their use in initial medical management.\n\n# Consideration of the evidence\n\nThe Committee considered the evidence available and the viewpoints expressed by the experts on the current management of ACS patients in the UK. It was emphasised that this appraisal related solely to the use of the GP IIb/IIIa inhibitors in the management of ACS, and that it did not extend to the role of PCI or the management of ACS in general.\n\nHistorically, PCI rates have been lower in the UK than in the countries where the majority of the published trials of the GP IIb/IIIa inhibitors in ACS have been carried out. The Committee took this into account when considering the validity of these trials in relation to current UK practice, together with evidence from the experts suggesting that PCI rates in the UK are now rising by approximately 20% per annum.\n\nThe Committee considered that the Assessment Group model provided the best estimates of cost effectiveness for the UK and, on the balance of clinical and cost effectiveness, the Committee concluded that use of GP IIb/IIIa inhibitors for initial medical management in high-risk patients was the preferred treatment strategy.\n\nThe current licensed indications for the GP IIb/IIIa inhibitors are for use with aspirin and unfractionated heparin. However, the Committee recognised that LMWH is used widely in the management of ACS in place of unfractionated heparin, and was aware of the ongoing trials using GP IIb/IIIa inhibitors in conjunction with LMWH.\n\nIf GP IIb/IIIa inhibitors are to be used as part of medical management in high-risk patients, the Committee thought that it was important that treatment should be initiated as soon as possible. This proves problematic if raised troponin alone is used to identify high-risk status, as the earliest that raised troponin levels can be accurately detected is 6 to 12 hours after the onset of chest pain. The Committee considered that, in the presence of sufficient high-risk factors (described in 1.4), GP IIb/IIIa inhibitor treatment should be initiated without delaying to confirm high-risk status with a positive cardiac troponin test.\n\nThe Committee considered that those ACS patients undergoing PCI should be treated with a GP IIb/IIIa inhibitor. In situations where this is not covered by initial medical management, the Committee thought that the administration of a GP IIb/IIIa inhibitor would still be appropriate. No clinical trial evidence is available on a strategy that involves a second administration of a GP IIb/IIIa inhibitor (that is, after initial medical management) for a delayed PCI.\n\nAt the same time, the Committee considered that, for clinically stable patients without diabetes who are undergoing procedurally uncomplicated, routine, elective single-vessel PCI, GP IIb/IIIa inhibitors may not be necessary and therefore should not be recommended for routine use unless unexpected immediate complications occur. The low risk of adverse events during such PCI procedures is demonstrated by UK audit data submitted by the British Cardiac Society and Royal College of Physicians (London).", 'Recommendations for further research': 'All of the trials currently available looked at the GP IIb/IIIa inhibitors in conjunction with heparin, in line with their licensed indications. There is an ongoing trial (A-Z trial) looking at the use of tirofiban in conjunction with LMWH; INTERACT, another ongoing trial, is looking at a combination of eptifibatide with a LMWH (enoxaparin). As LMWH is widely used instead of standard heparin, the results of these trials are awaited with interest.\n\nThe effects of GP IIb/IIIa inhibitors in current UK practice should be investigated in carefully designed research to assess their benefits in non-ST-segment-elevation ACS in patients who are not scheduled for PCI.\n\nResearch should be carried out to investigate the efficacy of GP IIb/IIIa inhibitors in subgroups such as women. A recently published meta-analysis of patient-level data has suggested that GP IIb/IIIa inhibitors may have no benefit in the medical management of ACS in women.\n\nThe results of the CURE trial may lead to a consideration of the use of clopidogrel for the management of patients with ACS. Research to establish the relative roles of the GP IIb/IIIa inhibitors and clopidogrel in the short-term management of patients with ACS will be necessary.\n\nResearch is needed to establish the statistical relationship between clinical risk factors and troponin levels, so as to assess the value added by the troponin result in the determination of risk level.', 'Implications for the NHS': 'Replacement of the September 2000 guidance with this revised guidance is not anticipated to increase costs to the NHS. Fewer patients undergoing elective PCI will receive GP IIb/IIIa inhibitors, which may result in some cost savings. Under the previous guidance it was assumed that a positive troponin test would be used to identify high risk and that therefore approximately one-third of people admitted with ACS would receive a GP IIb/IIIa inhibitor. The prevalence of the risk factors described in 1.4 among people admitted with ACS is unknown, but assuming a similar proportion will be identified as being at high risk as would have been identified using the troponin result, the impact of this section of the guidance remains unchanged.\n\nThe British Cardiovascular Intervention Society audit recorded 30,916 PCIs in NHS centres during 2000. However, since there are only limited data as to the case-mix of patients undergoing these procedures estimation of budget impact cannot be made.', 'Related guidance': 'The Institute issued the original guidance on the use of GP IIb/IIIa inhibitors in September 2000:\n\nNational Institute for Clinical Excellence (2000) The use of glycoprotein IIb/IIIa inhibitors in the treatment of acute coronary syndromes. NICE Technology Appraisal Guidance No. 12. London: National Institute for Clinical Excellence.\n\nThe Institute issued guidance on the use of coronary artery stents in April 2000:\n\nNational Institute for Clinical Excellence (2000). The use of coronary artery stents in ischaemic heart disease. NICE Technology Appraisal Guidance No. 4. London: National Institute for Clinical Excellence. [Replaced by NICE technology appraisal guidance 71]', 'Review of guidance': 'The review date for a technology appraisal refers to the month and year in which the Guidance Executive will consider any new evidence on the technology, in the form of an updated assessment report, and decide whether the technology should be referred to the Appraisal Committee for review.\n\nInformation on the review of the guidance on this technology is available on the NICE website.\n\nAndrew DillonChief ExecutiveSeptember 2002', 'Appendix C. The use of glycoprotein IIb/IIIa inhibitors in the treatment of acute coronary syndromes (review of existing guidance)': "'Understanding NICE Guidance', a summary of this guidance for patients and carers can be found on our website.", 'Appendix D. Detail on criteria for audit of the use of glycoprotein IIb/IIIa inhibitors in the treatment of acute coronary syndromes': '# Possible objectives for the audit\n\nAn audit on the appropriateness of the use of GP IIb/IIIa inhibitors could be carried out to ensure the following.\n\nSmall-molecule GP IIb/IIIa inhibitors are provided as part of initial medical management for patients with unstable angina or with NSTEMI who are at high risk of subsequent MI or death.\n\nA GP IIb/IIIa inhibitor (abciximab) is provided as an adjunct for patients at high risk for whom PCI is recommended but delayed beyond the initial medical management phase.\n\nA GP IIb/IIIa inhibitor (abciximab) is considered as an adjunct to PCI for all patients with diabetes who are undergoing elective PCI or for those patients undergoing complex procedures.\n\nA GP IIb/IIIa inhibitor (abciximab) is not provided for patients who are undergoing procedurally uncomplicated, elective PCI.\n\n# Possible patients to be included in the audit\n\nAn audit on the first objective above could be carried out on all patients presenting with unstable angina or NSTEMI over a suitable time period given the total number of patients with these conditions treated in 6 months or 1 year. If clinical coding is reliable, the patients can be identified through clinical or procedure codes. If clinical coding for these conditions is not entirely reliable, it may be necessary to retrieve cases of patients who are coded as unstable angina and those coded as myocardial infarction and screen these cases to find patients with NSTEMI.\n\nAn audit on the other objectives could be carried out using all patients booked and on the waiting list for PCI over a suitable time period given the total number of PCIs carried out in 6 months or 1 year.\n\n# Measures that can be used as a basis for the audit\n\nCriterion\n\nStandard\n\nException\n\nDefinition of Terms\n\n. A patient in any one of the following groups receives a GP IIb/IIIa inhibitor:\n\na. The patient has unstable angina and is at high risk\n\nb. The patient has NSTEMI and is at high risk.\n\n% of patients with unstable angina or NSTEMI who are at high risk.\n\nNone\n\nClinicians will have to agree locally how the initial medical management phase is identified for audit purposes.\n\nHigh risk = of subsequent MI or death as determined by clinician judgement based on risk factors such as: clinical history (including age, previous MI, previous PCI or CABG); clinical signs including continuing pain despite initial treatment; and clinical investigations such as ECG changes, particularly dynamic or unstable patterns indicating myocardial ischaemia, haemodynamic changes and raised cardiac troponin level, if available at the appropriate time.\n\nClinicians will have to agree locally on how high risk is documented for audit purposes.\n\nIn this approach, the audit involves finding the patients in the audit group who are at high risk and determining if all those patients had a GP IIb/IIIa inhibitor.\n\nAnother way to audit appropriateness of the use of GP IIb/IIIa inhibitors in initial medical management is first to find patients in the audit group who have had small-molecule GP IIb/IIIa inhibitors in the initial medical management phase, then to screen those cases to see if the patient was at high risk.\n\nThe measures that could be used in an audit of appropriateness of the use of a GP IIb/IIIa inhibitor (abciximab) as an adjunct to PCI are as set out below:\n\nCriterion\n\nStandard\n\nException\n\nDefinition of Terms\n\n. A GP IIb/IIIa inhibitor (abciximab) is provided for the patient who is at high risk and is recommended for PCI but the PCI is delayed beyond the initial medical management phase.\n\n% of patients who are at high risk and are scheduled for a PCI but the PCI is delayed beyond the initial medical management phase.\n\nNone\n\nSee above for a definition of high risk.\n\n. A GP IIb/IIIa inhibitor (abciximab) is considered for the patient who has diabetes and is undergoing an elective PCI.\n\n% of patients who have diabetes and are undergoing an elective PCI.\n\nNone\n\nClinicians will have to agree locally on what constitutes evidence that the treatment was considered for audit purposes.\n\n. A GP IIb/IIIa inhibitor (abciximab) is considered for the patient who is undergoing a complex procedure.\n\n% of patients who are undergoing a complex procedure.\n\nNone\n\nExamples of complex procedures = multi-vessel PCI, insertion of multiple stents, vein graft PCI, PCI for bifurcation lesions.\n\nClinicians will have to agree locally on what constitutes evidence that the treatment was considered for audit purposes.\n\n. A GP IIb/IIIa inhibitor (abciximab) is not provided for a patient who is undergoing a procedurally uncomplicated, routine elective PCI.\n\n% of patients who are undergoing an uncomplicated routine elective PCI.\n\nA. An unexpected immediate complication occurs.\n\n\n\nAnother way to audit the appropriateness of the use of a GP IIb/IIIa inhibitor (abciximab) as an adjunct to PCI is to screen all patients scheduled for or who have undergone PCI to find out whether, if a GP IIb/IIIa inhibitor (abciximab) was administered, the patient met the criteria listed in measures 1-3 above.\n\n# Calculation of compliance with the measure\n\nCompliance with each measure described in the table is calculated as follows:\n\nNumber of patients whose care is consistent with the criterion plus the number of patients who meet any exception\n\n/\n\nNumber of patients to whom the measure applies\n\nX 100\n\nClinicians should review the findings of measurement, identify if practice can be improved, agree on a plan to achieve any desired improvement and repeat the measurement of actual practice to confirm that the desired improvement is being achieved.', 'Changes after publication': "March 2014: minor maintenance\n\nMarch 2012: minor maintenance\n\nMarch 2010: This guidance has been partially updated by 'Unstable angina and NSTEMI' (NICE clinical guideline 94).\n\nThe Institute reviews each piece of guidance it issues. The review and re-appraisal of the glycoprotein IIb/IIIa inhibitors in the treatment of acute coronary syndromes (ACS) has resulted in a revision of the definition of high-risk patients in relation to the use of these agents in initial medical management of ACS, and in a clarification of the recommendation on the use of a glycoprotein IIb/IIIa inhibitor as an adjunct to percutaneous coronary intervention.", 'About this guidance': "NICE technology appraisal guidance is about the use of new and existing medicines and treatments in the NHS in England and Wales.\n\nThis guidance replaces 'Glycoprotein IIb/IIIa inhibitors in the treatment of acute coronary syndromes' (Technology Appraisal Guidance No 12) issued in September 2000.\n\nWe have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available.\n\nYour responsibility\n\nThis guidance represents the views of NICE and was arrived at after careful consideration of the evidence available. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. However, the guidance does not override the individual responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.\n\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.\n\nCopyright\n\n© National Institute for Health and Clinical Excellence 2002. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE."}	https://www.nice.org.uk/guidance/ta47	Evidence-based recommendations on glycoprotein IIb/IIIa inhibitors (abciximab, eptifibatide, tirofiban) for treating acute coronary syndromes in adults.
e12a43e59e5228742f8f22a0f4ea544b9ffb0e01	nice	Donor milk banks: service operation	Donor milk banks: service operation This guideline covers how donor milk banks should recruit, screen and support women who donate breast milk. It also covers how milk banks should handle and process the breast milk they receive from donors. It aims to improve the safety of donor milk and operation of donor milk services. # Introduction Research has consistently shown that breast milk is the best nourishment for babies and that it is highly beneficial to their health in the short, medium and long term. Women are recommended to breastfeed their baby exclusively for 6 months and continue to breastfeed after 6 months as part of a balanced diet (see the latest NHS advice on breastfeeding). If, after discussion with experienced staff, a mother is unable to express sufficient milk or does not wish to express milk for a baby unable to feed at the breast, donor breast milk can be used. In this guideline, donor breast milk is defined as breast milk expressed by a mother that is then processed by a donor milk bank for use by a recipient that is not the mother's own baby. Payment for the donated milk is not given. A Health Technology Assessment (HTA) report entitled 'Breastfeeding promotion for infants in neonatal units: a systematic review and economic analysis' was published in 2009. This report used systematic review methodology and health economic modelling to assess which interventions, including the availability of donor breast milk, effectively promote the initiation and duration of breastfeeding in neonatal, special and intensive care settings. The authors noted that in the UK, donor breast milk is neither widely nor readily available in the majority of units; this was reflected through modelling the use of donor breast milk by availability, not need. They concluded that if mechanisms by which donor milk is provided were improved, donor milk would become cost effective compared with using formula. This was based on a significant improvement in the operation of milk banking, and suggested models include setting up a national donor milk banking system similar to that for blood (Renfrew et al. 2009). Although this guideline does not make recommendations on the configuration of services, it does make recommendations on the safe and effective operation of donor milk services. Throughout development, the safety of donor breast milk was considered to be the aim of the guideline and recommendations were made to minimise the risk to recipients of donor milk. Maximising safety comes at a cost and recommendations were made to observe the best possible safety standards without exceeding opportunity costs acceptable to society.# Recommendations People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care. Making decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding. The recommendations in this guideline are all key to the process of donor milk banking and are dependent on each other. For example, the recommendations on testing milk post-pasteurisation are dependent on the application of the recommendations on quality assurance and equipment maintenance. The safety of donor milk therefore depends on the implementation of all recommendations. # Quality assurance There is no recognised NHS standard for human milk pasteurisers. In the UK, donor milk banks have been following guidance issued by various bodies, including in 1981, a report on the collection and storage of human milk. (Committee on Medical Aspects of Food Policy 1981) and more recently, guidelines issued in 2006 by the UK Association for Milk Banking. The following recommendations, specifically on maintenance of equipment, need to be viewed in this context. Use Hazard Analysis and Critical Control Point (HACCP) principles in all quality assurance processes. Clean and store all donor milk containers and equipment according to local protocols based on HACCP principles. Validate, calibrate and maintain all equipment used in donor milk handling and processing and keep records of this. Ensure that the equipment is used according to the manufacturer's instructions. Regularly inspect all equipment used in donor milk handling and processing, following the manufacturer's instructions. Ensure that all equipment that may affect temperature or contamination levels has sensors and alarms so that constant conditions can be maintained. All milk bank staff should have ongoing training that is relevant to their job and is recorded. Training should cover good practice and should ensure that each staff member: is competent in performing their job understands the technical processes relevant to their job understands how the milk bank is organised and how its health and safety and quality systems work understands the regulatory, legal and ethical aspects of their work. Train milk bank staff in HACCP principles, food hygiene and pasteurisation, and provide ongoing support so that practices reflect these principles. All donor milk administered in the NHS should be from milk banks that can demonstrate adherence to the NICE guidance on the operation of donor milk banks. Implement a quality control system that is followed by all staff and is reviewed regularly. It should encompass: collecting, testing, processing, storing and transporting milk personnel, required documentation, premises and equipment batch recall, external and internal auditing, non-conformance to processes and self-inspection continuous quality improvement. # Recruiting donors When promoting the donation of breast milk, aim to reach as many potential donors as possible through a variety of channels, including: providing written information to be left in: GP surgeries antenatal clinics and postnatal wards volunteer and other organisations working in maternity and childbirth children's or Sure Start centres maternity shops direct referrals or recommendations by: current and previous donors staff at neonatal intensive care units paediatricians assessing babies' progress health visitors (or other healthcare professionals providing postpartum care) childbirth educators -rganisers and attendees of prenatal and postnatal classes breastfeeding mothers' support groups and related organisations features in the media (including internet and social media). Use clear, non-technical language when communicating the use of donor milk and the process of donor milk banking in any written information and activities. # Screening and selecting donors The following strategy of screening and selection is part of the whole process of donor milk handling and therefore is intrinsically linked with the recommendations on testing and treating the donor breast milk. Follow the stepped screening process detailed in recommendations 1.12 to 1.21 when recruiting donors. Advise a potential donor that she is not eligible to donate milk if she: currently smokes or uses nicotine replacement therapy (NRT) regularly exceeds recommended alcohol levels for breastfeeding mothers (1 to 2 units, once or twice a week) (see the NHS website for information on breastfeeding and drinking alcohol) is using, or has recently used, recreational drugs has previously tested positive for HIV 1 or 2, hepatitis B or C, human T-lymphotropic virus (HTLV) type I or II, or syphilis is at an increased risk of Creutzfeldt–Jakob disease (CJD) (see information from Public Health England on the risk of CJD).Include this information in recruitment material so that potential donors can self-screen for these criteria. Using a process of informal interview, referring to medical sources (with consent) if necessary, ask the potential donor questions on the topics that follow. Use the information she gives to make a balanced decision about her eligibility to donate based on possible risks to recipients and/or the results of subsequent serological tests (see recommendations 1.16 and 1.17). Ask questions about: her health: to confirm that she is in good general health. For guidance on diet and breastfeeding, see recommendation 10 in the NICE guideline on NICE guideline on maternal and child nutrition. her baby: document the age and health of the baby any exposure to passive smoke: is she exposed to high or sustained levels of passive smoke (for example, do other members of her household smoke heavily)? any medication that she is taking: is she currently taking any medication or undergoing any other medical therapy? any significant environmental or chemical exposure (such as contamination of the local water supply): is she exposed to high or sustained levels of environmental or chemical contaminants that can be expressed in breast milk? any recent exposure to infection (including HIV 1 or 2, hepatitis B or C, HTLV I or II, syphilis, herpes, or acute or chronic infections). Depending on the assessment of level of risk, further testing may be needed. any recent medical intervention (for example, exposure to diagnostic radioactive isotopes) refer to guidance from the Department of Health on the safety of recent vaccination when breastfeeding.Advise the potential donor that depending on her answer to any of these questions she may not be eligible to donate milk. If a potential donor is donating previously expressed breast milk, ask her to answer the screening questions (recommendations 1.12 to 1.13) for the period when the milk was expressed. Conduct the screening interview, detailed in recommendations 1.12 and 1.13, with potential donors at a mutually acceptable time and place, either face-to-face or by telephone. # Serological testing When donors first contact the milk bank about donating milk, explain that serological testing is mandatory to reduce the risk of passing on infections. Obtain informed consent before testing. Undertake serological testing of all potential donors for the following and exclude women from donating who test positive for: HIV 1 or 2 hepatitis B or C HTLV I or II syphilis. Perform all serological screening tests at the time of enrolling for donor milk banking; do not rely on antenatal test results. All tests should be undertaken in laboratories with clinical pathology accreditation (CPA). Ensure that laboratories communicate the results of serological testing clearly and that they provide appropriate interpretive comments. Give serological test results to potential donors either in person or by telephone (unless they prefer to receive them in writing). If needed, offer further help and support based on local protocols, including information about counselling and local support groups. Laboratories should archive samples of blood received from donors. # Consent and continued eligibility Before accepting a donor's milk, obtain her consent for the processing and intended use of the donated milk. Advise her that once donated, milk will not be returned to her. While a donor continues to donate, ask regularly about her general health and the exclusion criteria detailed in recommendations 1.12 to 1.13. Advise her that if her status or circumstances change in relation to these, she should contact the milk bank immediately. Do not routinely repeat serological tests while the donor is donating milk. # Training and supporting donors The recommendations in this section are specific to mothers expressing milk for donation, and may differ from advice given to mothers expressing milk for their own babies. Provide all new donors with training, preferably face-to-face with additional information by telephone and in writing. Arrange training at a time and place suitable for both donor and trainer. Training for new donors should cover: hand washing and the importance of this good personal hygiene collecting and expressing milk, including cleaning and using breast pumps and containers storing donated milk (including cooling and freezing) labelling donated milk, and documenting storage conditions transportation of donated milk (if needed). Provide ongoing support to all donors according to their individual needs until no longer required. This may include: information and ongoing support on milk bank requirements for their diet and alcohol consumption continued support for collecting expressed milk and maintaining lactation emotional support. Offer additional support and information on milk collection to donors whose milk has significant or repeated microbial contamination. # Stopping or suspending milk donations The recommendations in this section are specific to mothers expressing milk for donation, and may differ from advice given to mothers expressing milk for their own babies. Consider no longer accepting breast milk from donors who, despite support, consistently supply: breast milk that does not meet the microbiological criteria (see recommendation 1.58) small amounts of breast milk. Advise donors to contact the milk bank to discuss suspending or stopping their breast milk donation if they develop a fever or have contact with a viral exanthematous disease. Advise donors who begin taking any medication that they should contact the milk bank to discuss suspending or stopping their breast milk donation. Use appropriate reference sources, such as the BNF for Children, the Drugs and Lactation Database LactMed or the UK Drugs in Lactation Advisory Service. Advise donors to contact the milk bank to discuss suspending or stopping their breast milk donation if they develop lesions or infections of the breast (including mastitis or herpes). Provide donors who are stopping their breast milk donations with as much advice and support as needed. Consider the size of the recipient population, the milk bank's stock levels, and the preferences of the donor when discussing how long a woman can donate milk. # Expressing milk at home for donation Advise donors to collect expressed milk rather than 'drip' milk (milk that is passively collected from one breast while the baby feeds at the other) for donation. Actively encourage donors to hand express milk; however, accept pump-expressed milk if donors prefer this method. # Handling donor milk at home The recommendations in this section are specific to mothers handling and storing milk for donation, and may differ from advice given to mothers expressing milk for their own babies. This is because donated milk needs to undergo various testing and treatment processes at the donor milk bank, all of which affect the nutritional and immunological composition of the milk. The aim therefore is to make sure that milk for donation reaches the donor milk bank as soon as possible to ensure the highest quality before processing. Advise donors that expressed milk collected for donation should be frozen as soon as possible to maintain the nutritional and microbiological quality of the milk. If this is not possible (for example, because of storage capacity), advise donors to refrigerate samples collected over 24 hours, and then freeze the batch. Advise donors that expressed milk for donation should remain frozen during storage at home, and if they have any concerns about storage conditions or freezer temperatures, they should discuss these with the milk bank. Advise donors that frozen expressed milk should be transported to the milk bank as soon as possible. However, if necessary, expressed milk for donation can be stored before transport to the milk bank for up to 3 months in a domestic freezer, at −18°C or lower. If a donor does not have access to a domestic freezer at her home, she may be able to access freezers for milk storage at local donor milk depots or children's centres. Advise donors that expressed milk can only be accepted by the milk bank if it has been collected and stored in milk collection containers provided by, or acceptable to, the milk bank. Advise donors that collection containers for expressed milk should be used according to instructions provided by the milk bank. Ensure that donors can check and document their freezer temperature every day; this may include providing a thermometer. # Handling donor milk during transportation Define critical conditions for transport, including temperature and time limit, to ensure that donor milk remains frozen during transport. Transport donor milk in secure, tamper-evident containers and packaging. If donor milk is transported to the milk bank by a contracted third party, ensure that a documented agreement is in place to maintain the conditions needed. Define in writing the milk bank's procedures for transporting and storing donor milk. Ensure that these procedures maintain the quality of the donor milk and allow accurate identification of samples. Keep records of inventory and distribution (see also recommendations 1.68 to 1.75 on tracking and tracing). Collect expressed milk from the donors, preferably using an agreed transport provider (ideally a medical courier) or a member of staff from the milk bank. In some instances, donors may be required or may wish to deliver their own milk to the milk bank or depot, in which case they should also follow the milk bank's requirements for transport as outlined. In all cases, use consistent monitoring processes, including recording the journey time. Collect expressed milk from either the donor's home (see recommendations 1.38 to 1.43) or from donor milk depots that have practices for monitoring freezers and maintaining standards for quality control, storage and security. Ensure that similar processes are in place in any location where the donor milk is stored. # Handling donor milk at the milk bank The following strategy of handling milk at the milk bank, specifically testing and treating donor milk, is part of the whole process of donor milk handling and therefore is intrinsically linked with the recommendations on recruiting and selecting the donors. It is also predicated on the effective functioning of the human milk pasteuriser. Process all donated milk under hygienic conditions (a sterile environment is not necessary). Practise good hand hygiene at all times, and wear gloves whenever handling donor milk. Check that donated milk arriving at the milk bank: is labelled correctly with the donor's name and the date of expression and has remained frozen and has not been tampered with. Transfer all donated milk immediately to the freezer. Store pasteurised and unpasteurised donor milk in separate freezers and refrigerators. Store donor milk awaiting pasteurisation in the freezer at the milk bank (at −20°C) for no longer than 3 months from the date of expression. Discard breast milk from donors who do not meet the selection criteria detailed in recommendations 1.12, 1.13 and 1.17. Before testing and pasteurising, thoroughly thaw the donor milk, and keep in the refrigerator for no longer than 24 hours. Prevent the donor milk from reaching 8°C while thawing. Only pool pre-pasteurised breast milk from the same donor. Do not pool: breast milk from different donors, or batches of pasteurised breast milk from the same donor. Before pasteurisation, test a sample from each batch of pooled donor milk for microbial contamination and discard if samples exceed a count of: colony-forming units (CFU)/ml for total viable microorganisms or CFU/ml for Enterobacteriaceae or CFU/ml for Staphylococcus aureus. Ensure that laboratories communicate the results of microbial testing clearly and that they provide appropriate interpretive comments. Seek help from microbiological laboratories to identify and investigate instances of significant or unusual contamination (for example, by undertaking further microbial tests). Pasteurise donated milk at 62.5°C for 30 minutes in a human milk pasteuriser. Rapidly cool the milk to a temperature of 4°C or lower. Remove one bottle for testing if appropriate, then move the remainder of the batch to the freezer. After pasteurising, store frozen donor milk for no longer than 6 months after the date of expression. Do not open the lid of batches of pasteurised donor milk until the milk is to be used, unless it is to test the milk. If the milk is tested, discard the opened bottle. Regularly test pasteurised donor milk for microbial contamination. Base the testing schedule on the volume and throughput of milk. Test: either at least once a month or every 10 cycles, depending on which comes first, and -n an ad-hoc basis if any new processes, equipment or staff are introduced, or if there are concerns about any part of the process. Discard pasteurised donor milk that has a total viable microbial count of 10 CFU/ml or more. Keep all donor milk in containers made of food grade materials. Staff at the milk bank should not be responsible for adding anything to the donated milk. # Tracking and tracing Track donated milk from the donor through to the recipient hospital. Tracking and monitoring of donor milk processing should include freezer temperatures, pasteurisation processes and stock control. At all stages, donor milk containers should be labelled clearly for identification. Clearly identify milk that is ready to be used. For each donor milk batch, keep the following records. About the donor: NHS number/donor ID consent relevant medical history results of serological tests. About each container before pasteurisation: donor ID a testing log, including the tests undertaken and their results. For each pasteurised container: samples making up the batch the batch number a testing log, including the tests undertaken and their results pasteurisation details, including date of the pasteurisation. The hospital or neonatal unit that receives the donated milk, or the disposal date of the donated milk, as appropriate. Label each container of pasteurised donor milk with the following information. A unique identification number. Confirmation that it contains pasteurised donor breast milk. Instructions to keep frozen, and use within 24 hours if defrosted. An expiry date (no later than 6 months from expression). Only supply donor milk to hospitals or neonatal units that agree to comply with the tracking procedures for milk outlined by the milk bank. The receiving hospital or neonatal unit should keep a record of how the donor milk is used. It should document for each bottle of donor milk: the baby's name, NHS number and date of birth, and the date administered the batch number and the date the donor milk was used in the patient record of each baby the condition of the donor milk on arrival following transport the storage conditions.Ensure that all records (including raw data) that are critical to the safety and quality of the donor milk are kept for at least 30 years after expiry date, use or disposal. These records should be confidential.# Recommendations for research We have made the following recommendations for research, based on our review of evidence, to improve NICE guidance in the future. Although it was not part of the scope of this guideline, it is known that there is limited high-quality evidence on the benefits of donor breast milk. The aim of this guideline is to provide guidance on the operation of donor milk banks; however, our expectation is that, once any risks of donor milk banking are minimised, further research can be undertaken to evaluate the benefits of donor milk, and to identify the recipient babies who would benefit most. The research recommendations below relate to the process of donor milk banking. Where appropriate, they also recommend evaluating outcomes in the recipient population. # The process of handling donor milk What is the effect of the process of milk banking on the nutritional and immunological components of donor milk? ## Why this is important The handling of donor milk includes a range of processes – including transport, storage and heat treatment – and is known to affect various biological, nutritional and immunological properties of breast milk. In addition, new methods of processing, such as heat or pressure treatment, are now being used in the food industry. However, there is very little comparative evidence on the different effects of the processes and how changes in the detailed process (for example, a change in temperature of 1°C) may affect the biological, nutritional and immunological properties of the milk. There is also no direct evidence of how these changes affect outcomes for recipients. Further research is needed on the comparative effects of all milk handling processes on nutritional and immunological components, and, where possible, the impact of these on health outcomes for the recipients and on resource use during milk banking and following supply to recipients. # Nutritional assessment of donor milk How and when should the nutritional components of donor breast milk be assessed? ## Why this is important It is known that the process of donor milk banking (for example, storage and heat treatment) affects the nutritional composition of milk. It is not clear how such changes affect health outcomes for recipients. Currently, in the UK, nutritional assessment of donor breast milk is not common practice. Further research is needed to define clinically important changes and to determine the most useful methods and timing of measuring these in UK milk banking practice. # Milk donors What are the attitudes and behaviours (including lifestyle factors such as diet) of milk donors, and can they affect the quality of donor milk? ## Why this is important There is very limited evidence on the attitudes and behaviours of milk donors, including the reason why they choose to donate. There is no evidence on how these factors (for example, ongoing donation or a one-off donation or dietary behaviours) may be associated with the quality of donated milk. Further research is needed to understand the link between donor attitudes or behaviours and the quality of milk.	{'Introduction': "Research has consistently shown that breast milk is the best nourishment for babies and that it is highly beneficial to their health in the short, medium and long term. Women are recommended to breastfeed their baby exclusively for 6\xa0months and continue to breastfeed after 6\xa0months as part of a balanced diet (see the latest NHS advice on breastfeeding).\n\nIf, after discussion with experienced staff, a mother is unable to express sufficient milk or does not wish to express milk for a baby unable to feed at the breast, donor breast milk can be used.\n\nIn this guideline, donor breast milk is defined as breast milk expressed by a mother that is then processed by a donor milk bank for use by a recipient that is not the mother's own baby. Payment for the donated milk is not given.\n\nA Health Technology Assessment (HTA) report entitled 'Breastfeeding promotion for infants in neonatal units: a systematic review and economic analysis' was published in 2009. This report used systematic review methodology and health economic modelling to assess which interventions, including the availability of donor breast milk, effectively promote the initiation and duration of breastfeeding in neonatal, special and intensive care settings. The authors noted that in the UK, donor breast milk is neither widely nor readily available in the majority of units; this was reflected through modelling the use of donor breast milk by availability, not need. They concluded that if mechanisms by which donor milk is provided were improved, donor milk would become cost effective compared with using formula. This was based on a significant improvement in the operation of milk banking, and suggested models include setting up a national donor milk banking system similar to that for blood (Renfrew et al. 2009).\n\nAlthough this guideline does not make recommendations on the configuration of services, it does make recommendations on the safe and effective operation of donor milk services.\n\nThroughout development, the safety of donor breast milk was considered to be the aim of the guideline and recommendations were made to minimise the risk to recipients of donor milk. Maximising safety comes at a cost and recommendations were made to observe the best possible safety standards without exceeding opportunity costs acceptable to society.", 'Recommendations': "People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.\n\nMaking decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.\n\nThe recommendations in this guideline are all key to the process of donor milk banking and are dependent on each other. For example, the recommendations on testing milk post-pasteurisation are dependent on the application of the recommendations on quality assurance and equipment maintenance. The safety of donor milk therefore depends on the implementation of all recommendations.\n\n# Quality assurance\n\nThere is no recognised NHS standard for human milk pasteurisers. In the UK, donor milk banks have been following guidance issued by various bodies, including in 1981, a report on the collection and storage of human milk. (Committee on Medical Aspects of Food Policy 1981) and more recently, guidelines issued in 2006 by the UK Association for Milk Banking. The following recommendations, specifically on maintenance of equipment, need to be viewed in this context.\n\nUse Hazard Analysis and Critical Control Point (HACCP) principles in all quality assurance processes.\n\nClean and store all donor milk containers and equipment according to local protocols based on HACCP principles.\n\nValidate, calibrate and maintain all equipment used in donor milk handling and processing and keep records of this. Ensure that the equipment is used according to the manufacturer's instructions.\n\nRegularly inspect all equipment used in donor milk handling and processing, following the manufacturer's instructions. Ensure that all equipment that may affect temperature or contamination levels has sensors and alarms so that constant conditions can be maintained.\n\nAll milk bank staff should have ongoing training that is relevant to their job and is recorded. Training should cover good practice and should ensure that each staff member:\n\nis competent in performing their job\n\nunderstands the technical processes relevant to their job\n\nunderstands how the milk bank is organised and how its health and safety and quality systems work\n\nunderstands the regulatory, legal and ethical aspects of their work.\n\nTrain milk bank staff in HACCP principles, food hygiene and pasteurisation, and provide ongoing support so that practices reflect these principles.\n\nAll donor milk administered in the NHS should be from milk banks that can demonstrate adherence to the NICE guidance on the operation of donor milk banks.\n\nImplement a quality control system that is followed by all staff and is reviewed regularly. It should encompass:\n\ncollecting, testing, processing, storing and transporting milk\n\npersonnel, required documentation, premises and equipment\n\nbatch recall, external and internal auditing, non-conformance to processes and self-inspection\n\ncontinuous quality improvement.\n\n# Recruiting donors\n\nWhen promoting the donation of breast milk, aim to reach as many potential donors as possible through a variety of channels, including:\n\nproviding written information to be left in:\n\n\n\nGP surgeries\n\nantenatal clinics and postnatal wards\n\nvolunteer and other organisations working in maternity and childbirth\n\nchildren's or Sure Start centres\n\nmaternity shops\n\n\n\ndirect referrals or recommendations by:\n\n\n\ncurrent and previous donors\n\nstaff at neonatal intensive care units\n\npaediatricians assessing babies' progress\n\nhealth visitors (or other healthcare professionals providing postpartum care)\n\nchildbirth educators\n\norganisers and attendees of prenatal and postnatal classes\n\nbreastfeeding mothers' support groups and related organisations\n\n\n\nfeatures in the media (including internet and social media).\n\nUse clear, non-technical language when communicating the use of donor milk and the process of donor milk banking in any written information and activities.\n\n# Screening and selecting donors\n\nThe following strategy of screening and selection is part of the whole process of donor milk handling and therefore is intrinsically linked with the recommendations on testing and treating the donor breast milk.\n\nFollow the stepped screening process detailed in recommendations 1.12 to 1.21 when recruiting donors.\n\nAdvise a potential donor that she is not eligible to donate milk if she:\n\ncurrently smokes or uses nicotine replacement therapy (NRT)\n\nregularly exceeds recommended alcohol levels for breastfeeding mothers (1 to 2 units, once or twice a week) (see the NHS website for information on breastfeeding and drinking alcohol)\n\nis using, or has recently used, recreational drugs\n\nhas previously tested positive for HIV 1 or 2, hepatitis B or C, human T-lymphotropic virus (HTLV) type I or II, or syphilis\n\nis at an increased risk of Creutzfeldt–Jakob disease (CJD) (see information from Public Health England on the risk of CJD).Include this information in recruitment material so that potential donors can self-screen for these criteria.\n\nUsing a process of informal interview, referring to medical sources (with consent) if necessary, ask the potential donor questions on the topics that follow. Use the information she gives to make a balanced decision about her eligibility to donate based on possible risks to recipients and/or the results of subsequent serological tests (see recommendations 1.16 and 1.17). Ask questions about:\n\nher health: to confirm that she is in good general health. For guidance on diet and breastfeeding, see recommendation 10 in the NICE guideline on NICE guideline on maternal and child nutrition.\n\nher baby: document the age and health of the baby\n\nany exposure to passive smoke: is she exposed to high or sustained levels of passive smoke (for example, do other members of her household smoke heavily)?\n\nany medication that she is taking: is she currently taking any medication or undergoing any other medical therapy?\n\nany significant environmental or chemical exposure (such as contamination of the local water supply): is she exposed to high or sustained levels of environmental or chemical contaminants that can be expressed in breast milk?\n\nany recent exposure to infection (including HIV 1 or 2, hepatitis B or C, HTLV I or II, syphilis, herpes, or acute or chronic infections). Depending on the assessment of level of risk, further testing may be needed.\n\nany recent medical intervention (for example, exposure to diagnostic radioactive isotopes)\n\n\n\nrefer to guidance from the Department of Health on the safety of recent vaccination when breastfeeding.Advise the potential donor that depending on her answer to any of these questions she may not be eligible to donate milk.\n\n\n\nIf a potential donor is donating previously expressed breast milk, ask her to answer the screening questions (recommendations 1.12 to 1.13) for the period when the milk was expressed.\n\nConduct the screening interview, detailed in recommendations 1.12 and 1.13, with potential donors at a mutually acceptable time and place, either face-to-face or by telephone.\n\n# Serological testing\n\nWhen donors first contact the milk bank about donating milk, explain that serological testing is mandatory to reduce the risk of passing on infections. Obtain informed consent before testing.\n\nUndertake serological testing of all potential donors for the following and exclude women from donating who test positive for:\n\nHIV 1 or 2\n\nhepatitis B or C\n\nHTLV I or II\n\nsyphilis.\n\nPerform all serological screening tests at the time of enrolling for donor milk banking; do not rely on antenatal test results.\n\nAll tests should be undertaken in laboratories with clinical pathology accreditation (CPA).\n\nEnsure that laboratories communicate the results of serological testing clearly and that they provide appropriate interpretive comments.\n\nGive serological test results to potential donors either in person or by telephone (unless they prefer to receive them in writing). If needed, offer further help and support based on local protocols, including information about counselling and local support groups.\n\nLaboratories should archive samples of blood received from donors.\n\n# Consent and continued eligibility\n\nBefore accepting a donor's milk, obtain her consent for the processing and intended use of the donated milk. Advise her that once donated, milk will not be returned to her.\n\nWhile a donor continues to donate, ask regularly about her general health and the exclusion criteria detailed in recommendations 1.12 to 1.13. Advise her that if her status or circumstances change in relation to these, she should contact the milk bank immediately.\n\nDo not routinely repeat serological tests while the donor is donating milk.\n\n# Training and supporting donors\n\nThe recommendations in this section are specific to mothers expressing milk for donation, and may differ from advice given to mothers expressing milk for their own babies.\n\nProvide all new donors with training, preferably face-to-face with additional information by telephone and in writing. Arrange training at a time and place suitable for both donor and trainer.\n\nTraining for new donors should cover:\n\nhand washing and the importance of this\n\ngood personal hygiene\n\ncollecting and expressing milk, including cleaning and using breast pumps and containers\n\nstoring donated milk (including cooling and freezing)\n\nlabelling donated milk, and documenting storage conditions\n\ntransportation of donated milk (if needed).\n\nProvide ongoing support to all donors according to their individual needs until no longer required. This may include:\n\ninformation and ongoing support on milk bank requirements for their diet and alcohol consumption\n\ncontinued support for collecting expressed milk and maintaining lactation\n\nemotional support.\n\nOffer additional support and information on milk collection to donors whose milk has significant or repeated microbial contamination.\n\n# Stopping or suspending milk donations\n\nThe recommendations in this section are specific to mothers expressing milk for donation, and may differ from advice given to mothers expressing milk for their own babies.\n\nConsider no longer accepting breast milk from donors who, despite support, consistently supply:\n\nbreast milk that does not meet the microbiological criteria (see recommendation 1.58)\n\nsmall amounts of breast milk.\n\nAdvise donors to contact the milk bank to discuss suspending or stopping their breast milk donation if they develop a fever or have contact with a viral exanthematous disease.\n\nAdvise donors who begin taking any medication that they should contact the milk bank to discuss suspending or stopping their breast milk donation. Use appropriate reference sources, such as the BNF for Children, the Drugs and Lactation Database LactMed or the UK Drugs in Lactation Advisory Service.\n\nAdvise donors to contact the milk bank to discuss suspending or stopping their breast milk donation if they develop lesions or infections of the breast (including mastitis or herpes).\n\nProvide donors who are stopping their breast milk donations with as much advice and support as needed.\n\nConsider the size of the recipient population, the milk bank's stock levels, and the preferences of the donor when discussing how long a woman can donate milk.\n\n# Expressing milk at home for donation\n\nAdvise donors to collect expressed milk rather than 'drip' milk (milk that is passively collected from one breast while the baby feeds at the other) for donation.\n\nActively encourage donors to hand express milk; however, accept pump-expressed milk if donors prefer this method.\n\n# Handling donor milk at home\n\nThe recommendations in this section are specific to mothers handling and storing milk for donation, and may differ from advice given to mothers expressing milk for their own babies. This is because donated milk needs to undergo various testing and treatment processes at the donor milk bank, all of which affect the nutritional and immunological composition of the milk. The aim therefore is to make sure that milk for donation reaches the donor milk bank as soon as possible to ensure the highest quality before processing.\n\nAdvise donors that expressed milk collected for donation should be frozen as soon as possible to maintain the nutritional and microbiological quality of the milk. If this is not possible (for example, because of storage capacity), advise donors to refrigerate samples collected over 24 hours, and then freeze the batch.\n\nAdvise donors that expressed milk for donation should remain frozen during storage at home, and if they have any concerns about storage conditions or freezer temperatures, they should discuss these with the milk bank.\n\nAdvise donors that frozen expressed milk should be transported to the milk bank as soon as possible. However, if necessary, expressed milk for donation can be stored before transport to the milk bank for up to 3 months in a domestic freezer, at −18°C or lower. If a donor does not have access to a domestic freezer at her home, she may be able to access freezers for milk storage at local donor milk depots or children's centres.\n\nAdvise donors that expressed milk can only be accepted by the milk bank if it has been collected and stored in milk collection containers provided by, or acceptable to, the milk bank.\n\nAdvise donors that collection containers for expressed milk should be used according to instructions provided by the milk bank.\n\nEnsure that donors can check and document their freezer temperature every day; this may include providing a thermometer.\n\n# Handling donor milk during transportation\n\nDefine critical conditions for transport, including temperature and time limit, to ensure that donor milk remains frozen during transport.\n\nTransport donor milk in secure, tamper-evident containers and packaging.\n\nIf donor milk is transported to the milk bank by a contracted third party, ensure that a documented agreement is in place to maintain the conditions needed.\n\nDefine in writing the milk bank's procedures for transporting and storing donor milk. Ensure that these procedures maintain the quality of the donor milk and allow accurate identification of samples. Keep records of inventory and distribution (see also recommendations 1.68 to 1.75 on tracking and tracing).\n\nCollect expressed milk from the donors, preferably using an agreed transport provider (ideally a medical courier) or a member of staff from the milk bank. In some instances, donors may be required or may wish to deliver their own milk to the milk bank or depot, in which case they should also follow the milk bank's requirements for transport as outlined. In all cases, use consistent monitoring processes, including recording the journey time.\n\nCollect expressed milk from either the donor's home (see recommendations 1.38 to 1.43) or from donor milk depots that have practices for monitoring freezers and maintaining standards for quality control, storage and security. Ensure that similar processes are in place in any location where the donor milk is stored.\n\n# Handling donor milk at the milk bank\n\nThe following strategy of handling milk at the milk bank, specifically testing and treating donor milk, is part of the whole process of donor milk handling and therefore is intrinsically linked with the recommendations on recruiting and selecting the donors. It is also predicated on the effective functioning of the human milk pasteuriser.\n\nProcess all donated milk under hygienic conditions (a sterile environment is not necessary). Practise good hand hygiene at all times, and wear gloves whenever handling donor milk.\n\nCheck that donated milk arriving at the milk bank:\n\nis labelled correctly with the donor's name and the date of expression and\n\nhas remained frozen and\n\nhas not been tampered with. Transfer all donated milk immediately to the freezer.\n\nStore pasteurised and unpasteurised donor milk in separate freezers and refrigerators.\n\nStore donor milk awaiting pasteurisation in the freezer at the milk bank (at −20°C) for no longer than 3 months from the date of expression.\n\nDiscard breast milk from donors who do not meet the selection criteria detailed in recommendations 1.12, 1.13 and 1.17.\n\nBefore testing and pasteurising, thoroughly thaw the donor milk, and keep in the refrigerator for no longer than 24 hours. Prevent the donor milk from reaching 8°C while thawing.\n\nOnly pool pre-pasteurised breast milk from the same donor.\n\nDo not pool:\n\nbreast milk from different donors, or\n\nbatches of pasteurised breast milk from the same donor.\n\nBefore pasteurisation, test a sample from each batch of pooled donor milk for microbial contamination and discard if samples exceed a count of:\n\ncolony-forming units (CFU)/ml for total viable microorganisms or\n\nCFU/ml for Enterobacteriaceae or\n\nCFU/ml for Staphylococcus aureus.\n\nEnsure that laboratories communicate the results of microbial testing clearly and that they provide appropriate interpretive comments.\n\nSeek help from microbiological laboratories to identify and investigate instances of significant or unusual contamination (for example, by undertaking further microbial tests).\n\nPasteurise donated milk at 62.5°C for 30 minutes in a human milk pasteuriser. Rapidly cool the milk to a temperature of 4°C or lower. Remove one bottle for testing if appropriate, then move the remainder of the batch to the freezer.\n\nAfter pasteurising, store frozen donor milk for no longer than 6\xa0months after the date of expression.\n\nDo not open the lid of batches of pasteurised donor milk until the milk is to be used, unless it is to test the milk. If the milk is tested, discard the opened bottle.\n\nRegularly test pasteurised donor milk for microbial contamination. Base the testing schedule on the volume and throughput of milk. Test:\n\neither at least once a month or every 10 cycles, depending on which comes first, and\n\non an ad-hoc basis if any new processes, equipment or staff are introduced, or if there are concerns about any part of the process.\n\nDiscard pasteurised donor milk that has a total viable microbial count of 10\xa0CFU/ml or more.\n\nKeep all donor milk in containers made of food grade materials.\n\nStaff at the milk bank should not be responsible for adding anything to the donated milk.\n\n# Tracking and tracing\n\nTrack donated milk from the donor through to the recipient hospital.\n\nTracking and monitoring of donor milk processing should include freezer temperatures, pasteurisation processes and stock control.\n\nAt all stages, donor milk containers should be labelled clearly for identification. Clearly identify milk that is ready to be used.\n\nFor each donor milk batch, keep the following records.\n\nAbout the donor:\n\n\n\nNHS number/donor ID\n\nconsent\n\nrelevant medical history\n\nresults of serological tests.\n\n\n\nAbout each container before pasteurisation:\n\n\n\ndonor ID\n\na testing log, including the tests undertaken and their results.\n\n\n\nFor each pasteurised container:\n\n\n\nsamples making up the batch\n\nthe batch number\n\na testing log, including the tests undertaken and their results\n\npasteurisation details, including date of the pasteurisation.\n\n\n\nThe hospital or neonatal unit that receives the donated milk, or the disposal date of the donated milk, as appropriate.\n\nLabel each container of pasteurised donor milk with the following information.\n\nA unique identification number.\n\nConfirmation that it contains pasteurised donor breast milk.\n\nInstructions to keep frozen, and use within 24 hours if defrosted.\n\nAn expiry date (no later than 6 months from expression).\n\nOnly supply donor milk to hospitals or neonatal units that agree to comply with the tracking procedures for milk outlined by the milk bank.\n\nThe receiving hospital or neonatal unit should keep a record of how the donor milk is used. It should document for each bottle of donor milk:\n\nthe baby's name, NHS number and date of birth, and the date administered\n\nthe batch number and the date the donor milk was used in the patient record of each baby\n\nthe condition of the donor milk on arrival following transport\n\nthe storage conditions.Ensure that all records (including raw data) that are critical to the safety and quality of the donor milk are kept for at least 30 years after expiry date, use or disposal. These records should be confidential.", 'Recommendations for research': 'We have made the following recommendations for research, based on our review of evidence, to improve NICE guidance in the future.\n\nAlthough it was not part of the scope of this guideline, it is known that there is limited high-quality evidence on the benefits of donor breast milk. The aim of this guideline is to provide guidance on the operation of donor milk banks; however, our expectation is that, once any risks of donor milk banking are minimised, further research can be undertaken to evaluate the benefits of donor milk, and to identify the recipient babies who would benefit most.\n\nThe research recommendations below relate to the process of donor milk banking. Where appropriate, they also recommend evaluating outcomes in the recipient population.\n\n# The process of handling donor milk\n\nWhat is the effect of the process of milk banking on the nutritional and immunological components of donor milk?\n\n## Why this is important\n\nThe handling of donor milk includes a range of processes – including transport, storage and heat treatment – and is known to affect various biological, nutritional and immunological properties of breast milk. In addition, new methods of processing, such as heat or pressure treatment, are now being used in the food industry. However, there is very little comparative evidence on the different effects of the processes and how changes in the detailed process (for example, a change in temperature of 1°C) may affect the biological, nutritional and immunological properties of the milk. There is also no direct evidence of how these changes affect outcomes for recipients.\n\nFurther research is needed on the comparative effects of all milk handling processes on nutritional and immunological components, and, where possible, the impact of these on health outcomes for the recipients and on resource use during milk banking and following supply to recipients.\n\n# Nutritional assessment of donor milk\n\nHow and when should the nutritional components of donor breast milk be assessed?\n\n## Why this is important\n\nIt is known that the process of donor milk banking (for example, storage and heat treatment) affects the nutritional composition of milk. It is not clear how such changes affect health outcomes for recipients. Currently, in the UK, nutritional assessment of donor breast milk is not common practice.\n\nFurther research is needed to define clinically important changes and to determine the most useful methods and timing of measuring these in UK milk banking practice.\n\n# Milk donors\n\nWhat are the attitudes and behaviours (including lifestyle factors such as diet) of milk donors, and can they affect the quality of donor milk?\n\n## Why this is important\n\nThere is very limited evidence on the attitudes and behaviours of milk donors, including the reason why they choose to donate. There is no evidence on how these factors (for example, ongoing donation or a one-off donation or dietary behaviours) may be associated with the quality of donated milk.\n\nFurther research is needed to understand the link between donor attitudes or behaviours and the quality of milk.'}	https://www.nice.org.uk/guidance/cg93	This guideline covers how donor milk banks should recruit, screen and support women who donate breast milk. It also covers how milk banks should handle and process the breast milk they receive from donors. It aims to improve the safety of donor milk and operation of donor milk services.
b1f86df1c1f1d62218153de76a5f9ebe12c34230	nice	Surgical correction of hallux valgus using minimal access techniques	Surgical correction of hallux valgus using minimal access techniques # Guidance Current evidence on the efficacy of surgical correction of hallux valgus using minimal access techniques is limited and inconsistent. In addition, the evidence relates to a range of different surgical techniques. The evidence on safety is inadequate. Therefore, this procedure should only be used with special arrangements for clinical governance, consent and audit or research. Clinicians wishing to undertake surgical correction of hallux valgus using minimal access techniques should take the following actions. Inform the clinical governance leads in their Trusts. Ensure that patients and their carers understand the uncertainty about the procedure's safety and efficacy and provide them with clear written information. In addition, the use of NICE's information for patients ('Understanding NICE guidance') is recommended. Audit and review clinical outcomes of all patients having surgical correction of hallux valgus using minimal access techniques (see section 3.1). Further research should evaluate clearly described minimal access procedures using well-defined modern forms of osteotomy. Both objective and functional outcome measures should be reported, together with measurements of pain relief and patient satisfaction, including cosmesis. All adverse events should be described. NICE may review this procedure on publication of further evidence.# The procedure # Indications and current treatments In hallux valgus the big toe is deviated towards the other toes and a bony protrusion (a bunion) is formed by medial deviation of the first metatarsal phalangeal joint. There may be damage to the skin over the bunion, pain when walking, cosmetic concerns and difficulty with footwear. Conservative treatment may include footwear modification, and use of insoles or toe spacers. Common surgical treatment options involve different types of first metatarsal osteotomy. # Outline of the procedure Surgical correction of hallux valgus using minimal access techniques is carried out with the patient under local or general anaesthesia and with X-ray or endoscopic monitoring. One or more small incisions are made close to the hallux metatarsophalangeal joint. The bunion is removed and the metatarsal is divided surgically. The bone fragments may be stabilised using plates, screws or wires. A dressing or plaster may be used to support the foot in the corrected position until the divided bone heals. Sections 2.3 and 2.4 describe efficacy and safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview. # Efficacy The evidence relates to studies that varied in osteotomy technique (regarding the location, shape and fixation of the osteotomy, and in the methods of visualisation or guidance). Where bone fixation was undertaken, it was usually with Kirschner wires, but use of plates and screws were also reported. Recurrence of hallux valgus was reported in 2% (2/94) and 1% (1/118) of treated feet in case series of 83 and 82 patients respectively (timing of events not stated). In a case series of 204 patients (301 feet), 83 reported preoperative pain. Of these, 84% (70/83) reported no pain after the operation, 8% (7/83) had decreased pain and 1% (1/83) had increased pain (mean follow-up 8.3 months). A series of 64 patients reported that 95% (61/64) of patients were pain free at a mean follow-up of 9 years. Case series of 204 and 168 patients reported postoperative decreases in mean hallux angle from 26° to 7.5° (p < 0.05) and 28° to 14° (significance not stated) at mean follow-up of 6 weeks and 31.5 months respectively. The case series of 204 patients (301 feet) reported that 74% (61/83) of survey respondents were very pleased with the procedure, 12% (10/83) were somewhat pleased, 4% (3/83) were not satisfied and 4% (3/83) regretted having had surgery (mean follow-up 8.3 months). The Specialist Advisers listed key efficacy outcomes as improvement in pain and deformity, patient satisfaction, radiographic correction of deformity and pedobarography (foot pressure measurement). # Safety Deep infection at the osteotomy site was reported in 1 patient (treated by intravenous antibiotics and resolved within 2 weeks) in the case series of 82 patients; 1 patient (Kirschner wire removed after 3 weeks and infection resolved) in a series of 31 patients; and in 4% (4/98) of feet in the series of 64 patients (98 feet). Osteonecrosis was reported in 8% (1/13) of patients in a case series of 13 patients (13 feet) (timing of event not stated). Delayed union was reported in 1% (4/301) of feet in the case series of 204 patients (301 feet) (at mean 8.3 month follow-up). A case series of 49 patients (59 feet) reported malunion and nonunion in 2 patients each (assessed radiographically at mean follow-up 31.5 months). Postoperative hallux varus was reported in 0.3% (1/301) (not otherwise described) and 1% (1/94) (1 year after surgery, treated by extensor hallucis longus transfer) of feet in case series of 204 (301 feet) and 83 (94 feet) patients respectively. Stress fracture of the second metatarsal was reported in 2% (7/301) of feet in the case series of 204 patients (timing of events not stated). Specialist Advisers expressed concerns about the safety of this procedure. They listed possible adverse events as nerve injury including complex regional pain syndrome, toe stiffness, skin necrosis, osteomyelitis, deep vein thrombosis, tendon injury, removal of fixation screw, recurrent deformity, fracture, tender scars and skin sensitivity. They considered theoretical adverse events to include burning soft tissue, damage to foot blood vessels, inflammatory reaction to bone debris, and first metatarsal malpositioning, shortening or necrosis.# Further information This guidance requires that clinicians undertaking the procedure make special arrangements for audit. NICE has identified relevant audit criteria and developed audit support (which is for use at local discretion). For related NICE guidance see our website. # Information for patients NICE has produced information on this procedure for patients and carers ('Understanding NICE guidance'). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.# About this guidance NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland. This guidance was developed using the NICE interventional procedure guidance process. We have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available. Changes since publication January 2012: minor maintenance. Your responsibility This guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer. Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties. Copyright © National Institute for Health and Clinical Excellence 2010. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE. Contact NICE National Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT www.nice.org.uk nice@nice.org.uk	{'Guidance': "Current evidence on the efficacy of surgical correction of hallux valgus using minimal access techniques is limited and inconsistent. In addition, the evidence relates to a range of different surgical techniques. The evidence on safety is inadequate. Therefore, this procedure should only be used with special arrangements for clinical governance, consent and audit or research.\n\nClinicians wishing to undertake surgical correction of hallux valgus using minimal access techniques should take the following actions.\n\nInform the clinical governance leads in their Trusts.\n\nEnsure that patients and their carers understand the uncertainty about the procedure's safety and efficacy and provide them with clear written information. In addition, the use of NICE's information for patients ('Understanding NICE guidance') is recommended.\n\nAudit and review clinical outcomes of all patients having surgical correction of hallux valgus using minimal access techniques (see section 3.1).\n\nFurther research should evaluate clearly described minimal access procedures using well-defined modern forms of osteotomy. Both objective and functional outcome measures should be reported, together with measurements of pain relief and patient satisfaction, including cosmesis. All adverse events should be described.\n\nNICE may review this procedure on publication of further evidence.", 'The procedure': '# Indications and current treatments\n\nIn hallux valgus the big toe is deviated towards the other toes and a bony protrusion (a bunion) is formed by medial deviation of the first metatarsal phalangeal joint. There may be damage to the skin over the bunion, pain when walking, cosmetic concerns and difficulty with footwear.\n\nConservative treatment may include footwear modification, and use of insoles or toe spacers. Common surgical treatment options involve different types of first metatarsal osteotomy.\n\n# Outline of the procedure\n\nSurgical correction of hallux valgus using minimal access techniques is carried out with the patient under local or general anaesthesia and with X-ray or endoscopic monitoring. One or more small incisions are made close to the hallux metatarsophalangeal joint. The bunion is removed and the metatarsal is divided surgically. The bone fragments may be stabilised using plates, screws or wires. A dressing or plaster may be used to support the foot in the corrected position until the divided bone heals.\n\nSections 2.3 and 2.4 describe efficacy and safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview.\n\n# Efficacy\n\nThe evidence relates to studies that varied in osteotomy technique (regarding the location, shape and fixation of the osteotomy, and in the methods of visualisation or guidance). Where bone fixation was undertaken, it was usually with Kirschner wires, but use of plates and screws were also reported.\n\nRecurrence of hallux valgus was reported in 2% (2/94) and 1% (1/118) of treated feet in case series of 83 and 82 patients respectively (timing of events not stated).\n\nIn a case series of 204 patients (301 feet), 83 reported preoperative pain. Of these, 84% (70/83) reported no pain after the operation, 8% (7/83) had decreased pain and 1% (1/83) had increased pain (mean follow-up 8.3 months). A series of 64 patients reported that 95% (61/64) of patients were pain free at a mean follow-up of 9 years.\n\nCase series of 204 and 168 patients reported postoperative decreases in mean hallux angle from 26° to 7.5° (p < 0.05) and 28° to 14° (significance not stated) at mean follow-up of 6 weeks and 31.5 months respectively.\n\nThe case series of 204 patients (301 feet) reported that 74% (61/83) of survey respondents were very pleased with the procedure, 12% (10/83) were somewhat pleased, 4% (3/83) were not satisfied and 4% (3/83) regretted having had surgery (mean follow-up 8.3 months).\n\nThe Specialist Advisers listed key efficacy outcomes as improvement in pain and deformity, patient satisfaction, radiographic correction of deformity and pedobarography (foot pressure measurement).\n\n# Safety\n\nDeep infection at the osteotomy site was reported in 1 patient (treated by intravenous antibiotics and resolved within 2 weeks) in the case series of 82 patients; 1 patient (Kirschner wire removed after 3 weeks and infection resolved) in a series of 31 patients; and in 4% (4/98) of feet in the series of 64 patients (98 feet).\n\nOsteonecrosis was reported in 8% (1/13) of patients in a case series of 13 patients (13 feet) (timing of event not stated).\n\nDelayed union was reported in 1% (4/301) of feet in the case series of 204 patients (301 feet) (at mean 8.3 month follow-up). A case series of 49 patients (59 feet) reported malunion and nonunion in 2 patients each (assessed radiographically at mean follow-up 31.5 months).\n\nPostoperative hallux varus was reported in 0.3% (1/301) (not otherwise described) and 1% (1/94) (1 year after surgery, treated by extensor hallucis longus transfer) of feet in case series of 204 (301 feet) and 83 (94 feet) patients respectively.\n\nStress fracture of the second metatarsal was reported in 2% (7/301) of feet in the case series of 204 patients (timing of events not stated).\n\nSpecialist Advisers expressed concerns about the safety of this procedure. They listed possible adverse events as nerve injury including complex regional pain syndrome, toe stiffness, skin necrosis, osteomyelitis, deep vein thrombosis, tendon injury, removal of fixation screw, recurrent deformity, fracture, tender scars and skin sensitivity. They considered theoretical adverse events to include burning soft tissue, damage to foot blood vessels, inflammatory reaction to bone debris, and first metatarsal malpositioning, shortening or necrosis.', 'Further information': "This guidance requires that clinicians undertaking the procedure make special arrangements for audit. NICE has identified relevant audit criteria and developed audit support (which is for use at local discretion).\n\nFor related NICE guidance see our website.\n\n# Information for patients\n\nNICE has produced information on this procedure for patients and carers ('Understanding NICE guidance'). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.", 'About this guidance': 'NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland.\n\nThis guidance was developed using the NICE interventional procedure guidance process.\n\nWe have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available.\n\nChanges since publication\n\nJanuary 2012: minor maintenance.\n\nYour responsibility\n\nThis guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.\n\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.\n\nCopyright\n\n© National Institute for Health and Clinical Excellence 2010. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.\n\nContact NICE\n\nNational Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT\n\nwww.nice.org.uk\n \n nice@nice.org.uk\n 0845 033 7780'}	https://www.nice.org.uk/guidance/ipg332
30ab1b499bfd9e4b84b929aba252c59c9422fe13	nice	Therapeutic endoscopic division of epidural adhesions	Therapeutic endoscopic division of epidural adhesions # Guidance This document replaces previous guidance on endoscopic division of epidural adhesions (interventional procedure guidance 88). Current evidence on therapeutic endoscopic division of epidural adhesions is limited to some evidence of short-term efficacy, and there are significant safety concerns. Therefore this procedure should only be used with special arrangements for clinical governance, consent and audit or research. Clinicians wishing to undertake therapeutic endoscopic division of epidural adhesions should take the following actions. Inform the clinical governance leads in their Trusts. Ensure that patients and their carers understand the uncertainty about the procedure's safety and efficacy, in particular the risk of neural damage, dural puncture and visual disturbance, and provide them with clear written information. In addition, the use of NICE's information for patients ('Understanding NICE guidance') is recommended. Audit and review clinical outcomes of all patients having therapeutic endoscopic division of epidural adhesions (see section 3.1). Further research on this procedure should clearly describe case selection. Outcomes should include pain relief, duration of effectiveness and whether other treatments are subsequently required.# The procedure # Indications and current treatments Chronic back or leg pain may be caused by adhesions formed around the spinal nerve roots. Conservative treatments may include analgesics, non-steroidal anti-inflammatory drugs and physical therapy. Open or blind adhesiolysis may be considered for neurological or persistent symptoms unresponsive to conservative treatment. # Outline of the procedure Endoscopic division of epidural adhesions aims to reduce or eliminate pain related to adhesions around spinal nerves. The procedure is carried out with the patient under local anaesthesia and mild sedation. The epidural space is accessed at the appropriate level using fluoroscopic guidance, and a guidewire and endoscope are inserted. The epidural space is distended by injection of saline. Endoscopic manipulation is used to identify painful nerve roots (by communication with the patient). Endoscopic instruments are used to divide epidural adhesions around the spinal nerve roots or the spinal cord. Sections 2.3 and 2.4 describe efficacy and safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview. # Efficacy A randomised controlled trial (RCT) of 83 patients treated by the procedure or diagnostic endoscopy alone (control group), reported a greater pain improvement from baseline (using a 10-point visual analogue scale ; lower scores indicate less pain) in the treatment (9.0 to 5.7) compared with the control group (8.9 to 8.6) at 12-month follow-up (p = 0.001 both for improvement from baseline and for between group comparisons). In a comparative case series of 183 patients treated by the procedure, patients with previous nerve decompression had significantly less leg and low-back pain at 3-month follow-up compared with those without such history (p < 0.05). The RCT of 83 patients reported a significant improvement from baseline in mean Oswestry Disability Index score (functional ability questionnaire with scores from 0% to 100% ) in the treatment group, from 36% at baseline to 25% at 12-month follow-up (p = 0.001). This compares with improvement in the control group from 34% to 33% (p = 0.001 compared with the treatment group). A prospective case series of 38 patients reported that patient satisfaction and subjective improvement did not change significantly after treatment at either 2- or 12-month follow-up (no further details provided). The Specialist Advisers listed key efficacy outcomes as pain relief, improved function and disability score, quality of life, psychological status, return to work and avoidance of spinal cord stimulation for chronic pain. # Safety Dural puncture was reported in 3% (4/124) and 2% (1/58) of patients in the case series of 183 and a case series of 58 patients, and in 1 patient in a case report. Contrast medium leakage into the cerebrospinal fluid space was also reported in this case report (causing postoperative rhabdomyolysis and acute encephalopathy; patient recovered after 20 hours, was able to walk after 24 hours and recovered fully). In a case series of 120 patients, subarachnoid puncture and subarachnoid block (potentially leading to neural damage, including paralysis) were reported in 12% (7/60) and 7% (4/60) of patients treated by the procedure and 7% (4/60) and 3% (2/60) of patients treated by non-endoscopic (radiologically guided) division of adhesions (timing of events not stated). The RCT of 83 patients reported 1 case of postoperative subarachnoid block in the intervention group (treated with steroids and resolved without sequelae). Visual disturbance (clinical significance and degree and speed of resolution not described) was recorded in 12 patients in a safety report on visual impairment because of retinal haemorrhage, treated by epidural injection, epiduroscopy or lysis of adhesions (denominator not stated). An additional case report described blurred vision and bilateral central scotomas immediately after the procedure (which resolved spontaneously within 2 months) in 1 patient. 'Non-persistent' lower limb paraesthesia was reported in 2 patients in the case series of 38 patients (timing and resolution of the event not stated). The Specialist Advisers considered theoretical adverse events to include catheter shearing, nerve root avulsion, nerve palsy, meningitis, arachnoiditis, paralysis, epidural infection or abscess and excessive epidural hydrostatic pressure associated with injection of fluid which could cause events such as spinal compression and haematoma. They listed anecdotal adverse events as numbness in the lower limbs and blindness.# Further information This guidance requires that clinicians undertaking the procedure make special arrangements for audit. NICE has identified relevant audit criteria and developed audit support (which is for use at local discretion). For related NICE guidance see our website. # Information for patients NICE has produced information on this procedure for patients and carers ('Understanding NICE guidance'). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.# About this guidance NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland. This guidance was developed using the NICE interventional procedure guidance process. It updates and replaces NICE interventional procedure guidance 88. We have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available. Changes since publication January 2012: minor maintenance. Your responsibility This guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer. Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties. Copyright © National Institute for Health and Clinical Excellence 2010. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE. Contact NICE National Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT www.nice.org.uk nice@nice.org.uk	{'Guidance': "This document replaces previous guidance on endoscopic division of epidural adhesions (interventional procedure guidance 88).\n\n\n\nCurrent evidence on therapeutic endoscopic division of epidural adhesions is limited to some evidence of short-term efficacy, and there are significant safety concerns. Therefore this procedure should only be used with special arrangements for clinical governance, consent and audit or research.\n\nClinicians wishing to undertake therapeutic endoscopic division of epidural adhesions should take the following actions.\n\nInform the clinical governance leads in their Trusts.\n\nEnsure that patients and their carers understand the uncertainty about the procedure's safety and efficacy, in particular the risk of neural damage, dural puncture and visual disturbance, and provide them with clear written information. In addition, the use of NICE's information for patients ('Understanding NICE guidance') is recommended.\n\nAudit and review clinical outcomes of all patients having therapeutic endoscopic division of epidural adhesions (see section 3.1).\n\nFurther research on this procedure should clearly describe case selection. Outcomes should include pain relief, duration of effectiveness and whether other treatments are subsequently required.", 'The procedure': "# Indications and current treatments\n\nChronic back or leg pain may be caused by adhesions formed around the spinal nerve roots.\n\nConservative treatments may include analgesics, non-steroidal anti-inflammatory drugs and physical therapy. Open or blind adhesiolysis may be considered for neurological or persistent symptoms unresponsive to conservative treatment.\n\n# Outline of the procedure\n\nEndoscopic division of epidural adhesions aims to reduce or eliminate pain related to adhesions around spinal nerves.\n\nThe procedure is carried out with the patient under local anaesthesia and mild sedation. The epidural space is accessed at the appropriate level using fluoroscopic guidance, and a guidewire and endoscope are inserted. The epidural space is distended by injection of saline. Endoscopic manipulation is used to identify painful nerve roots (by communication with the patient). Endoscopic instruments are used to divide epidural adhesions around the spinal nerve roots or the spinal cord.\n\nSections 2.3 and 2.4 describe efficacy and safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview.\n\n# Efficacy\n\nA randomised controlled trial (RCT) of 83 patients treated by the procedure or diagnostic endoscopy alone (control group), reported a greater pain improvement from baseline (using a 10-point visual analogue scale [VAS]; lower scores indicate less pain) in the treatment (9.0 to 5.7) compared with the control group (8.9 to 8.6) at 12-month follow-up (p = 0.001 both for improvement from baseline and for between group comparisons).\n\nIn a comparative case series of 183 patients treated by the procedure, patients with previous nerve decompression had significantly less leg and low-back pain at 3-month follow-up compared with those without such history (p < 0.05).\n\nThe RCT of 83 patients reported a significant improvement from baseline in mean Oswestry Disability Index score (functional ability questionnaire with scores from 0% [greater ability] to 100% [lower ability]) in the treatment group, from 36% at baseline to 25% at 12-month follow-up (p = 0.001). This compares with improvement in the control group from 34% to 33% (p = 0.001 compared with the treatment group).\n\nA prospective case series of 38 patients reported that patient satisfaction and subjective improvement did not change significantly after treatment at either 2- or 12-month follow-up (no further details provided).\n\nThe Specialist Advisers listed key efficacy outcomes as pain relief, improved function and disability score, quality of life, psychological status, return to work and avoidance of spinal cord stimulation for chronic pain.\n\n# Safety\n\nDural puncture was reported in 3% (4/124) and 2% (1/58) of patients in the case series of 183 and a case series of 58 patients, and in 1 patient in a case report. Contrast medium leakage into the cerebrospinal fluid space was also reported in this case report (causing postoperative rhabdomyolysis and acute encephalopathy; patient recovered after 20 hours, was able to walk after 24 hours and recovered fully).\n\nIn a case series of 120 patients, subarachnoid puncture and subarachnoid block (potentially leading to neural damage, including paralysis) were reported in 12% (7/60) and 7% (4/60) of patients treated by the procedure and 7% (4/60) and 3% (2/60) of patients treated by non-endoscopic (radiologically guided) division of adhesions (timing of events not stated). The RCT of 83 patients reported 1 case of postoperative subarachnoid block in the intervention group (treated with steroids and resolved without sequelae).\n\nVisual disturbance (clinical significance and degree and speed of resolution not described) was recorded in 12 patients in a safety report on visual impairment because of retinal haemorrhage, treated by epidural injection, epiduroscopy or lysis of adhesions (denominator not stated). An additional case report described blurred vision and bilateral central scotomas immediately after the procedure (which resolved spontaneously within 2 months) in 1 patient.\n\n'Non-persistent' lower limb paraesthesia was reported in 2 patients in the case series of 38 patients (timing and resolution of the event not stated).\n\nThe Specialist Advisers considered theoretical adverse events to include catheter shearing, nerve root avulsion, nerve palsy, meningitis, arachnoiditis, paralysis, epidural infection or abscess and excessive epidural hydrostatic pressure associated with injection of fluid which could cause events such as spinal compression and haematoma. They listed anecdotal adverse events as numbness in the lower limbs and blindness.", 'Further information': "This guidance requires that clinicians undertaking the procedure make special arrangements for audit. NICE has identified relevant audit criteria and developed audit support (which is for use at local discretion).\n\nFor related NICE guidance see our website.\n\n# Information for patients\n\nNICE has produced information on this procedure for patients and carers ('Understanding NICE guidance'). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.", 'About this guidance': 'NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland.\n\nThis guidance was developed using the NICE interventional procedure guidance process.\n\nIt updates and replaces NICE interventional procedure guidance 88.\n\nWe have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available.\n\nChanges since publication\n\nJanuary 2012: minor maintenance.\n\nYour responsibility\n\nThis guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.\n\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.\n\nCopyright\n\n© National Institute for Health and Clinical Excellence 2010. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.\n\nContact NICE\n\nNational Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT\n\nwww.nice.org.uk\n \n \n nice@nice.org.uk\n 0845 033 7780'}	https://www.nice.org.uk/guidance/ipg333
3deeb960ef2a2ddb940c223392640309e68b47fb	nice	Laparoscopic augmentation cystoplasty (including clam cystoplasty)	Laparoscopic augmentation cystoplasty (including clam cystoplasty) # Guidance Current evidence on the safety and efficacy of laparoscopic augmentation cystoplasty (including clam cystoplasty) is limited in quantity and quality but raises no major safety concerns, and the open procedure is well established. This procedure may therefore be used with normal arrangements for clinical governance, consent and audit. Patient selection and treatment should be carried out by a multidisciplinary team with specialist expertise in the management of urinary incontinence and experience in complex laparoscopic reconstructive surgery. Clinicians undertaking laparoscopic augmentation cystoplasty (including clam cystoplasty) should submit data on all patients undergoing the procedure to the Female and Reconstructive Urology database run by the British Association of Urological Surgeons to allow monitoring of safety outcomes in the long term.# The procedure # Indications and current treatments Laparoscopic augmentation cystoplasty (including clam cystoplasty) is indicated for a number of conditions including anatomically/structurally contracted bladder, neurogenic bladder and overactive bladder. Current treatment options include bladder training, anticholinergic drugs, intravesical botulinum toxin injections, intermittent self-catheterisation (ISC) and sacral neuromodulation. In patients whose condition is refractory to non-surgical treatment, open augmentation cystoplasty is an established procedure. Proposed advantages of a laparoscopic approach are less intraoperative blood loss, quicker recovery, less pain, a shorter stay in hospital and smaller scars. # Outline of the procedure Laparoscopic augmentation cystoplasty (including clam cystoplasty) (also known as ileocystoplasty, sigmoidocystoplasty, enterocystoplasty or bladder augmentation) increases bladder size and reduces intravesical pressure. Its aims are to reduce urgency and urge incontinence and reduce voiding frequency. The procedure is typically carried out through 4 or 5 laparoscopic ports with the patient under general anaesthesia. The bladder is incised and an isolated piece of bowel, usually ileum, is sutured to this opening. A urethral and/or suprapubic catheter is left in the reconstructed bladder. Once a 'watertight' reservoir has been demonstrated, 2–3 weeks after surgery, the urethral/subrapubic catheter is removed. Many patients require ISC and bladder washouts to reduce the risk of infection or stones in the augmented bladder. Patients need to empty the bladder at least every 4 hours (by passing urine spontaneously or by ISC) to prevent bladder rupture. Sections 2.3 and 2.4 describe efficacy and safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview. # Efficacy A case series of 17 patients reported a significant improvement in bladder control on the Bladder Control Scale (scoring system not described) from a mean preoperative score of 14.9 to 1.6 at an average 17-month follow-up (p = 0.0002). Case series of 23 and 6 patients treated by laparoscopic cystoplasty reported significant increases in mean postoperative bladder volume compared with preoperative volume – from 111 ml to 778 ml and 48 ml to 260 ml at 12-month follow-up (p < 0.01) and 13- to 16-month follow-up (significance not stated), respectively. Two case reports of 1 patient each reported increases in bladder volume from 85 ml preoperatively to 250 ml at 4-week follow-up and from 150 ml preoperatively to 315 ml at 3-month follow-up. The case series of 23 and 6 patients reported postoperative decreases in mean maximum detrusor pressure from 92 cm to 15 cm H2O at 12-month follow-up and from 35 cm to 12 cm H2O at an average of 13- to 16-month follow-up, respectively (significance not stated). The case series of 23 patients reported that all 19 patients with 12-month follow-up data were continent between ISC every 4–5 hours (39% of patients had been described as incontinent before the procedure). The case series of 6 patients reported that all patients were generally dry for 2–3 hours between catheterisations within 1 month of the procedure. The Specialist Advisers listed key efficacy outcomes as symptom relief, rapid recovery and shorter duration of hospital stay (compared with the open procedure), reduced need for analgesia, and cosmesis. # Safety Multiple bladder stones in the augmented pouch 13 months after surgery were reported in 1 patientin the case series of 23 patients (these were treated by cystolithotomy). In the same case series of 23 patients, spontaneous rupture of the pouch 15 months after augmentation was reported in 1 patient who neglected to undertake ISC as recommended. The rupture was repaired and a urethral catheter was inserted for 4 weeks. In the case series of 17 patients, a trocar-induced rectus sheath haematoma was reported in 1 patient during a sigmoidocystoplasty (this was controlled laparoscopically). Paralytic ileus (managed conservatively) was reported in another patient in the case series of 17 patients (timing of event not stated). Leakage from the suture line occurred in 1 patient in the case series of 6 patients: this resolved with conservative management. The Specialist Advisers considered theoretical adverse events to include bleeding, sepsis, infection, damage to the bowel, intestinal anastomotic leaks (bowel or bladder), and metabolic disturbance.# Further information For related NICE guidance see our website. # Information for patients NICE has produced information on this procedure for patients and carers ('Understanding NICE guidance'). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.# About this guidance NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland. This guidance was developed using the NICE interventional procedure guidance process. We have produced a summary of this guidance for patients and carers. Information about the evidence it is based on is also available. Changes since publication January 2012: minor maintenance. Your responsibility This guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer. Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties. Copyright © National Institute for Health and Clinical Excellence 2009. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE. Contact NICE National Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT www.nice.org.uk nice@nice.org.uk	{'Guidance': 'Current evidence on the safety and efficacy of laparoscopic augmentation cystoplasty (including clam cystoplasty) is limited in quantity and quality but raises no major safety concerns, and the open procedure is well established. This procedure may therefore be used with normal arrangements for clinical governance, consent and audit.\n\nPatient selection and treatment should be carried out by a multidisciplinary team with specialist expertise in the management of urinary incontinence and experience in complex laparoscopic reconstructive surgery.\n\nClinicians undertaking laparoscopic augmentation cystoplasty (including clam cystoplasty) should submit data on all patients undergoing the procedure to the Female and Reconstructive Urology database run by the British Association of Urological Surgeons to allow monitoring of safety outcomes in the long term.', 'The procedure': "# Indications and current treatments\n\nLaparoscopic augmentation cystoplasty (including clam cystoplasty) is indicated for a number of conditions including anatomically/structurally contracted bladder, neurogenic bladder and overactive bladder.\n\nCurrent treatment options include bladder training, anticholinergic drugs, intravesical botulinum toxin injections, intermittent self-catheterisation (ISC) and sacral neuromodulation. In patients whose condition is refractory to non-surgical treatment, open augmentation cystoplasty is an established procedure.\n\nProposed advantages of a laparoscopic approach are less intraoperative blood loss, quicker recovery, less pain, a shorter stay in hospital and smaller scars.\n\n# Outline of the procedure\n\nLaparoscopic augmentation cystoplasty (including clam cystoplasty) (also known as ileocystoplasty, sigmoidocystoplasty, enterocystoplasty or bladder augmentation) increases bladder size and reduces intravesical pressure. Its aims are to reduce urgency and urge incontinence and reduce voiding frequency.\n\nThe procedure is typically carried out through 4 or 5 laparoscopic ports with the patient under general anaesthesia. The bladder is incised and an isolated piece of bowel, usually ileum, is sutured to this opening. A urethral and/or suprapubic catheter is left in the reconstructed bladder.\n\nOnce a 'watertight' reservoir has been demonstrated, 2–3 weeks after surgery, the urethral/subrapubic catheter is removed. Many patients require ISC and bladder washouts to reduce the risk of infection or stones in the augmented bladder. Patients need to empty the bladder at least every 4 hours (by passing urine spontaneously or by ISC) to prevent bladder rupture.\n\nSections 2.3 and 2.4 describe efficacy and safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview.\n\n# Efficacy\n\nA case series of 17 patients reported a significant improvement in bladder control on the Bladder Control Scale (scoring system not described) from a mean preoperative score of 14.9 to 1.6 at an average 17-month follow-up (p = 0.0002).\n\nCase series of 23 and 6 patients treated by laparoscopic cystoplasty reported significant increases in mean postoperative bladder volume compared with preoperative volume – from 111 ml to 778 ml and 48 ml to 260 ml at 12-month follow-up (p < 0.01) and 13- to 16-month follow-up (significance not stated), respectively. Two case reports of 1 patient each reported increases in bladder volume from 85 ml preoperatively to 250 ml at 4-week follow-up and from 150 ml preoperatively to 315 ml at 3-month follow-up.\n\nThe case series of 23 and 6 patients reported postoperative decreases in mean maximum detrusor pressure from 92 cm to 15 cm H2O at 12-month follow-up and from 35 cm to 12 cm H2O at an average of 13- to 16-month follow-up, respectively (significance not stated).\n\nThe case series of 23 patients reported that all 19 patients with 12-month follow-up data were continent between ISC every 4–5 hours (39% [9/23] of patients had been described as incontinent before the procedure). The case series of 6 patients reported that all patients were generally dry for 2–3 hours between catheterisations within 1 month of the procedure.\n\nThe Specialist Advisers listed key efficacy outcomes as symptom relief, rapid recovery and shorter duration of hospital stay (compared with the open procedure), reduced need for analgesia, and cosmesis.\n\n# Safety\n\nMultiple bladder stones in the augmented pouch 13 months after surgery were reported in 1 patientin the case series of 23 patients (these were treated by cystolithotomy).\n\nIn the same case series of 23 patients, spontaneous rupture of the pouch 15 months after augmentation was reported in 1 patient who neglected to undertake ISC as recommended. The rupture was repaired and a urethral catheter was inserted for 4 weeks.\n\nIn the case series of 17 patients, a trocar-induced rectus sheath haematoma was reported in 1 patient during a sigmoidocystoplasty (this was controlled laparoscopically). Paralytic ileus (managed conservatively) was reported in another patient in the case series of 17 patients (timing of event not stated).\n\nLeakage from the suture line occurred in 1 patient in the case series of 6 patients: this resolved with conservative management.\n\nThe Specialist Advisers considered theoretical adverse events to include bleeding, sepsis, infection, damage to the bowel, intestinal anastomotic leaks (bowel or bladder), and metabolic disturbance.", 'Further information': "For related NICE guidance see our website.\n\n# Information for patients\n\nNICE has produced information on this procedure for patients and carers ('Understanding NICE guidance'). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.", 'About this guidance': 'NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland.\n\nThis guidance was developed using the NICE interventional procedure guidance process.\n\nWe have produced a summary of this guidance for patients and carers. Information about the evidence it is based on is also available.\n\nChanges since publication\n\nJanuary 2012: minor maintenance.\n\nYour responsibility\n\nThis guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.\n\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.\n\nCopyright\n\n© National Institute for Health and Clinical Excellence 2009. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.\n\nContact NICE\n\nNational Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT\n\nwww.nice.org.uk\n \n nice@nice.org.uk\n 0845 033 7780'}	https://www.nice.org.uk/guidance/ipg326
441d5ff3c2aa4fca47265a13fd1dddfbb89661ab	nice	Radiofrequency ablation for colorectal liver metastases	Radiofrequency ablation for colorectal liver metastases # Guidance This guidance replaces previous guidance on radiofrequency ablation for the treatment of colorectal metastases in the liver (interventional procedure guidance 92) Current evidence on the safety and efficacy of radiofrequency (RF) ablation for colorectal liver metastases is adequate to support the use of this procedure in patients unfit or otherwise unsuitable for hepatic resection, or in those who have previously had hepatic resection, provided that normal arrangements are in place for clinical governance, consent and audit. Patient selection should be carried out by a hepatobiliary cancer multidisciplinary team.# The procedure # Indications and current treatments Colorectal cancer is the second most common cancer in women and the third most common cancer in men in the UK. The liver is the most common site for metastases. Curative treatment for patients with liver metastases from colorectal cancer may be provided by liver resection. However, fitness for surgery and the number, location and size of the metastases may dictate the use of alternative treatment options. These include systemic chemotherapy, radiotherapy, thermal ablation, chemoembolisation and selective internal radiation therapy. Radiofrequency ablation may be indicated as the primary treatment for liver metastases if the patient is unfit for surgery or in the treatment of postresection recurrence. It may also be used as an adjunct to hepatic resection to ablate small-volume disease in the future remnant liver. # Outline of the procedure A percutaneous or intraoperative approach may be used, with the patient under local or general anaesthesia. Needle electrodes are inserted into the target tumour area (or areas) using imaging guidance. A high-frequency alternating current is applied, resulting in heat generation, which causes localised coagulative necrosis and tissue destruction around the electrodes. Several different types of RF electrodes are available. Sections 2.3 and 2.4 describe efficacy and safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview. # Efficacy The selection criteria in the following studies means that patients who had RF ablation or RF ablation plus surgery could not have been treated by surgery alone. A non-randomised controlled trial of 46 patients treated by RF ablation or surgical resection described in a systematic review reported that median survival after diagnosis of liver metastases was 44 months and 54 months, respectively (significance not stated). In the same systematic review, 6 case series reported survival ranging from 17% (1/6) at 11-month follow-up to 88% (7/8) at 2- to 6-month follow-up. A non-randomised controlled trial of 418 patients reported that patients treated by surgical resection had overall survival rates of 73%, 65% and 58% at 3-, 4- and 5-year follow-up, respectively. These rates were significantly higher than those from patients treated by RF ablation alone, or by RF ablation plus resection (absolute figures not stated) (p < 0.0001). In the same study, the difference in survival between patients treated by RF ablation alone and RF ablation plus surgical resection was not significant (p = 0.36). A non-randomised controlled trial of 258 patients reported that 3-year disease-free survival was significantly greater in patients treated by surgical resection alone (40%) than in those treated by RF ablation plus resection (34%) (absolute figures not stated) (p = 0.01). A case series of 243 patients with unresectable metastases reported survival rates of 20% and 18% at 3- and 5-year follow-up, respectively (absolute figures not stated). The non-randomised controlled trial of 418 patients reported that recurrence at any site occurred more often in the RF ablation group (84%) than in the surgical resection group (52%) at a median 21-month follow-up (absolute figures not stated) (p < 0.001). The non-randomised controlled trial of 258 patients reported that recurrence at any site at 1-year follow-up was significantly lower in the surgical resection group (24%) than in the RF ablation plus resection group (61%) or the RF ablation alone group (66%) (absolute figures not stated) (p < 0.001). The Specialist Advisers listed key efficacy outcomes as overall survival and local recurrence rate. # Safety Haemorrhage requiring transfusion (required hospital stay of more than 72 hours) was reported in 1% (7/617) of treatment sessions in a case series of 309 patients. Three cases series described in the systematic review reported postoperative complication rates between 0% and 33%. The complications included bowel perforation, peritoneal seeding (metastasis), bile duct stricture, wound infection and postoperative bleeding (absolute figures not stated). A case report of a patient previously treated by both surgical resection and cryoablation described cutaneous fistula formation between the site of electrode insertion and the gastric antrum at 3-week follow-up. This had resolved at 6-month follow-up. Visceral thermal injury (required hospital stay of more than 72 hours) was reported in less than 1% (4/617) of treatment sessions in the case series of 309 patients. A case series of 122 patients reported infected biloma development (requiring percutaneous drainage) in 1% (1/122) of patients, and biliary dilation and cholangitis leading to biliobronchial fistula in 1% (1/122) of patients. Minor complications (not requiring intervention) included development of a small haemoperitoneum in 2% (3/122), biliary dilation in 3% (4/122) and persistent pain (location not reported) in 2% (3/122) of patients. Another case report described a patient with pain and fever (40°C) at 5-day follow-up. Abdominal ultrasound revealed an intrahepatic abscess which required drainage. The patient recovered uneventfully. The Specialist Advisers listed anecdotal adverse events as damage to the biliary tree and bradycardia. They considered theoretical adverse events to include injury to the bowel or diaphragm, and damage to the pleura or lungs. # Other comments The Committee noted that the evidence was difficult to interpret because patient selection criteria and the use of concomitant treatments differed between the studies.# Further information For related NICE guidance see our website. # Information for patients NICE has produced information on this procedure for patients and carers ('Understanding NICE guidance'). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.# About this guidance NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland. This guidance was developed using the NICE interventional procedure guidance process. It updates and replaces NICE interventional procedure guidance 92. This guidance has been incorporated into the NICE pathway on colorectal cancer, along with other related guidance and products. We have produced a summary of this guidance for patients and carers. Information about the evidence it is based on is also available. Changes since publication January 2012: minor maintenance. Your responsibility This guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer. Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties. Copyright © National Institute for Health and Clinical Excellence 2009. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE. Contact NICE National Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT www.nice.org.uk nice@nice.org.uk	{'Guidance': 'This guidance replaces previous guidance on radiofrequency ablation for the treatment of colorectal metastases in the liver (interventional procedure guidance 92)\n\nCurrent evidence on the safety and efficacy of radiofrequency (RF) ablation for colorectal liver metastases is adequate to support the use of this procedure in patients unfit or otherwise unsuitable for hepatic resection, or in those who have previously had hepatic resection, provided that normal arrangements are in place for clinical governance, consent and audit.\n\nPatient selection should be carried out by a hepatobiliary cancer multidisciplinary team.', 'The procedure': '# Indications and current treatments\n\nColorectal cancer is the second most common cancer in women and the third most common cancer in men in the UK. The liver is the most common site for metastases.\n\nCurative treatment for patients with liver metastases from colorectal cancer may be provided by liver resection. However, fitness for surgery and the number, location and size of the metastases may dictate the use of alternative treatment options. These include systemic chemotherapy, radiotherapy, thermal ablation, chemoembolisation and selective internal radiation therapy. Radiofrequency ablation may be indicated as the primary treatment for liver metastases if the patient is unfit for surgery or in the treatment of postresection recurrence. It may also be used as an adjunct to hepatic resection to ablate small-volume disease in the future remnant liver.\n\n# Outline of the procedure\n\nA percutaneous or intraoperative approach may be used, with the patient under local or general anaesthesia. Needle electrodes are inserted into the target tumour area (or areas) using imaging guidance. A high-frequency alternating current is applied, resulting in heat generation, which causes localised coagulative necrosis and tissue destruction around the electrodes.\n\nSeveral different types of RF electrodes are available.\n\nSections 2.3 and 2.4 describe efficacy and safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview.\n\n# Efficacy\n\nThe selection criteria in the following studies means that patients who had RF ablation or RF ablation plus surgery could not have been treated by surgery alone.\n\nA non-randomised controlled trial of 46 patients treated by RF ablation or surgical resection described in a systematic review reported that median survival after diagnosis of liver metastases was 44 months and 54 months, respectively (significance not stated). In the same systematic review, 6 case series reported survival ranging from 17% (1/6) at 11-month follow-up to 88% (7/8) at 2- to 6-month follow-up. A non-randomised controlled trial of 418 patients reported that patients treated by surgical resection had overall survival rates of 73%, 65% and 58% at 3-, 4- and 5-year follow-up, respectively. These rates were significantly higher than those from patients treated by RF ablation alone, or by RF ablation plus resection (absolute figures not stated) (p < 0.0001). In the same study, the difference in survival between patients treated by RF ablation alone and RF ablation plus surgical resection was not significant (p = 0.36). A non-randomised controlled trial of 258 patients reported that 3-year disease-free survival was significantly greater in patients treated by surgical resection alone (40%) than in those treated by RF ablation plus resection (34%) (absolute figures not stated) (p = 0.01).\n\nA case series of 243 patients with unresectable metastases reported survival rates of 20% and 18% at 3- and 5-year follow-up, respectively (absolute figures not stated).\n\nThe non-randomised controlled trial of 418 patients reported that recurrence at any site occurred more often in the RF ablation group (84%) than in the surgical resection group (52%) at a median 21-month follow-up (absolute figures not stated) (p < 0.001). The non-randomised controlled trial of 258 patients reported that recurrence at any site at 1-year follow-up was significantly lower in the surgical resection group (24%) than in the RF ablation plus resection group (61%) or the RF ablation alone group (66%) (absolute figures not stated) (p < 0.001).\n\nThe Specialist Advisers listed key efficacy outcomes as overall survival and local recurrence rate.\n\n# Safety\n\nHaemorrhage requiring transfusion (required hospital stay of more than 72 hours) was reported in 1% (7/617) of treatment sessions in a case series of 309 patients.\n\nThree cases series described in the systematic review reported postoperative complication rates between 0% and 33%. The complications included bowel perforation, peritoneal seeding (metastasis), bile duct stricture, wound infection and postoperative bleeding (absolute figures not stated).\n\nA case report of a patient previously treated by both surgical resection and cryoablation described cutaneous fistula formation between the site of electrode insertion and the gastric antrum at 3-week follow-up. This had resolved at 6-month follow-up.\n\nVisceral thermal injury (required hospital stay of more than 72 hours) was reported in less than 1% (4/617) of treatment sessions in the case series of 309 patients.\n\nA case series of 122 patients reported infected biloma development (requiring percutaneous drainage) in 1% (1/122) of patients, and biliary dilation and cholangitis leading to biliobronchial fistula in 1% (1/122) of patients. Minor complications (not requiring intervention) included development of a small haemoperitoneum in 2% (3/122), biliary dilation in 3% (4/122) and persistent pain (location not reported) in 2% (3/122) of patients.\n\nAnother case report described a patient with pain and fever (40°C) at 5-day follow-up. Abdominal ultrasound revealed an intrahepatic abscess which required drainage. The patient recovered uneventfully.\n\nThe Specialist Advisers listed anecdotal adverse events as damage to the biliary tree and bradycardia. They considered theoretical adverse events to include injury to the bowel or diaphragm, and damage to the pleura or lungs.\n\n# Other comments\n\nThe Committee noted that the evidence was difficult to interpret because patient selection criteria and the use of concomitant treatments differed between the studies.', 'Further information': "For related NICE guidance see our website.\n\n# Information for patients\n\nNICE has produced information on this procedure for patients and carers ('Understanding NICE guidance'). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.", 'About this guidance': 'NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland.\n\nThis guidance was developed using the NICE interventional procedure guidance process.\n\nIt updates and replaces NICE interventional procedure guidance 92.\n\nThis guidance has been incorporated into the NICE pathway on colorectal cancer, along with other related guidance and products.\n\nWe have produced a summary of this guidance for patients and carers. Information about the evidence it is based on is also available.\n\nChanges since publication\n\nJanuary 2012: minor maintenance.\n\nYour responsibility\n\nThis guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.\n\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.\n\nCopyright\n\n© National Institute for Health and Clinical Excellence 2009. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.\n\nContact NICE\n\nNational Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT\n\nwww.nice.org.uk\n \n nice@nice.org.uk\n 0845 033 7780'}	https://www.nice.org.uk/guidance/ipg327
a4dfc5040c79ebefb33f258541866b7ec1bbe0b8	nice	Suction diathermy adenoidectomy	Suction diathermy adenoidectomy # Guidance Current evidence on the safety and efficacy of suction diathermy adenoidectomy is adequate to support the use of this procedure provided that normal arrangements are in place for clinical governance, consent and audit. This procedure should be carried out only by surgeons with specific training in the use of diathermy for adenoidectomy because thermal damage to surrounding tissues can, rarely, cause Grisel's syndrome (subluxation of the atlantoaxial joint).# The procedure # Indications and current treatments Adenoidectomy is usually carried out in children, for conditions including nasal obstruction, recurrent otitis media with effusion and obstructive sleep apnoea. Depending on the indication, it is often combined with tonsillectomy and/or grommet insertion. Traditional adenoidectomy is carried out by 'cold' curettage. A potential problem with this technique is persistent bleeding, which may require control by electrocautery or packing of the nasopharynx. # Outline of the procedure Suction diathermy adenoidectomy (also known as suction electrocautery or suction coagulation) aims to remove the adenoids while minimising intraoperative blood loss and risk of secondary haemorrhage. It involves the use of heat generated by an electric current to ablate or liquefy adenoid tissue, which is then removed using suction. The procedure is performed with the patient under general anaesthesia. Direct (using a mirror) or endoscopic visualisation is used. A suction diathermy probe (coagulator) is passed into the mouth and applied to the adenoid tissue in the nasopharynx, to liquefy and remove it. The procedure is considered to be complete when the choanae are clearly visible and the nasopharynx has a smooth contour. Several different devices are available for this procedure, which may require different diathermy settings to minimise the risk of heat damage. Sections 2.3 and 2.4 describe efficacy and safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview. # Efficacy A meta-analysis of 2252 patients reported a subjective success rate (definition varied for each study) for 1812 patients treated by suction diathermy across 6 studies of 95% (1721/1812; 95% confidence interval 92.7 to 97.3; p < 0.001). A randomised controlled trial of 100 patients treated by suction diathermy or by curettage reported that suction diathermy-treated patients had significantly fewer Wormald and Prescott grade 3 remnant adenoids than patients treated by curettage at 6-month follow-up (p = 0.0184) (scale ranges from grade 1 to grade 3 ). A prospective audit of 126 patients treated by suction diathermy or by curettage used a scale from 0 (best) to 6 (worst) to measure nasal obstruction, loudness and frequency of snoring, duration of coloured rhinorrhoea and presence of irregular sleep patterns. It reported significantly lower mean postoperative symptom scores after both treatments (0.4 and 0.7, respectively) compared with mean preoperative scores (3.3 and 3.0, respectively) (p < 0.001 for both groups). No significant difference in mean symptom score change from baseline was reported between the 2 treatment groups (absolute figures not stated) (p = 0.07). The Specialist Advisers listed key efficacy outcomes as reduced blood loss (especially important in small children), completeness of adenoidectomy and relief of symptoms (for example, infection and obstructive sleep apnoea). # Safety In the meta-analysis of 2522 patients treated by suction diathermy or curettage, mean intraoperative blood loss was 4.31 ml (95% CI 0.4 to 8.2; p = 0.03; 5 studies, n = 359) and 24.00 ml (95% CI 0 to 48.3; p = 0.052; 3 studies, n = 139), respectively. A non-randomised controlled trial of 149 patients reported no (0/77) postoperative bleeding episodes in patients treated by suction diathermy compared with 10% (7/72) in those treated by curettage (p < 0.001). In the prospective audit of 126 patients, secondary bleeds (defined in the paper as pink-stained nasal discharge) were reported in 4% (3/68) of patients treated by suction diathermy and in 2% (1/58) of those treated by curettage (no intervention required). Postoperative neck stiffness was reported in a non-randomised controlled trial of 276 patients treated by suction diathermy, curettage, or microdebrider adenoidectomy to have occurred in 9% (8/93), 10% (8/84) and 17% (17/99) of patients, respectively (p = 0.08, not stated if 'overall' or pair-wise comparison). Grisel's syndrome was reported in 1 patient in the retrospective study of 1206 patients and 1 patient in a case report. One of these patients had torticollis and type I atlantoaxial subluxation which resolved in 3 weeks and the other patient had a reduced range of neck movement at 9-month follow-up. Retropharyngeal fluid collection resulting in neck stiffness and low-grade fever was reported in 1 patient in the retrospective study of 1206 patients. Cervical osteomyelitis was reported in 1 patient after suction electrocautery, in a case report: this resolved completely after 4 weeks of medical therapy. Velopharyngeal insufficiency (improper closing of the soft palate against the posterior pharyngeal wall during speech and swallowing) was reported in 16 patients in the case series of 1206 patients: this resolved within 6 months in all but 1 patient, in whom it persisted for more than 2 years. The prospective audit reported that 4% (3/68) of patients treated by suction diathermy had transient velopharyngeal insufficiency compared with 7% (4/58) of patients treated by curettage: it resolved in all 7 patients within 2–4 weeks. The Specialist Advisers considered theoretical adverse events to include Grisel's syndrome, thermal damage or burns to the nasopharynx and surrounding structures from diathermy, scarring and infection.# Further information For related NICE guidance see our website. # Information for patients NICE has produced information on this procedure for patients and carers ('Understanding NICE guidance'). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.# About this guidance NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland. This guidance was developed using the NICE interventional procedure guidance process. We have produced a summary of this guidance for patients and carers. Information about the evidence it is based on is also available. Changes since publication January 2012: minor maintenance. Your responsibility This guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer. Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties. Copyright © National Institute for Health and Clinical Excellence 2009. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE. Contact NICE National Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT www.nice.org.uk nice@nice.org.uk	{'Guidance': "Current evidence on the safety and efficacy of suction diathermy adenoidectomy is adequate to support the use of this procedure provided that normal arrangements are in place for clinical governance, consent and audit.\n\nThis procedure should be carried out only by surgeons with specific training in the use of diathermy for adenoidectomy because thermal damage to surrounding tissues can, rarely, cause Grisel's syndrome (subluxation of the atlantoaxial joint).", 'The procedure': "# Indications and current treatments\n\nAdenoidectomy is usually carried out in children, for conditions including nasal obstruction, recurrent otitis media with effusion and obstructive sleep apnoea. Depending on the indication, it is often combined with tonsillectomy and/or grommet insertion.\n\nTraditional adenoidectomy is carried out by 'cold' curettage. A potential problem with this technique is persistent bleeding, which may require control by electrocautery or packing of the nasopharynx.\n\n# Outline of the procedure\n\nSuction diathermy adenoidectomy (also known as suction electrocautery or suction coagulation) aims to remove the adenoids while minimising intraoperative blood loss and risk of secondary haemorrhage. It involves the use of heat generated by an electric current to ablate or liquefy adenoid tissue, which is then removed using suction.\n\nThe procedure is performed with the patient under general anaesthesia. Direct (using a mirror) or endoscopic visualisation is used. A suction diathermy probe (coagulator) is passed into the mouth and applied to the adenoid tissue in the nasopharynx, to liquefy and remove it. The procedure is considered to be complete when the choanae are clearly visible and the nasopharynx has a smooth contour.\n\nSeveral different devices are available for this procedure, which may require different diathermy settings to minimise the risk of heat damage.\n\nSections 2.3 and 2.4 describe efficacy and safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview.\n\n# Efficacy\n\nA meta-analysis of 2252 patients reported a subjective success rate (definition varied for each study) for 1812 patients treated by suction diathermy across 6 studies of 95% (1721/1812; 95% confidence interval [CI] 92.7 to 97.3; p < 0.001).\n\nA randomised controlled trial of 100 patients treated by suction diathermy or by curettage reported that suction diathermy-treated patients had significantly fewer Wormald and Prescott grade 3 remnant adenoids than patients treated by curettage at 6-month follow-up (p = 0.0184) (scale ranges from grade 1 [less than one third of the posterior choanae are obstructed] to grade 3 [more than two thirds of the posterior choanae are obstructed]).\n\nA prospective audit of 126 patients treated by suction diathermy or by curettage used a scale from 0 (best) to 6 (worst) to measure nasal obstruction, loudness and frequency of snoring, duration of coloured rhinorrhoea and presence of irregular sleep patterns. It reported significantly lower mean postoperative symptom scores after both treatments (0.4 and 0.7, respectively) compared with mean preoperative scores (3.3 and 3.0, respectively) (p < 0.001 for both groups). No significant difference in mean symptom score change from baseline was reported between the 2 treatment groups (absolute figures not stated) (p = 0.07).\n\nThe Specialist Advisers listed key efficacy outcomes as reduced blood loss (especially important in small children), completeness of adenoidectomy and relief of symptoms (for example, infection and obstructive sleep apnoea).\n\n# Safety\n\nIn the meta-analysis of 2522 patients treated by suction diathermy or curettage, mean intraoperative blood loss was 4.31 ml (95% CI 0.4 to 8.2; p = 0.03; 5 studies, n = 359) and 24.00 ml (95% CI 0 to 48.3; p = 0.052; 3 studies, n = 139), respectively.\n\nA non-randomised controlled trial of 149 patients reported no (0/77) postoperative bleeding episodes in patients treated by suction diathermy compared with 10% (7/72) in those treated by curettage (p < 0.001). In the prospective audit of 126 patients, secondary bleeds (defined in the paper as pink-stained nasal discharge) were reported in 4% (3/68) of patients treated by suction diathermy and in 2% (1/58) of those treated by curettage (no intervention required).\n\nPostoperative neck stiffness was reported in a non-randomised controlled trial of 276 patients treated by suction diathermy, curettage, or microdebrider adenoidectomy to have occurred in 9% (8/93), 10% (8/84) and 17% (17/99) of patients, respectively (p = 0.08, not stated if 'overall' or pair-wise comparison).\n\nGrisel's syndrome was reported in 1 patient in the retrospective study of 1206 patients and 1 patient in a case report. One of these patients had torticollis and type I atlantoaxial subluxation which resolved in 3 weeks and the other patient had a reduced range of neck movement at 9-month follow-up. Retropharyngeal fluid collection resulting in neck stiffness and low-grade fever was reported in 1 patient in the retrospective study of 1206 patients.\n\nCervical osteomyelitis was reported in 1 patient after suction electrocautery, in a case report: this resolved completely after 4 weeks of medical therapy.\n\nVelopharyngeal insufficiency (improper closing of the soft palate against the posterior pharyngeal wall during speech and swallowing) was reported in 16 patients in the case series of 1206 patients: this resolved within 6 months in all but 1 patient, in whom it persisted for more than 2 years. The prospective audit reported that 4% (3/68) of patients treated by suction diathermy had transient velopharyngeal insufficiency compared with 7% (4/58) of patients treated by curettage: it resolved in all 7 patients within 2–4 weeks.\n\nThe Specialist Advisers considered theoretical adverse events to include Grisel's syndrome, thermal damage or burns to the nasopharynx and surrounding structures from diathermy, scarring and infection.", 'Further information': "For related NICE guidance see our website.\n\n# Information for patients\n\nNICE has produced information on this procedure for patients and carers ('Understanding NICE guidance'). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.", 'About this guidance': 'NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland.\n\nThis guidance was developed using the NICE interventional procedure guidance process.\n\nWe have produced a summary of this guidance for patients and carers. Information about the evidence it is based on is also available.\n\nChanges since publication\n\nJanuary 2012: minor maintenance.\n\nYour responsibility\n\nThis guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.\n\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.\n\nCopyright\n\n© National Institute for Health and Clinical Excellence 2009. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.\n\nContact NICE\n\nNational Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT\n\nwww.nice.org.uk\n \n nice@nice.org.uk\n 0845 033 7780'}	https://www.nice.org.uk/guidance/ipg328
6ab3f48e60b7b8d0c16e88c47b711be0a3264589	nice	Balloon catheter insertion for Bartholin's cyst or abscess	Balloon catheter insertion for Bartholin's cyst or abscess # Guidance Current evidence on the safety and efficacy of balloon catheter insertion for Bartholin's cyst or abscess is adequate to support the use of this procedure provided that normal arrangements are in place for clinical governance, consent and audit.# The procedure # Indications and current treatments Bartholin's glands are located at the vaginal entrance. During sexual arousal, they secrete a lubricant which enters the vagina through a small duct from each gland. A cyst may form if the duct becomes obstructed, and if the cyst becomes infected then an abscess develops. Conservative management of symptomatic cysts or abscesses may include warm baths, compresses, analgesics, and antibiotics when appropriate. Persistent and symptomatic cysts or abscesses are often treated surgically, by incision and drainage, or by marsupialisation (where the cyst is opened, and the skin edges are stitched to allow continual free drainage of the fluid from the cyst cavity). # Outline of the procedure The aim of the procedure is to establish drainage of the abscess or cyst by creating a fistula or sinus track that will remain open in the long term. The underlying principle is that a foreign body reaction (to the balloon and catheter) induces formation of an epithelialised fistula. With the patient under local or general anaesthesia, an incision is made into the abscess or cyst on the mucosal surface of the labia minora. A tissue specimen (biopsy) and/or swab may be taken to test for neoplasia and/or infection (including sexually transmitted diseases). The abscess or cyst is drained. A specially designed balloon catheter is inserted into the abscess or cyst cavity through the incision, and the balloon is inflated with saline to secure it in place. If pain persists after the balloon is inflated, it is partially deflated, leaving enough fluid to keep the catheter in position. A suture may be used to partially close the incision and hold the catheter in place. The catheter stays in, usually for up to 4 weeks, to allow epithelialisation of the tract, after which it is deflated and removed. A period of a few weeks may be required for epithelialisation. Sections 2.3 and 2.4 describe efficacy and safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview. # Efficacy A prospective case series of 35 women with Bartholin's abscess treated by balloon catheter insertion reported operative success (defined as short-term abscess resolution with no need for marsupialisation and no recurrence) in 97% (34/35) of women. The study reported that 89% (24/27) of women who retained the catheter for 4 weeks would recommend the procedure. In the case series of 35 women, catheters were successfully inserted in 34. Of these, 7 fell out: 3 after 24 hours, 3 after 1 week and 1 after 11 days. Despite their catheters falling out, 6 of the 7 women were reported as having successful outcomes. One woman had subsequent marsupialisation. Epithelialisation was judged to have occurred in the remaining 27 women 4 weeks after treatment. A case series of 46 women with Bartholin's cyst or abscess treated by balloon catheter reported recurrence in 17% (8/46) of women, and the procedure was repeated in all patients (the paper did not state whether these repeat procedures were successful or not). Another case series (68 women with Bartholin's cyst or abscess) reported 2 cyst recurrences (without infection) 6 months and 5 years after the procedure. For the first recurrence, it was thought that the catheter was removed prematurely. The Specialist Advisers listed key efficacy outcomes as healing in the short term and absence of abscess recurrence 6 months after the procedure. # Safety The case series of 68 women reported necrotic abscess development in 1 woman because the inflated balloon eroded the cutaneous surface of the labium (time of occurrence not stated). This was considered to have been caused by improper insertion of the catheter. The same case series reported that another woman was admitted to hospital for 9 days because the catheter had been inserted between the vestibular mucosa and the cyst wall. The cyst remained 1 year after the operation. The case series of 35 women reported that 5 women complained of mild discomfort (scoring 2–3 on a pain scale from 0 to 10 ) on sitting at 1-week follow-up. One woman reported moderate discomfort (scoring 5 on the same scale) and a continuous sensation of labial swelling, which subsided when 2 ml of fluid was removed from the balloon (time of occurrence not stated). The Specialist Advisers listed an anecdotal adverse event as pain if the catheter is overfilled, which could be relieved by slightly deflating it. They considered theoretical adverse events to include infection, abscess recurrence, bleeding, pain from having the catheter in situ, scarring, expulsion of the bulb of the catheter and dyspareunia.# Further information # Information for patients NICE has produced information on this procedure for patients and carers ('Understanding NICE guidance'). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.# About this guidance NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland. This guidance was developed using the NICE interventional procedure guidance process. We have produced a summary of this guidance for patients and carers. Information about the evidence it is based on is also available. Changes since publication January 2012: minor maintenance. Your responsibility This guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer. Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties. Copyright © National Institute for Health and Clinical Excellence 2009. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE. Contact NICE National Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT www.nice.org.uk nice@nice.org.uk	{'Guidance': "Current evidence on the safety and efficacy of balloon catheter insertion for Bartholin's cyst or abscess is adequate to support the use of this procedure provided that normal arrangements are in place for clinical governance, consent and audit.", 'The procedure': "# Indications and current treatments\n\nBartholin's glands are located at the vaginal entrance. During sexual arousal, they secrete a lubricant which enters the vagina through a small duct from each gland. A cyst may form if the duct becomes obstructed, and if the cyst becomes infected then an abscess develops.\n\nConservative management of symptomatic cysts or abscesses may include warm baths, compresses, analgesics, and antibiotics when appropriate. Persistent and symptomatic cysts or abscesses are often treated surgically, by incision and drainage, or by marsupialisation (where the cyst is opened, and the skin edges are stitched to allow continual free drainage of the fluid from the cyst cavity).\n\n# Outline of the procedure\n\nThe aim of the procedure is to establish drainage of the abscess or cyst by creating a fistula or sinus track that will remain open in the long term. The underlying principle is that a foreign body reaction (to the balloon and catheter) induces formation of an epithelialised fistula.\n\nWith the patient under local or general anaesthesia, an incision is made into the abscess or cyst on the mucosal surface of the labia minora. A tissue specimen (biopsy) and/or swab may be taken to test for neoplasia and/or infection (including sexually transmitted diseases). The abscess or cyst is drained.\n\nA specially designed balloon catheter is inserted into the abscess or cyst cavity through the incision, and the balloon is inflated with saline to secure it in place. If pain persists after the balloon is inflated, it is partially deflated, leaving enough fluid to keep the catheter in position. A suture may be used to partially close the incision and hold the catheter in place. The catheter stays in, usually for up to 4 weeks, to allow epithelialisation of the tract, after which it is deflated and removed.\n\nA period of a few weeks may be required for epithelialisation.\n\nSections 2.3 and 2.4 describe efficacy and safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview.\n\n# Efficacy\n\nA prospective case series of 35 women with Bartholin's abscess treated by balloon catheter insertion reported operative success (defined as short-term abscess resolution with no need for marsupialisation and no recurrence) in 97% (34/35) of women. The study reported that 89% (24/27) of women who retained the catheter for 4 weeks would recommend the procedure.\n\nIn the case series of 35 women, catheters were successfully inserted in 34. Of these, 7 fell out: 3 after 24 hours, 3 after 1 week and 1 after 11 days. Despite their catheters falling out, 6 of the 7 women were reported as having successful outcomes. One woman had subsequent marsupialisation. Epithelialisation was judged to have occurred in the remaining 27 women 4 weeks after treatment.\n\nA case series of 46 women with Bartholin's cyst or abscess treated by balloon catheter reported recurrence in 17% (8/46) of women, and the procedure was repeated in all patients (the paper did not state whether these repeat procedures were successful or not). Another case series (68 women with Bartholin's cyst or abscess) reported 2 cyst recurrences (without infection) 6 months and 5 years after the procedure. For the first recurrence, it was thought that the catheter was removed prematurely.\n\nThe Specialist Advisers listed key efficacy outcomes as healing in the short term and absence of abscess recurrence 6 months after the procedure.\n\n# Safety\n\nThe case series of 68 women reported necrotic abscess development in 1 woman because the inflated balloon eroded the cutaneous surface of the labium (time of occurrence not stated). This was considered to have been caused by improper insertion of the catheter. The same case series reported that another woman was admitted to hospital for 9 days because the catheter had been inserted between the vestibular mucosa and the cyst wall. The cyst remained 1 year after the operation.\n\nThe case series of 35 women reported that 5 women complained of mild discomfort (scoring 2–3 on a pain scale from 0 [no pain] to 10 [severe pain]) on sitting at 1-week follow-up. One woman reported moderate discomfort (scoring 5 on the same scale) and a continuous sensation of labial swelling, which subsided when 2 ml of fluid was removed from the balloon (time of occurrence not stated).\n\nThe Specialist Advisers listed an anecdotal adverse event as pain if the catheter is overfilled, which could be relieved by slightly deflating it. They considered theoretical adverse events to include infection, abscess recurrence, bleeding, pain from having the catheter in situ, scarring, expulsion of the bulb of the catheter and dyspareunia.", 'Further information': "# Information for patients\n\nNICE has produced information on this procedure for patients and carers ('Understanding NICE guidance'). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.", 'About this guidance': 'NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland.\n\nThis guidance was developed using the NICE interventional procedure guidance process.\n\nWe have produced a summary of this guidance for patients and carers. Information about the evidence it is based on is also available.\n\nChanges since publication\n\nJanuary 2012: minor maintenance.\n\nYour responsibility\n\nThis guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.\n\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.\n\nCopyright\n\n© National Institute for Health and Clinical Excellence 2009. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.\n\nContact NICE\n\nNational Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT\n\nwww.nice.org.uk\n \n nice@nice.org.uk\n 0845 033 7780'}	https://www.nice.org.uk/guidance/ipg323
3d924981ec2b536fdd05572ba4fee44cfcd759fe	nice	Electrocautery cutting balloon treatment for pelviureteric junction obstruction	Electrocautery cutting balloon treatment for pelviureteric junction obstruction # Guidance Current evidence on the efficacy of electrocauterycutting balloon treatment for pelviureteric junction(PUJ) obstruction is limited in quantity. Theevidence on safety raises concern about the risk ofbleeding. Therefore this procedure should only beused with special arrangements for clinicalgovernance, consent and audit or research. Clinicians wishing to undertake electrocauterycutting balloon treatment for PUJ obstructionshould take the following actions. Inform the clinical governance leads intheir Trusts. Ensure that patients and their parents/carersunderstand that there is a risk of bleeding as aresult of the procedure, and a risk ofobstruction recurrence in the longer term, andprovide them with clear written information. Inaddition, the use of NICE's information for patients ('Understanding NICE guidance') isrecommended. Audit and review clinical outcomes of allpatients having electrocautery cutting balloontreatment for PUJ obstruction (see section 3.1). Patient selection and treatment should be carried out only in units that can offer a range of procedures including laparoscopic pyeloplasty.# The procedure # Indications and current treatments Pelviureteric junction obstruction is a congenital or acquired stenosis of the junction between the renal pelvis and the ureter, which inhibits normal urine flow. It can cause chronic or recurrent flank pain as well as urinary tract infections. Conservative treatment may include long-term use of low-dose antibiotics. Current surgical options to reconstruct and normalise the anatomy of the PUJ include open or laparoscopic pyeloplasty (with or without robotic assistance) and endopyelotomy. # Outline of the procedure The aim of the procedure is to widen the abnormally narrowed part of the PUJ. With the patient under general anaesthesia and using fluoroscopic guidance, a device containing a monopolar diathermy wire on the surface of a low-pressure tamponade balloon is inserted through the ureter and into the PUJ. The balloon is partially inflated to determine the area of stenosis (seen as a waist in the balloon) and to fix it in position for incision. The diathermy wire incises the target area of the PUJ, through the wall of the ureter, into the periureteric fat. The balloon is fully inflated to apply pressure (tamponade) following incision to promote haemostasis. A stent is inserted across the PUJ, with the aim of maintaining patency, and is removed after several weeks. Sections 2.3 and 2.4 describe efficacy and safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview. # Efficacy A randomised controlled trial (RCT) of 40 patients treated by electrocautery cutting balloon versus laser endopyelotomy reported a 'successful outcome' (defined as subjective relief or symptom improvement plus objective relief of obstruction and improvement in glomerular filtration rate) in 65% (13/20) and 85% (17/20) of patients respectively at a mean follow-up of 30 months (p = 0.14). A non-randomised controlled trial of 64 patients reported no significant difference in success rate (defined as relief of symptoms, decreased caliectasis, and diuretic renography half-time values indicating absence of obstruction) between patients treated by electrocautery cutting balloon (78% ) and those treated by laser endopyelotomy (74% ) at a mean follow-up of 76 months. A non-randomised controlled trial of 149 patients reported 'subjective success' (defined as a 50% improvement in preoperative discomfort) in 85% of 52 patients with primary PUJ obstruction treated by electrocautery cutting balloon and 90% of 40 patients treated by antegrade electrode ablation endopyelotomy at a mean follow-up of 16 months (absolute numbers and significance not stated). The non-randomised controlled trial of 64 patients reported no significant difference in reoperation rates following electrocautery cutting balloon treatment (6% ), antegrade endopyelotomy (0% ) or retrograde cold knife endopyelotomy (17% ) (p = 0.13) (mean follow-up 67 months). The Specialist Advisers listed key efficacy outcomes as short-term pain relief, resolution of obstruction on imaging and no obstruction recurrence in the long term. # Safety Bleeding requiring transfusion and embolisation of a lower-pole vessel was reported in 7% (2/27) of patients in the electrocautery cutting balloon group compared with 0% (0/37) of patients in the laser endopyelotomy treatment group in the non-randomised controlled trial of 64 patients (p = 0.13). Ureteral bleeding requiring transfusion was reported in 4% (3/76) of patients in a case series of 76 patients treated by electrocautery cutting balloon for PUJ obstruction; embolisation of a lower-pole artery was required in 2 patients. Haematuria (managed conservatively) was reported in 15% (3/20) of patients treated by electrocautery cutting balloon at follow-ups ranging from 2 to 5 days in the RCT of 40 patients. A case report of 2 patients described 1 patient with a large perirenal haematoma caused by incision of an aberrant renal artery during electrocautery cutting balloon treatment, which was ligated at open surgery, and 1 patient who developed a pseudoaneurysm of an aberrant lower-pole artery, which was embolised. One case report described a broken cutting balloon wire in the PUJ, which had become calcified and required ureteroscopically-guided laser ablation. Balloon rupture was reported in 1 patient in the RCT of 40 patients. The Specialist Advisers listed adverse events as infection and need for transfusion. # Other comments The Committee was advised that electrocautery cutting balloon treatment for PUJ obstruction is used infrequently because of the increased use of laparoscopic pyeloplasty, but that it may have a particular role in the management of obstruction recurrence.# Further information This guidance requires that clinicians undertaking the procedure make special arrangements for audit. NICE has identified relevant audit criteria and has developed audit support (which is for use at local discretion). For related NICE guidance see our website. # Information for patients NICE has produced information on this procedure for patients and carers ('Understanding NICE guidance'). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.# About this guidance NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland. This guidance was developed using the NICE interventional procedure guidance process. We have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available. Changes since publication January 2012: minor maintenance. Your responsibility This guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer. Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties. Copyright © National Institute for Health and Clinical Excellence 2009. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE. Contact NICE National Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT www.nice.org.uk nice@nice.org.uk	{'Guidance': "Current evidence on the efficacy of electrocauterycutting balloon treatment for pelviureteric junction(PUJ) obstruction is limited in quantity. Theevidence on safety raises concern about the risk ofbleeding. Therefore this procedure should only beused with special arrangements for clinicalgovernance, consent and audit or research.\n\nClinicians wishing to undertake electrocauterycutting balloon treatment for PUJ obstructionshould take the following actions.\n\nInform the clinical governance leads intheir Trusts.\n\nEnsure that patients and their parents/carersunderstand that there is a risk of bleeding as aresult of the procedure, and a risk ofobstruction recurrence in the longer term, andprovide them with clear written information. Inaddition, the use of NICE's information for patients ('Understanding NICE guidance') isrecommended.\n\nAudit and review clinical outcomes of allpatients having electrocautery cutting balloontreatment for PUJ obstruction (see section 3.1).\n\nPatient selection and treatment should be carried out only in units that can offer a range of procedures including laparoscopic pyeloplasty.", 'The procedure': "# Indications and current treatments\n\nPelviureteric junction obstruction is a congenital or acquired stenosis of the junction between the renal pelvis and the ureter, which inhibits normal urine flow. It can cause chronic or recurrent flank pain as well as urinary tract infections.\n\nConservative treatment may include long-term use of low-dose antibiotics. Current surgical options to reconstruct and normalise the anatomy of the PUJ include open or laparoscopic pyeloplasty (with or without robotic assistance) and endopyelotomy.\n\n# Outline of the procedure\n\nThe aim of the procedure is to widen the abnormally narrowed part of the PUJ. With the patient under general anaesthesia and using fluoroscopic guidance, a device containing a monopolar diathermy wire on the surface of a low-pressure tamponade balloon is inserted through the ureter and into the PUJ. The balloon is partially inflated to determine the area of stenosis (seen as a waist in the balloon) and to fix it in position for incision. The diathermy wire incises the target area of the PUJ, through the wall of the ureter, into the periureteric fat. The balloon is fully inflated to apply pressure (tamponade) following incision to promote haemostasis. A stent is inserted across the PUJ, with the aim of maintaining patency, and is removed after several weeks.\n\nSections 2.3 and 2.4 describe efficacy and safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview.\n\n# Efficacy\n\nA randomised controlled trial (RCT) of 40 patients treated by electrocautery cutting balloon versus laser endopyelotomy reported a 'successful outcome' (defined as subjective relief or symptom improvement plus objective relief of obstruction and improvement in glomerular filtration rate) in 65% (13/20) and 85% (17/20) of patients respectively at a mean follow-up of 30 months (p = 0.14).\n\nA non-randomised controlled trial of 64 patients reported no significant difference in success rate (defined as relief of symptoms, decreased caliectasis, and diuretic renography half-time values indicating absence of obstruction) between patients treated by electrocautery cutting balloon (78% [21/27]) and those treated by laser endopyelotomy (74% [26/35]) at a mean follow-up of 76 months.\n\nA non-randomised controlled trial of 149 patients reported 'subjective success' (defined as a 50% improvement in preoperative discomfort) in 85% of 52 patients with primary PUJ obstruction treated by electrocautery cutting balloon and 90% of 40 patients treated by antegrade electrode ablation endopyelotomy at a mean follow-up of 16 months (absolute numbers and significance not stated).\n\nThe non-randomised controlled trial of 64 patients reported no significant difference in reoperation rates following electrocautery cutting balloon treatment (6% [1/17]), antegrade endopyelotomy (0% [0/18]) or retrograde cold knife endopyelotomy (17% [5/29]) (p = 0.13) (mean follow-up 67 months).\n\nThe Specialist Advisers listed key efficacy outcomes as short-term pain relief, resolution of obstruction on imaging and no obstruction recurrence in the long term.\n\n# Safety\n\nBleeding requiring transfusion and embolisation of a lower-pole vessel was reported in 7% (2/27) of patients in the electrocautery cutting balloon group compared with 0% (0/37) of patients in the laser endopyelotomy treatment group in the non-randomised controlled trial of 64 patients (p = 0.13). Ureteral bleeding requiring transfusion was reported in 4% (3/76) of patients in a case series of 76 patients treated by electrocautery cutting balloon for PUJ obstruction; embolisation of a lower-pole artery was required in 2 patients. Haematuria (managed conservatively) was reported in 15% (3/20) of patients treated by electrocautery cutting balloon at follow-ups ranging from 2 to 5 days in the RCT of 40 patients.\n\nA case report of 2 patients described 1 patient with a large perirenal haematoma caused by incision of an aberrant renal artery during electrocautery cutting balloon treatment, which was ligated at open surgery, and 1 patient who developed a pseudoaneurysm of an aberrant lower-pole artery, which was embolised.\n\nOne case report described a broken cutting balloon wire in the PUJ, which had become calcified and required ureteroscopically-guided laser ablation. Balloon rupture was reported in 1 patient in the RCT of 40 patients.\n\nThe Specialist Advisers listed adverse events as infection and need for transfusion.\n\n# Other comments\n\nThe Committee was advised that electrocautery cutting balloon treatment for PUJ obstruction is used infrequently because of the increased use of laparoscopic pyeloplasty, but that it may have a particular role in the management of obstruction recurrence.", 'Further information': "This guidance requires that clinicians undertaking the procedure make special arrangements for audit. NICE has identified relevant audit criteria and has developed audit support (which is for use at local discretion).\n\nFor related NICE guidance see our website.\n\n# Information for patients\n\nNICE has produced information on this procedure for patients and carers ('Understanding NICE guidance'). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.", 'About this guidance': 'NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland.\n\nThis guidance was developed using the NICE interventional procedure guidance process.\n\nWe have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available.\n\nChanges since publication\n\nJanuary 2012: minor maintenance.\n\nYour responsibility\n\nThis guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.\n\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.\n\nCopyright\n\n© National Institute for Health and Clinical Excellence 2009. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.\n\nContact NICE\n\nNational Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT\n\nwww.nice.org.uk\n \n nice@nice.org.uk\n 0845 033 7780'}	https://www.nice.org.uk/guidance/ipg324
2ac2397c862cd631e4354f5d732fc7c389785387	nice	Endopyelotomy for pelviureteric junction obstruction	Endopyelotomy for pelviureteric junction obstruction # Guidance Current evidence shows that endopyelotomy for pelviureteric junction (PUJ) obstruction is efficacious in the short and medium term although there is a risk of obstruction recurrence in the long term. The evidence on safety raises no major concerns. Therefore this procedure may be used provided that normal arrangements are in place for clinical governance, consent and audit. This procedure should be carried out only in units with specific expertise in endopyelotomy for PUJ obstruction, by specialist teams who can offer a range of procedures including laparoscopic pyeloplasty.# The procedure # Indications and current treatments Pelviureteric junction obstruction is a congenital or acquired stenosis of the junction between the renal pelvis and the ureter, which inhibits normal urine flow. It can cause chronic or recurrent flank pain as well as urinary tract infections. Conservative treatment may include long-term use of low-dose antibiotics. Current surgical options to reconstruct and normalise the anatomy of the PUJ include open or laparoscopic pyeloplasty (with or without robotic assistance) and electrocautery cutting balloon treatment. # Outline of the procedure The aim of the procedure is to widen the abnormally narrowed part of the PUJ. With the patient under general anaesthesia, a cutting device (which may be a laser or a diathermy probe, or an endoscopic knife) is inserted into the PUJ area endoscopically via the ureter, or via a percutaneous approach in the flank. Under endoscopic visualisation a full-thickness incision is made, through the wall of the ureter, into the periureteric fat. A stent is inserted across the PUJ, with the aim of maintaining patency, and is removed after several weeks. Sections 2.3 and 2.4 describe efficacy and safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview. # Efficacy A randomised controlled trial (RCT) of 40 patients treated by laser endopyelotomy versus electrocautery cutting balloon reported a successful outcome (defined as subjective relief or symptom improvement, plus objective relief of obstruction and improvement in glomerular filtration rate) in 85% (17/20) and 65% (13/20) of patients respectively at a mean follow-up of 30 months (p = 0.14). There was no significant difference between the treatment groups in the success rates for patients with primary or secondary PUJ obstruction (p = 0.38 and p = 0.26 respectively). A non-randomised controlled trial of 436 patients reported that success (defined as complete symptomatic relief plus resolution or improvement in obstruction on imaging) was achieved in 61% (111/182) of endopyelotomy-treated patients and 82% (144/175) of pyeloplasty-treated patients at a mean follow-up of 3.5 years (significance not stated). A non-randomised controlled trial of 273 patients reported that success (defined as symptom resolution plus improvement or stability of radiographic parameters) was achieved in 60% of patients in the endopyelotomy group, 89% of the laparoscopic pyeloplasty group, and 100% of the robotically assisted pyeloplasty group at a mean follow-up of 20 months (absolute numbers and significance not stated). Multivariate analysis (excluding the robotically assisted group) showed that endopyelotomy (compared with laparoscopic pyeloplasty) was an independent predictor of treatment failure (hazard ratio 3.16; 95% confidence interval 1.70 to 5.86, p < 0.001). In the non-randomised controlled trial of 436 patients, the 10-year estimated recurrence-free survival was 41% (n = 8) in the endopyelotomy group and 75% (n = 21) in the pyeloplasty group (absolute figures not stated). The Specialist Advisers listed key efficacy outcomes as short-term pain relief, resolution of symptoms and normalisation of renographic obstruction, preservation of renal function and no obstruction recurrence in the long term. # Safety The RCT of 40 patients treated by laser endopyelotomy versus electrocautery cutting balloon reported no significant difference in the rate of overall complications (not otherwise defined) between treatment groups (10% and 25% respectively; p = 0.20) (mean follow-up 30-months). The non-randomised controlled trial of 436 patients reported that the rate of overall complications was not significantly different between the endopyelotomy (11% ) and the pyeloplasty groups (8% ) (p = 0.33) at a mean follow-up of 3.5 years. Bleeding requiring transfusion occurred in 1% (3/225) of patients in the endopyelotomy group and 1% (2/211) of patients in the pyeloplasty group in the non-randomised controlled trial of 436 patients (significance not stated). Haemorrhage requiring electrocoagulation occurred in 1% (4/320) and haemorrhage requiring transfusion in 1% (2/212) of patients (1 patient required further intervention ) in case series of 320 and 212 patients, respectively. Ureteral avulsion requiring an open procedure was reported in 1 of 212 patients in a case series. One case report described a patient who developed renal atrophy, renal hypertension, perinephric fibrosis and calcification, vena caval stenosis and renal vein obstruction after endopyelotomy: the patient needed a nephrectomy 8 years later. The primary event was thought to have been development of a subcapsular haematoma after endopyelotomy. A second case report described ureteral intussusception following endopyelotomy at 3-month follow-up, treated by pyeloplasty reconstruction (not otherwise described). Reoperation (repeat endopyelotomy, open pyeloplasty or nephrectomy) was required in 10% (33/320) of patients in the case series of 320 patients. In the case series of 212 patients, repeat endopyelotomy was required in less than 1% (1/212), secondary intervention by pyeloplasty in 8% (18/212), ureterocalicostomy in 2% (4/212), and ileal interposition in 1 patient. The Specialist Advisers listed adverse events as haemorrhage, stent-related problems and aorto-ureteral fistula. They considered theoretical adverse events to include failure/obstruction recurrence, infection, perforation and fibrosis. # Other comments The Committee was advised that endopyelotomy for PUJ obstruction is used less frequently than in the past because of the increased use of laparoscopic pyeloplasty, but that it may have a particular role in the management of obstruction recurrence.# Further information For related NICE guidance see our website. # Information for patients NICE has produced information on this procedure for patients and carers ('Understanding NICE guidance'). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.# About this guidance NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland. This guidance was developed using the NICE interventional procedure guidance process. We have produced a summary of this guidance for patients and carers. Information about the evidence it is based on is also available. Changes since publication January 2012: minor maintenance Your responsibility This guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer. Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties. Copyright © National Institute for Health and Clinical Excellence 2009. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE. Contact NICE National Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT www.nice.org.uk nice@nice.org.uk	{'Guidance': 'Current evidence shows that endopyelotomy for pelviureteric junction (PUJ) obstruction is efficacious in the short and medium term although there is a risk of obstruction recurrence in the long term. The evidence on safety raises no major concerns. Therefore this procedure may be used provided that normal arrangements are in place for clinical governance, consent and audit.\n\nThis procedure should be carried out only in units with specific expertise in endopyelotomy for PUJ obstruction, by specialist teams who can offer a range of procedures including laparoscopic pyeloplasty.', 'The procedure': '# Indications and current treatments\n\nPelviureteric junction obstruction is a congenital or acquired stenosis of the junction between the renal pelvis and the ureter, which inhibits normal urine flow. It can cause chronic or recurrent flank pain as well as urinary tract infections.\n\nConservative treatment may include long-term use of low-dose antibiotics. Current surgical options to reconstruct and normalise the anatomy of the PUJ include open or laparoscopic pyeloplasty (with or without robotic assistance) and electrocautery cutting balloon treatment.\n\n# Outline of the procedure\n\nThe aim of the procedure is to widen the abnormally narrowed part of the PUJ. With the patient under general anaesthesia, a cutting device (which may be a laser or a diathermy probe, or an endoscopic knife) is inserted into the PUJ area endoscopically via the ureter, or via a percutaneous approach in the flank. Under endoscopic visualisation a full-thickness incision is made, through the wall of the ureter, into the periureteric fat. A stent is inserted across the PUJ, with the aim of maintaining patency, and is removed after several weeks.\n\nSections 2.3 and 2.4 describe efficacy and safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview.\n\n# Efficacy\n\nA randomised controlled trial (RCT) of 40 patients treated by laser endopyelotomy versus electrocautery cutting balloon reported a successful outcome (defined as subjective relief or symptom improvement, plus objective relief of obstruction and improvement in glomerular filtration rate) in 85% (17/20) and 65% (13/20) of patients respectively at a mean follow-up of 30 months (p = 0.14). There was no significant difference between the treatment groups in the success rates for patients with primary or secondary PUJ obstruction (p = 0.38 and p = 0.26 respectively).\n\nA non-randomised controlled trial of 436 patients reported that success (defined as complete symptomatic relief plus resolution or improvement in obstruction on imaging) was achieved in 61% (111/182) of endopyelotomy-treated patients and 82% (144/175) of pyeloplasty-treated patients at a mean follow-up of 3.5 years (significance not stated).\n\nA non-randomised controlled trial of 273 patients reported that success (defined as symptom resolution plus improvement or stability of radiographic parameters) was achieved in 60% of patients in the endopyelotomy group, 89% of the laparoscopic pyeloplasty group, and 100% of the robotically assisted pyeloplasty group at a mean follow-up of 20 months (absolute numbers and significance not stated). Multivariate analysis (excluding the robotically assisted group) showed that endopyelotomy (compared with laparoscopic pyeloplasty) was an independent predictor of treatment failure (hazard ratio 3.16; 95% confidence interval 1.70 to 5.86, p < 0.001).\n\nIn the non-randomised controlled trial of 436 patients, the 10-year estimated recurrence-free survival was 41% (n = 8) in the endopyelotomy group and 75% (n = 21) in the pyeloplasty group (absolute figures not stated).\n\nThe Specialist Advisers listed key efficacy outcomes as short-term pain relief, resolution of symptoms and normalisation of renographic obstruction, preservation of renal function and no obstruction recurrence in the long term.\n\n# Safety\n\nThe RCT of 40 patients treated by laser endopyelotomy versus electrocautery cutting balloon reported no significant difference in the rate of overall complications (not otherwise defined) between treatment groups (10% [2/20] and 25% [5/20] respectively; p = 0.20) (mean follow-up 30-months). The non-randomised controlled trial of 436 patients reported that the rate of overall complications was not significantly different between the endopyelotomy (11% [25/225]) and the pyeloplasty groups (8% [17/211]) (p = 0.33) at a mean follow-up of 3.5 years.\n\nBleeding requiring transfusion occurred in 1% (3/225) of patients in the endopyelotomy group and 1% (2/211) of patients in the pyeloplasty group in the non-randomised controlled trial of 436 patients (significance not stated). Haemorrhage requiring electrocoagulation occurred in 1% (4/320) and haemorrhage requiring transfusion in 1% (2/212) of patients (1 patient required further intervention [not otherwise stated]) in case series of 320 and 212 patients, respectively.\n\nUreteral avulsion requiring an open procedure was reported in 1 of 212 patients in a case series.\n\nOne case report described a patient who developed renal atrophy, renal hypertension, perinephric fibrosis and calcification, vena caval stenosis and renal vein obstruction after endopyelotomy: the patient needed a nephrectomy 8 years later. The primary event was thought to have been development of a subcapsular haematoma after endopyelotomy. A second case report described ureteral intussusception following endopyelotomy at 3-month follow-up, treated by pyeloplasty reconstruction (not otherwise described).\n\nReoperation (repeat endopyelotomy, open pyeloplasty or nephrectomy) was required in 10% (33/320) of patients in the case series of 320 patients. In the case series of 212 patients, repeat endopyelotomy was required in less than 1% (1/212), secondary intervention by pyeloplasty in 8% (18/212), ureterocalicostomy in 2% (4/212), and ileal interposition in 1 patient.\n\nThe Specialist Advisers listed adverse events as haemorrhage, stent-related problems and aorto-ureteral fistula. They considered theoretical adverse events to include failure/obstruction recurrence, infection, perforation and fibrosis.\n\n# Other comments\n\nThe Committee was advised that endopyelotomy for PUJ obstruction is used less frequently than in the past because of the increased use of laparoscopic pyeloplasty, but that it may have a particular role in the management of obstruction recurrence.', 'Further information': "For related NICE guidance see our website.\n\n# Information for patients\n\nNICE has produced information on this procedure for patients and carers ('Understanding NICE guidance'). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.", 'About this guidance': 'NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland.\n\nThis guidance was developed using the NICE interventional procedure guidance process.\n\nWe have produced a summary of this guidance for patients and carers. Information about the evidence it is based on is also available.\n\nChanges since publication\n\nJanuary 2012: minor maintenance\n\nYour responsibility\n\nThis guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.\n\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.\n\nCopyright\n\n© National Institute for Health and Clinical Excellence 2009. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.\n\nContact NICE\n\nNational Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT\n\nwww.nice.org.uk\n \n nice@nice.org.uk\n 0845 033 7780'}	https://www.nice.org.uk/guidance/ipg325
30f92087718000e25483679344d0dc2b64e33ac9	nice	Topotecan for the treatment of relapsed small-cell lung cancer	Topotecan for the treatment of relapsed small-cell lung cancer Evidence-based recommendations on topotecan for treating relapsed small-cell cancer in adults. # Guidance Oral topotecan is recommended as an option only for people with relapsed small-cell lung cancer for whom: re-treatment with the first-line regimen is not considered appropriate and the combination of cyclophosphamide, doxorubicin and vincristine (CAV) is contraindicated (for details of the contraindications to CAV see the summary of product characteristics for each of the component drugs). Intravenous topotecan is not recommended for people with relapsed small-cell lung cancer. People with relapsed small-cell lung cancer currently receiving oral topotecan who do not meet the criteria specified in 1.1, or who are receiving intravenous topotecan should have the option to continue their treatment until they and their clinicians consider it appropriate to stop.# Clinical need and practice Lung cancer can be categorised into four major cell types: small-cell lung cancer, squamous-cell carcinoma, adenocarcinoma and large-cell carcinoma. The last three types are usually described as non-small-cell lung cancer. Small-cell lung cancer grows rapidly and spreads quickly to distant sites (metastasises). It is classified using a two-stage system. The first is limited-stage disease, in which the disease is generally confined to one side of the chest or to the neck lymph nodes. The second is extensive-stage disease, in which the disease has spread outside one side of the chest and there are systemic metastases. The 'tumour node metastases' stage scores are not usually relevant in small-cell lung cancer because of the high proportion of patients presenting with metastases and the poor prognosis associated with the disease. Lung cancer is one of the most common cancers in England and accounted for 15% of cancers in men and 11% of cancers in women in 2005. In England and Wales there were 33,181 new cases of lung cancer in 2005. The disease accounts for around 33,000 deaths per year. It is estimated that small-cell lung cancer makes up about 10–20% of the total cases of lung cancer, but this percentage is falling. The reasons for this are unclear, but changing smoking habits and a reduction in the tar content of cigarettes may be involved. At diagnosis, about 33% of people with small-cell lung cancer have limited-stage disease, but the majority of people have extensive-stage disease. In most patients the disease is symptomatic on presentation. In some patients there are non-specific symptoms such as fatigue, loss of appetite and weight loss, while in others there are more direct symptoms such as breathlessness, chest discomfort and haemoptysis (blood-stained sputum). The risk factors for lung cancer include smoking, passive smoking, occupational exposure to asbestos, radon, chromium or nickel, male gender and chronic lung disease. Smoking is the leading cause of lung cancer, accounting for approximately 80–90% of cases. Smoking has been shown to be much more strongly linked to small-cell lung cancer than non-small-cell lung cancer. The prognosis for people with small-cell lung cancer is poor. Without treatment, it has an aggressive clinical course with a life expectancy of approximately 3.5 months for limited-stage disease and 6 weeks for extensive-stage disease. The median survival with treatment is approximately 14–18 months for limited-stage disease and 9–12 months for extensive-stage disease. Approximately 20–40% of patients with limited-stage disease and less than 5% of patients with extensive-stage disease survive for 2 years. Survivors often continue to relapse up to, and occasionally after, 5 years. Prognosis has been linked to performance status and the extent of the disease. Selection of the most appropriate first-line treatment for small-cell lung cancer is determined primarily by the performance status of the patient and the stage of the disease. Current management of small-cell lung cancer usually consists of combination chemotherapy regimens. Radiotherapy may be given concurrently with chemotherapy or as part of palliative care. Surgery is not appropriate for the majority of patients because the disease is often widespread at the time of diagnosis. For further guidance on the management of small-cell lung cancer, see 'Lung cancer: the diagnosis and treatment of lung cancer' (NICE clinical guideline 24) .# The technology Topotecan (Hycamtin, GlaxoSmithKline) acts by inhibiting topoisomerase I, an enzyme that is required for DNA replication, leading to cell death. Topotecan is indicated as monotherapy for patients with relapsed small-cell lung cancer for whom re-treatment with the first-line regimen is not considered appropriate. The marketing authorisation for this indication was granted by the European Medicines Agency (EMEA) in 2006 for intravenous therapy, and an extension to the marketing authorisation was granted in 2008 for oral capsules. Adverse effects commonly associated with topotecan include nausea, vomiting, neutropenia, leukopenia, anaemia, fatigue and alopecia. Topotecan is not recommended in patients with severe renal or hepatic impairment. For full details of adverse effects and contraindications, see the summary of product characteristics. The acquisition cost for intravenous topotecan is £97.65 for a 1-mg vial or £290.62 for a 4-mg vial and for oral topotecan is £30 per 1 mg capsule (excluding VAT, 'British national formulary' edition 58). The recommended dose of intravenous topotecan is 1.5 mg/m2 body surface area on 5 consecutive days with a 21-day interval between the start of each course. Oral topotecan is administered at 2.3 mg/m2 on 5 consecutive days with a 21-day interval between the start of each course. Assuming a body surface area of 1.8 m2, the cost per cycle is £1495 for intravenous topotecan and £638 for oral topotecan. Patients in the key clinical trials received intravenous topotecan and oral topotecan for approximately 4 cycles, equating to an average treatment cost per patient of £5980 for intravenous topotecan and £2552 for oral topotecan. Costs may vary in different settings because of negotiated procurement discounts.# Evidence and interpretation The Appraisal Committee (appendix A) considered evidence from a number of sources (appendix B). # Clinical effectiveness The Assessment Group reviewed the clinical effectiveness of topotecan (oral and intravenous) compared with best supportive care or other chemotherapy regimens for the treatment of relapsed small-cell lung cancer. Five randomised controlled trials (RCTs) met the inclusion criteria of the review. The reporting and methodological quality was judged to be good in two trials and unknown in three trials. The RCTs differed in design and recruited different study populations for topotecan and the relevant comparators. Therefore the Assessment Group considered that it was not appropriate to pool the results. ## Oral topotecan compared with best supportive care One trial compared oral topotecan plus best supportive care with best supportive care alone as a treatment for patients with limited- or extensive-stage relapsed small-cell lung cancer for whom further intravenous chemotherapy was considered unsuitable (n = 141). The primary outcome was overall survival. Quality of life was also measured using the EQ-5D. The median overall survival for patients receiving oral topotecan was 25.9 weeks (95% confidence interval 18.3 to 31.6) compared with 13.9 weeks (95% CI 11.1 to 18.6) for patients receiving best supportive care alone. The hazard ratio (using Kaplan–Meier analysis) for overall survival was 0.64 (95% CI 0.45 to 0.90) in favour of topotecan plus best supportive care. EQ-5D data were recorded for each patient in the trial at the start of each cycle (21-day period) up to cycle 12. Individual patient data were available for 600 (39%) 21-day survival periods. The rate of deterioration in the EQ-5D score per 3-month period was −0.05 (95% CI −0.11 to 0.02) for patients receiving oral topotecan plus best supportive care compared with −0.20 (95% CI −0.27 to −0.12) for best supportive care alone. The mean change in EQ-5D score from baseline to the averaged on-treatment assessment (pooled analysis) and the mean change from baseline to the last evaluation showed statistically significant differences between the two groups: −0.03 for topotecan plus best supportive care compared with −0.12 for best supportive care alone (p = 0.0036) and −0.10 for topotecan plus best supportive care compared with −0.30 for best supportive care alone (p = 0.0034), respectively. Rates of non-haematological adverse events appeared to be similar between the two patient groups (statistical significance was not reported). Treatment-related toxicity for the topotecan plus best supportive care arm was reported: 61% of patients had neutropenia that was severe or life-threatening, 3% had febrile neutropenia, 38% had thrombocytopenia that was severe or life-threatening, and 25% had anaemia. ## Oral topotecan compared with intravenous topotecan Two trials compared oral topotecan with intravenous topotecan as a treatment for patients with limited- or extensive-stage relapsed small-cell lung cancer who had complete response or partial response to first-line therapy with disease recurrence after 90 days or longer (n = 309 and n = 106). There were no statistically significant differences in overall survival or overall response rates between oral and intravenous topotecan in either of the trials. In the smaller study, the median overall survival for patients treated with oral topotecan was higher than for those patients treated with intravenous topotecan, but the difference was not statistically significant. No statistical analyses of adverse events were reported in either study. Severe or life-threatening adverse events were similar between intravenous topotecan and oral topotecan in the studies, with the exception of neutropenia, which appeared to occur more frequently with intravenous topotecan. The larger of the two studies assessed health-related quality of life using a disease-specific measure, the functional assessment of cancer therapy-lung (FACT-L) scale – a core set of measures with a lung-cancer subscale. In addition the trial outcome index was derived from a subgroup of the data. The mean change from baseline indicated no statistical difference between treatment groups for subscale dimension scores or the lung-cancer subscale, the FACT-L total scores or the trial outcome index. ## Intravenous topotecan compared with CAV One trial compared intravenous topotecan with CAV in patients with progressive, limited- or extensive-stage relapsed small-cell lung cancer with the date of progression 60 days or longer after completion of first-line therapy (n = 211). The primary outcomes were response rate and duration of response. An unvalidated, symptom-specific small-cell lung cancer questionnaire was used to measure symptoms of patients in the trial. The median overall survival for patients receiving intravenous topotecan was 25 weeks (95% CI 0.4 to 90.7) compared with 24.7 weeks (95% CI 1.3 to 101.3) for patients receiving CAV. This difference was not statistically significant. The 6-month survival rates were 46.7% and 45.2% for patients receiving intravenous topotecan and CAV, respectively. The 12-month survival rates were 14.2% and 14.4%, respectively (statistical testing was not reported). The results showed an increase in the overall response rate for intravenous topotecan (24.3%) compared with CAV (18.3%) but this difference was not statistically significant. In patients who received intravenous topotecan, greater symptomatic improvement was seen for dyspnoea (p = 0.002), anorexia (p = 0.042), hoarseness (p = 0.043), fatigue (p = 0.032) and interference with daily activity (p = 0.023) compared with CAV. The adverse events reported in the study were similar for the two patient groups, although the incidence of fatigue was lower and the incidence of alopecia was higher in participants receiving topotecan compared with those receiving CAV. No statistical comparison was reported. ## Intravenous topotecan compared with intravenous amrubicin One RCT was identified that compared intravenous topotecan with intravenous amrubicin. It was conducted in Japan in patients previously treated with platinum whose disease had relapsed after completing first-line therapy (n = 59). The primary outcome was overall response rate. The results showed no statistically significant differences in the overall survival for intravenous topotecan compared with intravenous amrubicin (8.4 months and 8.1 months, respectively) or the median progression-free survival (2.2 months and 3.5 months, respectively). Intravenous amrubicin was associated with a statistically significant improvement in overall response rate compared with intravenous topotecan (38% compared with 13%, p = 0.039). However, the topotecan dose of 1.0 mg/m2/day (the approved dose in Japan) was below the dose currently being used in the UK (1.5 mg/m2/day). In addition, the study was of an unknown quality because of the lack of details reported in the publication. # Cost effectiveness Systematic searches conducted by the Assessment Group identified no relevant, published economic evaluations of oral or intravenous topotecan for the treatment of relapsed small-cell lung cancer in patients for whom re-treatment with the first-line regimen was not considered appropriate. Limited information on quality of life or utilities was identified in patients with relapsed small-cell lung cancer. The manufacturer of topotecan submitted an economic evaluation. The aim of the manufacturer's analysis was to compare the cost effectiveness of oral topotecan plus best supportive care with best supportive care alone in people with relapsed small-cell lung cancer for whom treatment with intravenous chemotherapy was not considered appropriate. The analysis was based on patient-level data from the RCT that compared oral topotecan with best supportive care in patients for whom intravenous chemotherapy was not considered appropriate. CAV was excluded as a comparator from the analysis on the basis that topotecan (oral or intravenous) would not provide a cost-effective alternative to CAV in the majority of patients, because of its higher acquisition cost. The perspective was that of the NHS and personal social services (PSS), and included only the costs and benefits directly relevant to the intervention. The submission stated that costs and outcomes for each treatment arm were estimated over a lifetime horizon. However, survival was not modelled beyond the duration of the trial. Patients who were still alive at final follow-up were assumed to have died the next day. Health-related quality of life was recorded in the study using the EQ-5D, for up to 12 cycles (36 weeks), and valued using a UK general population tariff. Missing values were estimated using data from the trial, using the mean utility score (across both trial arms) for missing values up to cycle 12. When patients receiving topotecan survived with non-progressive disease beyond the 36-week data collection, the last observation was carried forward until disease progression occurred. Once these patients developed progressive disease, values for those receiving best supportive care alone were applied. The costs included in the model were drug acquisition costs, drug administration costs, drug monitoring costs, costs of treating haematological and non-haematological adverse events, and costs of providing care in the additional period of life attributable to oral topotecan combined with best supportive care. Resource use not collected in the trial was taken from clinical opinion. The cost year for the model was 2007–08. In the manufacturer's base case, the incremental life years and quality-adjusted life years (QALYs) gained for the cohort of patients receiving oral topotecan plus best supportive care compared with those receiving best supportive care alone were estimated at 0.259 life years and 0.211 QALYs gained, respectively. The incremental cost was £5671, giving an incremental cost-effectiveness ratio (ICER) of £21,878 per life year gained and £26,833 per QALY gained. Deterministic sensitivity analysis showed that the results were sensitive to methods of estimating utility (methods of carrying forward utility scores when there were missing data), drug administration cost (significantly higher costs if a patient attended as an outpatient on 5 days of the cycle to receive chemotherapy compared with 1 day of the cycle) and adverse event costs (halving or doubling adverse event costs). Probabilistic sensitivity analyses were also performed. The Assessment Group developed a survival model to estimate the cost effectiveness of topotecan compared with best supportive care in a cohort of adults with relapsed small-cell lung cancer for whom re-treatment with the first-line regimen was not considered appropriate. The model included three states: relapsed small-cell lung cancer (entry to the trial), progressive disease and death. The economic evaluation was a cost–utility analysis and the perspective was that of the NHS and PSS. The outcomes evaluated were life years and QALYs gained over the lifetime of the patients. The base-case model had a 5-year time horizon. The base-case analysis of the model was limited to oral topotecan plus best supportive care compared with best supportive care alone (based on the same study as the manufacturer's analysis). The Assessment Group also completed an analysis of intravenous topotecan compared with best supportive care, based on an indirect comparison. The Assessment Group had reservations about this analysis given the uncertainty of whether the trials on which the analysis was based fully met the criteria for the review, the comparability of the patient populations in the RCTs and the suitability of pooling their results. The model used the published Kaplan–Meier estimates for overall survival and time to progression included in the manufacturer's submission. The survival curves were extrapolated using a regression analysis (log-logistic survival function). The mean time to progression for oral topotecan plus best supportive care was estimated using an exponential approximation to derive the risk of disease progression from the reported median time to progression, because no Kaplan–Meier estimates for time to progression were reported. The mean time to progression was then calculated to be 23.52 weeks. An adjusted indirect comparison was undertaken to assess the effect of intravenous topotecan on overall survival relative to best supportive care, using data from three RCTs included in the clinical-effectiveness review. The relative risk for overall survival with intravenous topotecan was 0.68 (95% CI 0.45 to 1.02) compared with best supportive care. The utility values used in the model were those reported for patients in the RCT comparing oral topotecan plus best supportive care with best supportive care alone. This was the only relevant study identified in the Assessment Group's review of quality-of-life data. EQ-5D scores from the trial were reported as a rate of deterioration per 3-month interval for patients in each arm of the trial, controlling for baseline utility. The baseline utility for all patients in the model was assumed to be 0.7. The reported reductions over 3 months were converted to daily utility reductions (with regression analysis) for use in the Assessment Group's model and applied to the baseline utility value. The rate of deterioration reported for oral topotecan plus best supportive care was used for patients prior to disease progression. To allow for reduced quality of life in patients following disease progression, the rate of deterioration reported for best supportive care alone was applied to patients receiving oral topotecan who had experienced disease progression. The resource-use was estimated from the RCTs included in the clinical-effectiveness review, the manufacturer's submission and advice from clinical specialists. When insufficient detail was available (such as for palliative care), appropriate costs were taken from published sources. Drug costs were taken from the BNF, edition 56. Other unit costs were taken from NHS reference costs, Southampton University Hospitals Trust or published sources. The cost base for the evaluation was 2007–08. Costs were adjusted for inflation when taken from other cost years. The addition of oral topotecan to best supportive care resulted in a life-expectancy gain of 0.33 years (approximately 16.9 weeks) and a gain of 0.1830 QALYs. The incremental cost was approximately £6200, resulting in an ICER of £33,851 per QALY gained. Intravenous topotecan was associated with a gain in life expectancy of 0.30 years (approximately 15.9 weeks). The QALY gain associated with intravenous topotecan was between 0.163 and 0.191 and the incremental cost was between £12,060 and £12,514, depending on the assumptions regarding time to progression. The resulting ICER for intravenous topotecan compared with best supportive care was between £74,074 and £65,507 per QALY gained. Compared with oral topotecan, intravenous topotecan was either strictly dominated (worse outcomes at higher cost) or resulted in an ICER of £783,734 per QALY gained, depending on assumptions regarding time to progression. The Assessment Group's survival model gave a higher estimate of mean survival than the manufacturer's model using the patient-level data. This difference was mainly because of the assumption, in the manufacturer's model, that censored patients die on the day after censoring. The manufacturer and the Assessment Group also used different ways to estimate the utilities in the analysis. The manufacturer used the observed mean EQ-5D scores from the first 12 cycles from both arms of the trial to take account of missing data from the corresponding cycles. When patients receiving topotecan survived with non-progressive disease beyond the 36-week (12 cycles) data collection, the last observation was carried forward until disease progression occurred. Once these patients developed progressive disease, values for those receiving best supportive care alone were applied. The Assessment Group used a regression analysis to estimate the daily rate of deterioration in utility and applied this to the baseline utility values from the RCT comparing oral topotecan with best supportive care, in order to model utility beyond the last observation and beyond the trial. The Assessment Group's base-case ICER was higher than that of the manufacturer for oral topotecan plus best supportive care compared with best supportive care alone (£33,851 and £26,833 per QALY gained, respectively). The Assessment Group did not conduct a formal economic analysis of oral topotecan compared with CAV because of the lack of evidence that directly compared the two treatments. There were uncertainties around the comparability of the patient populations in the clinical trials, which the Assessment Group considered undermined the robustness of the indirect comparison. In addition, there were limitations in developing a robust economic analysis for this comparison, as key data required for the model for CAV were missing (including survival curves for time to progression and utility data). However, the Assessment Group provided a detailed cost comparison of oral topotecan compared with CAV and also a threshold analysis showing what magnitude of QALY gain and respective utility difference would need to be achieved with oral topotecan to make it a cost-effective alternative to CAV. The total chemotherapy cost per cycle calculated by the Assessment Group for CAV was £740.29 (first cycle) and £669.41 (subsequent cycles) and for oral topotecan was £911.64, resulting in a higher cost for oral topotecan of between £171 and £242 per cycle. Total costs of chemotherapy were calculated to be between £900 and £1800 higher for oral topotecan compared with CAV, depending on the number of cycles of CAV provided (3 or 4 cycles) and whether costs of managing adverse events were included. In the Assessment Group's threshold analysis, it was calculated that QALY gains of between 0.03 and 0.09 were required for oral topotecan to be cost effective compared with CAV depending on: the number of cycles of CAV received (3 or 4 cycles) whether adverse event costs were included the cost-effectiveness threshold assumed. As the evidence suggested no survival benefit for oral topotecan compared with CAV, any QALY gains would need to arise from quality-of-life improvements or higher utilities for patients who received oral topotecan. A number of different scenarios were developed based on possible time intervals over which oral topotecan might produce a higher utility than CAV. These included receiving oral rather than intravenous chemotherapy (9 weeks or 12 weeks of utility gain), differences in symptom improvements (20 weeks or 28 weeks of utility gain), and increased time to worsening of symptoms (9.4 weeks of utility gain). Utility differences of between 0.06 and 0.52 would be required to achieve the minimum QALY gains for oral topotecan to be cost effective compared with CAV depending on: the number of cycles of CAV received (3 or 4 cycles) whether adverse event costs were included the cost-effectiveness threshold assumed the duration of the utility gain with oral topotecan. # Consideration of the evidence The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of topotecan for the treatment of relapsed small-cell lung cancer, having considered evidence on the nature of small-cell lung cancer and the value placed on the benefits of topotecan for the treatment of relapsed small-cell lung cancer by people with the condition, those who represent them, and clinical specialists. It also took into account the effective use of NHS resources. The Committee reviewed the clinical-effectiveness results for the trials included in the review by the Assessment Group. The Committee noted the statistically significant improvement in overall survival for oral topotecan plus best supportive care compared with best supportive care alone. It also noted that the mean change in the EQ-5D score from baseline for the pooled analysis and the last evaluation analysis (section 4.1.3) showed a statistically significant difference for oral topotecan plus best supportive care compared with best supportive care alone, indicating a smaller decline in health status for those patients receiving oral topotecan plus best supportive care. The Committee noted that the reasons for further intravenous chemotherapy being considered unsuitable for the patients in the study were not reported by the investigators. However, the Committee concluded that this study confirmed the clinical effectiveness of oral topotecan in extending survival relative to best supportive care alone in people with relapsed small-cell lung cancer. The Committee discussed the results of the two clinical trials that compared oral topotecan with intravenous topotecan. It noted that there were no statistically significant differences between oral topotecan and intravenous topotecan in any of the clinical outcomes measured in either of the trials. The Committee accepted that oral topotecan and intravenous topotecan were similar in terms of clinical efficacy. The Committee was aware that adverse events were similar between intravenous topotecan and oral topotecan, with the exception of neutropenia, which appeared to occur more frequently with intravenous topotecan. The Committee heard from the clinical specialist and patient expert that intravenous treatment with topotecan required patients to attend hospital for 5 consecutive days each cycle which was inconvenient for patients and costly. The Committee concluded that intravenous topotecan had no clinical advantages over oral topotecan. The Committee then discussed the trial that compared intravenous topotecan with CAV. It noted that patients receiving intravenous topotecan showed a higher overall response rate compared with CAV, but that this was not statistically significant. The results for overall survival, median response duration, median time to response and median time to progression were also not statistically significantly different. The Committee noted that a greater proportion of patients who received intravenous topotecan reported improvements in symptoms of dyspnoea, anorexia, hoarseness, fatigue and interference with daily activity, and that these differences were statistically significant. However, it was aware that symptoms were measured using an unvalidated instrument. The Committee heard from the clinical specialist that these symptoms were likely to be related to disease activity, and would be expected to be similar if the response rates were the same. The Committee concluded that intravenous topotecan might have some benefits over CAV in terms of symptomatic relief, but these were difficult to confirm or quantify on the basis of current evidence. The Committee also noted that CAV only required patients to attend hospital once per cycle compared with five times for intravenous topotecan. The Committee concluded that the effectiveness of the two regimens was similar, that some symptomatic gains were conceivable with intravenous topotecan, but that CAV was more convenient for patients because of the lower requirement for hospital attendance. The Committee considered the clinical trial that compared intravenous topotecan with intravenous amrubicin. The Committee noted that the trial used a lower dose of topotecan than is currently licensed and used in the UK. It also noted that amrubicin does not currently hold a marketing authorisation for use in the UK. It heard from the clinical specialist that amrubicin is not routinely used in UK clinical practice and there are limited data available on the clinical effectiveness of amrubicin for small-cell lung cancer. It therefore concluded that amrubicin should not be considered as a comparator for topotecan. The Committee then reviewed the economic analyses presented by the manufacturer and the Assessment Group. The Committee noted that the manufacturer's model gave an ICER for oral topotecan plus best supportive care compared with best supportive care alone of £26,800 per QALY gained in patients for whom intravenous chemotherapy was considered unsuitable, compared with the Assessment Group model which gave an ICER of £33,900 per QALY gained. It was aware that the difference in the results was mainly driven by the different methods used to manage missing utility data. The manufacturer used the mean utility score (across both trial arms) for missing values up to cycle 12 and the last observation carried forward after that, whereas the Assessment Group used regression analysis to calculate a daily reduction in utility from the study data and applied this to the baseline utility value. The Committee preferred the method adopted by the Assessment Group, because it considered that a declining utility over time was a more accurate reflection of what happened in real life for this population than a constant utility value. The Committee understood that the manufacturer had argued that the Assessment Group's model undercounted disease monitoring costs in the control arm. The Committee heard that this would only be an issue if monitoring was as intensive off treatment as on treatment, but the clinical specialist confirmed that this is not current UK practice. Thus the Committee concluded that the Assessment Group's approach to monitoring costs was acceptable. Overall, the Committee considered the Assessment Group's model to be preferred even though it was based on aggregated data rather than individual patient data. Furthermore, taking into account the sensitivity analyses presented by the Assessment Group, the Committee concluded that the ICER for oral topotecan compared with best supportive care was unlikely to be much greater than that resulting from the Assessment Group base-case analysis. The Committee noted that the Assessment Group's analysis showed that the ICER for intravenous topotecan versus oral topotecan was either very high or that intravenous topotecan was dominated. It also noted that the ICER for intravenous topotecan compared with best supportive care was very high. The Committee therefore concluded that intravenous topotecan could not be recommended for the treatment of relapsed small-cell lung cancer. The Committee considered supplementary advice from NICE that should be taken into account when appraising treatments that may extend the life of patients with a short life expectancy, and that are licensed for indications that affect small numbers of people with incurable illnesses. For this advice to be applied, all the following criteria must be met: The treatment is indicated for patients with a short life expectancy, normally less than 24 months. There is sufficient evidence to indicate that the treatment offers an extension to life, normally of at least an additional 3 months, compared with current NHS treatment. The treatment is licensed, or otherwise indicated, for small patient populations.In addition, when taking these criteria into account, the Committee must be persuaded that the estimates of the extension to life are robust and that the assumptions used in the reference case economic modelling are plausible, objective and robust. With respect to the comparison between oral topotecan and best supportive care for people in whom treatment with CAV is contraindicated and who would otherwise receive only best supportive care, the Committee considered whether the evidence for this group satisfied the criteria for end-of-life treatments. The Committee noted from the clinical trial that normal life expectancy with best supportive care alone was unlikely to be greater than 24 months and was potentially as low as 14 weeks. It also noted that oral topotecan extended survival by approximately 12 weeks in the clinical trial and 17 weeks in the Assessment Group's model. The Committee noted that median overall survival of 25.9 weeks for patients receiving oral topotecan compared with 13.9 weeks receiving best supportive care alone had been seen in a clinical trial. The Committee concluded that the evidence in support of extended survival with oral topotecan was sufficiently robust. The Committee was aware that the number of patients with relapsed small-cell lung cancer in England and Wales was between 800 and 1600. Although the Committee noted that topotecan is licensed for other indications than for which it is being appraised, the Committee considered topotecan to fulfil the small population criterion for an end-of-life treatment. The Committee agreed that the evidence for oral topotecan for people in whom treatment with CAV is contraindicated and who would otherwise receive only best supportive care satisfied the criteria for end-of-life treatments. The Committee next considered the cost-effectiveness estimate for oral topotecan calculated by the Assessment Group, in light of the appraisal of a life-extending, end-of-life treatment. It considered the impact of giving a greater weight to QALYs achieved in the later stages of terminal diseases, using the assumption that the extended survival period is experienced at the full quality of life anticipated for a healthy person of the same age and the magnitude of additional weight that would need to be assigned to the original QALY benefits in this patient group for the cost effectiveness of the drug to fall within the current threshold range. Although the best estimate of the ICER for oral topotecan plus best supportive care compared with best supportive care alone was in excess of the normal range for cost effectiveness for the NHS, the Committee concluded that oral topotecan should be recommended for patients with relapsed small-cell lung cancer for whom re-treatment with the first-line regimen is not considered appropriate, and for whom treatment with CAV is contraindicated. (For details of the contraindications to CAV see the summary of product characteristics for each of the component drugs.) The Committee then considered the role of oral topotecan for patients who were able to receive CAV. The Committee heard from the clinical specialist that most patients who were well enough to receive chemotherapy of any kind would be able to receive CAV. The Committee considered that although there were no clinical data available that directly compared oral topotecan with CAV, it was reasonable to assume equivalence in effectiveness from the trial comparing intravenous topotecan with CAV. The clinical specialist and the patient expert stated that even when CAV was appropriate, some patients might prefer treatment with oral topotecan because it is more convenient to take treatment at home rather than attending hospital for intravenous treatment. However, the Committee noted that no consultees or commentators suggested that oral topotecan had a place when CAV was appropriate. Furthermore the Committee noted that neither the manufacturer nor the Assessment Group provided a detailed economic analysis comparing oral topotecan with CAV. It discussed the detailed cost comparison provided by the Assessment Group and noted the higher total treatment costs associated with oral topotecan compared with CAV. The Committee also considered the threshold analysis that calculated the minimum QALY gains required for oral topotecan to be cost effective compared with CAV, and the associated utility gains needed to achieve the minimum QALY gain. The Committee agreed that it was unlikely that the actual utility differences between the two treatments would be large enough to achieve the minimum QALY gains required for oral topotecan to be cost effective compared with CAV. The Committee therefore concluded that it could not recommend oral topotecan as an alternative treatment to CAV for the treatment of relapsed small-cell lung cancer.# Ongoing research The Committee noted the following ongoing clinical trials related to this appraisal. NCT00547651 is a phase III, randomised controlled trial comparing intravenous amrubicin (40 mg/m2) with intravenous topotecan (1.5 mg/m2) in adults with extensive-stage or limited-stage small-cell lung cancer sensitive or refractory to first-line (platinum-based) chemotherapy. Estimated study completion date: March 2011.# Related NICE guidance Lung cancer. NICE clinical guideline 121 (2011).# Review of guidance The guidance on this technology will be considered for review by the Guidance Executive in November 2012. Andrew DillonChief ExecutiveNovember 2009# Changes after publication February 2014: implementation section updated to clarify that topotecan is recommended as an option for treating relapsed small-cell lung cancer. Additional minor maintenance update also carried out. March 2012: minor maintenance# About this guidance NICE technology appraisal guidance is about the use of new and existing medicines and treatments in the NHS in England and Wales. This guidance was developed using the NICE multiple technology appraisal process. We have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available. Your responsibility This guidance represents the views of NICE and was arrived at after careful consideration of the evidence available. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. However, the guidance does not override the individual responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or guardian or carer. Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties. Copyright © National Institute for Health and Clinical Excellence 2009. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.	{'Guidance': 'Oral topotecan is recommended as an option only for people with relapsed small-cell lung cancer for whom:\n\nre-treatment with the first-line regimen is not considered appropriate and\n\nthe combination of cyclophosphamide, doxorubicin and vincristine (CAV) is contraindicated (for details of the contraindications to CAV see the summary of product characteristics for each of the component drugs).\n\nIntravenous topotecan is not recommended for people with relapsed small-cell lung cancer.\n\nPeople with relapsed small-cell lung cancer currently receiving oral topotecan who do not meet the criteria specified in 1.1, or who are receiving intravenous topotecan should have the option to continue their treatment until they and their clinicians consider it appropriate to stop.', 'Clinical need and practice': "Lung cancer can be categorised into four major cell types: small-cell lung cancer, squamous-cell carcinoma, adenocarcinoma and large-cell carcinoma. The last three types are usually described as non-small-cell lung cancer. Small-cell lung cancer grows rapidly and spreads quickly to distant sites (metastasises). It is classified using a two-stage system. The first is limited-stage disease, in which the disease is generally confined to one side of the chest or to the neck lymph nodes. The second is extensive-stage disease, in which the disease has spread outside one side of the chest and there are systemic metastases. The 'tumour node metastases' stage scores are not usually relevant in small-cell lung cancer because of the high proportion of patients presenting with metastases and the poor prognosis associated with the disease.\n\nLung cancer is one of the most common cancers in England and accounted for 15% of cancers in men and 11% of cancers in women in 2005. In England and Wales there were 33,181 new cases of lung cancer in 2005. The disease accounts for around 33,000 deaths per year. It is estimated that small-cell lung cancer makes up about 10–20% of the total cases of lung cancer, but this percentage is falling. The reasons for this are unclear, but changing smoking habits and a reduction in the tar content of cigarettes may be involved. At diagnosis, about 33% of people with small-cell lung cancer have limited-stage disease, but the majority of people have extensive-stage disease.\n\nIn most patients the disease is symptomatic on presentation. In some patients there are non-specific symptoms such as fatigue, loss of appetite and weight loss, while in others there are more direct symptoms such as breathlessness, chest discomfort and haemoptysis (blood-stained sputum). The risk factors for lung cancer include smoking, passive smoking, occupational exposure to asbestos, radon, chromium or nickel, male gender and chronic lung disease. Smoking is the leading cause of lung cancer, accounting for approximately 80–90% of cases. Smoking has been shown to be much more strongly linked to small-cell lung cancer than non-small-cell lung cancer.\n\nThe prognosis for people with small-cell lung cancer is poor. Without treatment, it has an aggressive clinical course with a life expectancy of approximately 3.5\xa0months for limited-stage disease and 6\xa0weeks for extensive-stage disease. The median survival with treatment is approximately 14–18\xa0months for limited-stage disease and 9–12\xa0months for extensive-stage disease. Approximately 20–40% of patients with limited-stage disease and less than 5% of patients with extensive-stage disease survive for 2\xa0years. Survivors often continue to relapse up to, and occasionally after, 5\xa0years. Prognosis has been linked to performance status and the extent of the disease.\n\nSelection of the most appropriate first-line treatment for small-cell lung cancer is determined primarily by the performance status of the patient and the stage of the disease. Current management of small-cell lung cancer usually consists of combination chemotherapy regimens. Radiotherapy may be given concurrently with chemotherapy or as part of palliative care. Surgery is not appropriate for the majority of patients because the disease is often widespread at the time of diagnosis. For further guidance on the management of small-cell lung cancer, see 'Lung cancer: the diagnosis and treatment of lung cancer' (NICE clinical guideline\xa024) [replaced by NICE clinical guideline 121].", 'The technology': "Topotecan (Hycamtin, GlaxoSmithKline) acts by inhibiting topoisomerase I, an enzyme that is required for DNA replication, leading to cell death. Topotecan is indicated as monotherapy for patients with relapsed small-cell lung cancer for whom re-treatment with the first-line regimen is not considered appropriate. The marketing authorisation for this indication was granted by the European Medicines Agency (EMEA) in 2006 for intravenous therapy, and an extension to the marketing authorisation was granted in 2008 for oral capsules.\n\nAdverse effects commonly associated with topotecan include nausea, vomiting, neutropenia, leukopenia, anaemia, fatigue and alopecia. Topotecan is not recommended in patients with severe renal or hepatic impairment. For full details of adverse effects and contraindications, see the summary of product characteristics.\n\nThe acquisition cost for intravenous topotecan is £97.65 for a 1-mg vial or £290.62 for a 4-mg vial and for oral topotecan is £30 per 1\xa0mg capsule (excluding VAT, 'British national formulary' [BNF] edition 58). The recommended dose of intravenous topotecan is 1.5\xa0mg/m2 body surface area on 5\xa0consecutive days with a 21-day interval between the start of each course. Oral topotecan is administered at 2.3\xa0mg/m2 on 5\xa0consecutive days with a 21-day interval between the start of each course. Assuming a body surface area of 1.8\xa0m2, the cost per cycle is £1495 for intravenous topotecan and £638 for oral topotecan. Patients in the key clinical trials received intravenous topotecan and oral topotecan for approximately 4\xa0cycles, equating to an average treatment cost per patient of £5980 for intravenous topotecan and £2552 for oral topotecan. Costs may vary in different settings because of negotiated procurement discounts.", 'Evidence and interpretation': "The Appraisal Committee (appendix A) considered evidence from a number of sources (appendix B).\n\n# Clinical effectiveness\n\nThe Assessment Group reviewed the clinical effectiveness of topotecan (oral and intravenous) compared with best supportive care or other chemotherapy regimens for the treatment of relapsed small-cell lung cancer. Five randomised controlled trials (RCTs) met the inclusion criteria of the review. The reporting and methodological quality was judged to be good in two trials and unknown in three trials. The RCTs differed in design and recruited different study populations for topotecan and the relevant comparators. Therefore the Assessment Group considered that it was not appropriate to pool the results.\n\n## Oral topotecan compared with best supportive care\n\nOne trial compared oral topotecan plus best supportive care with best supportive care alone as a treatment for patients with limited- or extensive-stage relapsed small-cell lung cancer for whom further intravenous chemotherapy was considered unsuitable (n\xa0=\xa0141). The primary outcome was overall survival. Quality of life was also measured using the EQ-5D. The median overall survival for patients receiving oral topotecan was 25.9\xa0weeks (95% confidence interval [CI] 18.3 to 31.6) compared with 13.9\xa0weeks (95% CI 11.1 to 18.6) for patients receiving best supportive care alone. The hazard ratio (using Kaplan–Meier analysis) for overall survival was 0.64 (95% CI 0.45 to 0.90) in favour of topotecan plus best supportive care.\n\nEQ-5D data were recorded for each patient in the trial at the start of each cycle (21-day period) up to cycle\xa012. Individual patient data were available for 600 (39%) 21-day survival periods. The rate of deterioration in the EQ-5D score per 3-month period was −0.05 (95% CI −0.11 to 0.02) for patients receiving oral topotecan plus best supportive care compared with −0.20 (95% CI −0.27 to −0.12) for best supportive care alone. The mean change in EQ-5D score from baseline to the averaged on-treatment assessment (pooled analysis) and the mean change from baseline to the last evaluation showed statistically significant differences between the two groups: −0.03 for topotecan plus best supportive care compared with −0.12 for best supportive care alone (p\xa0=\xa00.0036) and −0.10 for topotecan plus best supportive care compared with −0.30 for best supportive care alone (p\xa0=\xa00.0034), respectively.\n\nRates of non-haematological adverse events appeared to be similar between the two patient groups (statistical significance was not reported). Treatment-related toxicity for the topotecan plus best supportive care arm was reported: 61% of patients had neutropenia that was severe or life-threatening, 3% had febrile neutropenia, 38% had thrombocytopenia that was severe or life-threatening, and 25% had anaemia.\n\n## Oral topotecan compared with intravenous topotecan\n\nTwo trials compared oral topotecan with intravenous topotecan as a treatment for patients with limited- or extensive-stage relapsed small-cell lung cancer who had complete response or partial response to first-line therapy with disease recurrence after 90\xa0days or longer (n\xa0=\xa0309 and n\xa0=\xa0106). There were no statistically significant differences in overall survival or overall response rates between oral and intravenous topotecan in either of the trials. In the smaller study, the median overall survival for patients treated with oral topotecan was higher than for those patients treated with intravenous topotecan, but the difference was not statistically significant. No statistical analyses of adverse events were reported in either study. Severe or life-threatening adverse events were similar between intravenous topotecan and oral topotecan in the studies, with the exception of neutropenia, which appeared to occur more frequently with intravenous topotecan.\n\nThe larger of the two studies assessed health-related quality of life using a disease-specific measure, the functional assessment of cancer therapy-lung (FACT-L) scale – a core set of measures with a lung-cancer subscale. In addition the trial outcome index was derived from a subgroup of the data. The mean change from baseline indicated no statistical difference between treatment groups for subscale dimension scores or the lung-cancer subscale, the FACT-L total scores or the trial outcome index.\n\n## Intravenous topotecan compared with CAV\n\nOne trial compared intravenous topotecan with CAV in patients with progressive, limited- or extensive-stage relapsed small-cell lung cancer with the date of progression 60\xa0days or longer after completion of first-line therapy (n\xa0=\xa0211). The primary outcomes were response rate and duration of response. An unvalidated, symptom-specific small-cell lung cancer questionnaire was used to measure symptoms of patients in the trial.\n\nThe median overall survival for patients receiving intravenous topotecan was 25\xa0weeks (95% CI 0.4 to 90.7) compared with 24.7\xa0weeks (95% CI 1.3 to 101.3) for patients receiving CAV. This difference was not statistically significant. The 6-month survival rates were 46.7% and 45.2% for patients receiving intravenous topotecan and CAV, respectively. The 12-month survival rates were 14.2% and 14.4%, respectively (statistical testing was not reported). The results showed an increase in the overall response rate for intravenous topotecan (24.3%) compared with CAV (18.3%) but this difference was not statistically significant.\n\nIn patients who received intravenous topotecan, greater symptomatic improvement was seen for dyspnoea (p\xa0=\xa00.002), anorexia (p\xa0=\xa00.042), hoarseness (p\xa0=\xa00.043), fatigue (p\xa0=\xa00.032) and interference with daily activity (p\xa0=\xa00.023) compared with CAV. The adverse events reported in the study were similar for the two patient groups, although the incidence of fatigue was lower and the incidence of alopecia was higher in participants receiving topotecan compared with those receiving CAV. No statistical comparison was reported.\n\n## Intravenous topotecan compared with intravenous amrubicin\n\nOne RCT was identified that compared intravenous topotecan with intravenous amrubicin. It was conducted in Japan in patients previously treated with platinum whose disease had relapsed after completing first-line therapy (n\xa0=\xa059). The primary outcome was overall response rate.\n\nThe results showed no statistically significant differences in the overall survival for intravenous topotecan compared with intravenous amrubicin (8.4\xa0months and 8.1\xa0months, respectively) or the median progression-free survival (2.2\xa0months and 3.5\xa0months, respectively). Intravenous amrubicin was associated with a statistically significant improvement in overall response rate compared with intravenous topotecan (38% compared with 13%, p\xa0=\xa00.039). However, the topotecan dose of 1.0\xa0mg/m2/day (the approved dose in Japan) was below the dose currently being used in the UK (1.5\xa0mg/m2/day). In addition, the study was of an unknown quality because of the lack of details reported in the publication.\n\n# Cost effectiveness\n\nSystematic searches conducted by the Assessment Group identified no relevant, published economic evaluations of oral or intravenous topotecan for the treatment of relapsed small-cell lung cancer in patients for whom re-treatment with the first-line regimen was not considered appropriate. Limited information on quality of life or utilities was identified in patients with relapsed small-cell lung cancer. The manufacturer of topotecan submitted an economic evaluation.\n\nThe aim of the manufacturer's analysis was to compare the cost effectiveness of oral topotecan plus best supportive care with best supportive care alone in people with relapsed small-cell lung cancer for whom treatment with intravenous chemotherapy was not considered appropriate. The analysis was based on patient-level data from the RCT that compared oral topotecan with best supportive care in patients for whom intravenous chemotherapy was not considered appropriate. CAV was excluded as a comparator from the analysis on the basis that topotecan (oral or intravenous) would not provide a cost-effective alternative to CAV in the majority of patients, because of its higher acquisition cost.\n\nThe perspective was that of the NHS and personal social services (PSS), and included only the costs and benefits directly relevant to the intervention. The submission stated that costs and outcomes for each treatment arm were estimated over a lifetime horizon. However, survival was not modelled beyond the duration of the trial. Patients who were still alive at final follow-up were assumed to have died the next day.\n\nHealth-related quality of life was recorded in the study using the EQ-5D, for up to 12\xa0cycles (36\xa0weeks), and valued using a UK general population tariff. Missing values were estimated using data from the trial, using the mean utility score (across both trial arms) for missing values up to cycle\xa012. When patients receiving topotecan survived with non-progressive disease beyond the 36-week data collection, the last observation was carried forward until disease progression occurred. Once these patients developed progressive disease, values for those receiving best supportive care alone were applied.\n\nThe costs included in the model were drug acquisition costs, drug administration costs, drug monitoring costs, costs of treating haematological and non-haematological adverse events, and costs of providing care in the additional period of life attributable to oral topotecan combined with best supportive care. Resource use not collected in the trial was taken from clinical opinion. The cost year for the model was 2007–08.\n\nIn the manufacturer's base case, the incremental life years and quality-adjusted life years (QALYs) gained for the cohort of patients receiving oral topotecan plus best supportive care compared with those receiving best supportive care alone were estimated at 0.259\xa0life years and 0.211 QALYs gained, respectively. The incremental cost was £5671, giving an incremental cost-effectiveness ratio (ICER) of £21,878 per life year gained and £26,833 per QALY gained.\n\nDeterministic sensitivity analysis showed that the results were sensitive to methods of estimating utility (methods of carrying forward utility scores when there were missing data), drug administration cost (significantly higher costs if a patient attended as an outpatient on 5\xa0days of the cycle to receive chemotherapy compared with 1\xa0day of the cycle) and adverse event costs (halving or doubling adverse event costs). Probabilistic sensitivity analyses were also performed.\n\nThe Assessment Group developed a survival model to estimate the cost effectiveness of topotecan compared with best supportive care in a cohort of adults with relapsed small-cell lung cancer for whom re-treatment with the first-line regimen was not considered appropriate. The model included three states: relapsed small-cell lung cancer (entry to the trial), progressive disease and death. The economic evaluation was a cost–utility analysis and the perspective was that of the NHS and PSS. The outcomes evaluated were life years and QALYs gained over the lifetime of the patients. The base-case model had a 5-year time horizon.\n\nThe base-case analysis of the model was limited to oral topotecan plus best supportive care compared with best supportive care alone (based on the same study as the manufacturer's analysis). The Assessment Group also completed an analysis of intravenous topotecan compared with best supportive care, based on an indirect comparison. The Assessment Group had reservations about this analysis given the uncertainty of whether the trials on which the analysis was based fully met the criteria for the review, the comparability of the patient populations in the RCTs and the suitability of pooling their results.\n\nThe model used the published Kaplan–Meier estimates for overall survival and time to progression included in the manufacturer's submission. The survival curves were extrapolated using a regression analysis (log-logistic survival function). The mean time to progression for oral topotecan plus best supportive care was estimated using an exponential approximation to derive the risk of disease progression from the reported median time to progression, because no Kaplan–Meier estimates for time to progression were reported. The mean time to progression was then calculated to be 23.52\xa0weeks. An adjusted indirect comparison was undertaken to assess the effect of intravenous topotecan on overall survival relative to best supportive care, using data from three RCTs included in the clinical-effectiveness review. The relative risk for overall survival with intravenous topotecan was 0.68 (95% CI 0.45 to 1.02) compared with best supportive care.\n\nThe utility values used in the model were those reported for patients in the RCT comparing oral topotecan plus best supportive care with best supportive care alone. This was the only relevant study identified in the Assessment Group's review of quality-of-life data. EQ-5D scores from the trial were reported as a rate of deterioration per 3-month interval for patients in each arm of the trial, controlling for baseline utility. The baseline utility for all patients in the model was assumed to be 0.7. The reported reductions over 3\xa0months were converted to daily utility reductions (with regression analysis) for use in the Assessment Group's model and applied to the baseline utility value. The rate of deterioration reported for oral topotecan plus best supportive care was used for patients prior to disease progression. To allow for reduced quality of life in patients following disease progression, the rate of deterioration reported for best supportive care alone was applied to patients receiving oral topotecan who had experienced disease progression.\n\nThe resource-use was estimated from the RCTs included in the clinical-effectiveness review, the manufacturer's submission and advice from clinical specialists. When insufficient detail was available (such as for palliative care), appropriate costs were taken from published sources. Drug costs were taken from the BNF, edition 56. Other unit costs were taken from NHS reference costs, Southampton University Hospitals Trust or published sources. The cost base for the evaluation was 2007–08. Costs were adjusted for inflation when taken from other cost years.\n\nThe addition of oral topotecan to best supportive care resulted in a life-expectancy gain of 0.33\xa0years (approximately 16.9\xa0weeks) and a gain of 0.1830 QALYs. The incremental cost was approximately £6200, resulting in an ICER of £33,851 per QALY gained.\n\nIntravenous topotecan was associated with a gain in life expectancy of 0.30\xa0years (approximately 15.9\xa0weeks). The QALY gain associated with intravenous topotecan was between 0.163 and 0.191 and the incremental cost was between £12,060 and £12,514, depending on the assumptions regarding time to progression. The resulting ICER for intravenous topotecan compared with best supportive care was between £74,074 and £65,507 per QALY gained.\n\nCompared with oral topotecan, intravenous topotecan was either strictly dominated (worse outcomes at higher cost) or resulted in an ICER of £783,734 per QALY gained, depending on assumptions regarding time to progression.\n\nThe Assessment Group's survival model gave a higher estimate of mean survival than the manufacturer's model using the patient-level data. This difference was mainly because of the assumption, in the manufacturer's model, that censored patients die on the day after censoring. The manufacturer and the Assessment Group also used different ways to estimate the utilities in the analysis. The manufacturer used the observed mean EQ-5D scores from the first 12\xa0cycles from both arms of the trial to take account of missing data from the corresponding cycles. When patients receiving topotecan survived with non-progressive disease beyond the 36-week (12\xa0cycles) data collection, the last observation was carried forward until disease progression occurred. Once these patients developed progressive disease, values for those receiving best supportive care alone were applied. The Assessment Group used a regression analysis to estimate the daily rate of deterioration in utility and applied this to the baseline utility values from the RCT comparing oral topotecan with best supportive care, in order to model utility beyond the last observation and beyond the trial. The Assessment Group's base-case ICER was higher than that of the manufacturer for oral topotecan plus best supportive care compared with best supportive care alone (£33,851 and £26,833 per QALY gained, respectively).\n\nThe Assessment Group did not conduct a formal economic analysis of oral topotecan compared with CAV because of the lack of evidence that directly compared the two treatments. There were uncertainties around the comparability of the patient populations in the clinical trials, which the Assessment Group considered undermined the robustness of the indirect comparison. In addition, there were limitations in developing a robust economic analysis for this comparison, as key data required for the model for CAV were missing (including survival curves for time to progression and utility data). However, the Assessment Group provided a detailed cost comparison of oral topotecan compared with CAV and also a threshold analysis showing what magnitude of QALY gain and respective utility difference would need to be achieved with oral topotecan to make it a cost-effective alternative to CAV.\n\nThe total chemotherapy cost per cycle calculated by the Assessment Group for CAV was £740.29 (first cycle) and £669.41 (subsequent cycles) and for oral topotecan was £911.64, resulting in a higher cost for oral topotecan of between £171 and £242 per cycle. Total costs of chemotherapy were calculated to be between £900 and £1800 higher for oral topotecan compared with CAV, depending on the number of cycles of CAV provided (3 or 4\xa0cycles) and whether costs of managing adverse events were included.\n\nIn the Assessment Group's threshold analysis, it was calculated that QALY gains of between 0.03 and 0.09 were required for oral topotecan to be cost effective compared with CAV depending on:\n\nthe number of cycles of CAV received (3 or 4\xa0cycles)\n\nwhether adverse event costs were included\n\nthe cost-effectiveness threshold assumed. As the evidence suggested no survival benefit for oral topotecan compared with CAV, any QALY gains would need to arise from quality-of-life improvements or higher utilities for patients who received oral topotecan. A number of different scenarios were developed based on possible time intervals over which oral topotecan might produce a higher utility than CAV. These included receiving oral rather than intravenous chemotherapy (9\xa0weeks or 12\xa0weeks of utility gain), differences in symptom improvements (20\xa0weeks or 28\xa0weeks of utility gain), and increased time to worsening of symptoms (9.4\xa0weeks of utility gain). Utility differences of between 0.06 and 0.52 would be required to achieve the minimum QALY gains for oral topotecan to be cost effective compared with CAV depending on:\n\nthe number of cycles of CAV received (3 or 4\xa0cycles)\n\nwhether adverse event costs were included\n\nthe cost-effectiveness threshold assumed\n\nthe duration of the utility gain with oral topotecan.\n\n# Consideration of the evidence\n\nThe Appraisal Committee reviewed the data available on the clinical and cost effectiveness of topotecan for the treatment of relapsed small-cell lung cancer, having considered evidence on the nature of small-cell lung cancer and the value placed on the benefits of topotecan for the treatment of relapsed small-cell lung cancer by people with the condition, those who represent them, and clinical specialists. It also took into account the effective use of NHS resources.\n\nThe Committee reviewed the clinical-effectiveness results for the trials included in the review by the Assessment Group. The Committee noted the statistically significant improvement in overall survival for oral topotecan plus best supportive care compared with best supportive care alone. It also noted that the mean change in the EQ-5D score from baseline for the pooled analysis and the last evaluation analysis (section 4.1.3) showed a statistically significant difference for oral topotecan plus best supportive care compared with best supportive care alone, indicating a smaller decline in health status for those patients receiving oral topotecan plus best supportive care. The Committee noted that the reasons for further intravenous chemotherapy being considered unsuitable for the patients in the study were not reported by the investigators. However, the Committee concluded that this study confirmed the clinical effectiveness of oral topotecan in extending survival relative to best supportive care alone in people with relapsed small-cell lung cancer.\n\nThe Committee discussed the results of the two clinical trials that compared oral topotecan with intravenous topotecan. It noted that there were no statistically significant differences between oral topotecan and intravenous topotecan in any of the clinical outcomes measured in either of the trials. The Committee accepted that oral topotecan and intravenous topotecan were similar in terms of clinical efficacy. The Committee was aware that adverse events were similar between intravenous topotecan and oral topotecan, with the exception of neutropenia, which appeared to occur more frequently with intravenous topotecan. The Committee heard from the clinical specialist and patient expert that intravenous treatment with topotecan required patients to attend hospital for 5\xa0consecutive days each cycle which was inconvenient for patients and costly. The Committee concluded that intravenous topotecan had no clinical advantages over oral topotecan.\n\nThe Committee then discussed the trial that compared intravenous topotecan with CAV. It noted that patients receiving intravenous topotecan showed a higher overall response rate compared with CAV, but that this was not statistically significant. The results for overall survival, median response duration, median time to response and median time to progression were also not statistically significantly different. The Committee noted that a greater proportion of patients who received intravenous topotecan reported improvements in symptoms of dyspnoea, anorexia, hoarseness, fatigue and interference with daily activity, and that these differences were statistically significant. However, it was aware that symptoms were measured using an unvalidated instrument. The Committee heard from the clinical specialist that these symptoms were likely to be related to disease activity, and would be expected to be similar if the response rates were the same. The Committee concluded that intravenous topotecan might have some benefits over CAV in terms of symptomatic relief, but these were difficult to confirm or quantify on the basis of current evidence. The Committee also noted that CAV only required patients to attend hospital once per cycle compared with five times for intravenous topotecan. The Committee concluded that the effectiveness of the two regimens was similar, that some symptomatic gains were conceivable with intravenous topotecan, but that CAV was more convenient for patients because of the lower requirement for hospital attendance.\n\nThe Committee considered the clinical trial that compared intravenous topotecan with intravenous amrubicin. The Committee noted that the trial used a lower dose of topotecan than is currently licensed and used in the UK. It also noted that amrubicin does not currently hold a marketing authorisation for use in the UK. It heard from the clinical specialist that amrubicin is not routinely used in UK clinical practice and there are limited data available on the clinical effectiveness of amrubicin for small-cell lung cancer. It therefore concluded that amrubicin should not be considered as a comparator for topotecan.\n\nThe Committee then reviewed the economic analyses presented by the manufacturer and the Assessment Group. The Committee noted that the manufacturer's model gave an ICER for oral topotecan plus best supportive care compared with best supportive care alone of £26,800 per QALY gained in patients for whom intravenous chemotherapy was considered unsuitable, compared with the Assessment Group model which gave an ICER of £33,900 per QALY gained. It was aware that the difference in the results was mainly driven by the different methods used to manage missing utility data. The manufacturer used the mean utility score (across both trial arms) for missing values up to cycle\xa012 and the last observation carried forward after that, whereas the Assessment Group used regression analysis to calculate a daily reduction in utility from the study data and applied this to the baseline utility value. The Committee preferred the method adopted by the Assessment Group, because it considered that a declining utility over time was a more accurate reflection of what happened in real life for this population than a constant utility value.\n\nThe Committee understood that the manufacturer had argued that the Assessment Group's model undercounted disease monitoring costs in the control arm. The Committee heard that this would only be an issue if monitoring was as intensive off treatment as on treatment, but the clinical specialist confirmed that this is not current UK practice. Thus the Committee concluded that the Assessment Group's approach to monitoring costs was acceptable.\n\nOverall, the Committee considered the Assessment Group's model to be preferred even though it was based on aggregated data rather than individual patient data. Furthermore, taking into account the sensitivity analyses presented by the Assessment Group, the Committee concluded that the ICER for oral topotecan compared with best supportive care was unlikely to be much greater than that resulting from the Assessment Group base-case analysis. The Committee noted that the Assessment Group's analysis showed that the ICER for intravenous topotecan versus oral topotecan was either very high or that intravenous topotecan was dominated. It also noted that the ICER for intravenous topotecan compared with best supportive care was very high. The Committee therefore concluded that intravenous topotecan could not be recommended for the treatment of relapsed small-cell lung cancer.\n\nThe Committee considered supplementary advice from NICE that should be taken into account when appraising treatments that may extend the life of patients with a short life expectancy, and that are licensed for indications that affect small numbers of people with incurable illnesses. For this advice to be applied, all the following criteria must be met:\n\nThe treatment is indicated for patients with a short life expectancy, normally less than 24\xa0months.\n\nThere is sufficient evidence to indicate that the treatment offers an extension to life, normally of at least an additional 3\xa0months, compared with current NHS treatment.\n\nThe treatment is licensed, or otherwise indicated, for small patient populations.In addition, when taking these criteria into account, the Committee must be persuaded that the estimates of the extension to life are robust and that the assumptions used in the reference case economic modelling are plausible, objective and robust.\n\nWith respect to the comparison between oral topotecan and best supportive care for people in whom treatment with CAV is contraindicated and who would otherwise receive only best supportive care, the Committee considered whether the evidence for this group satisfied the criteria for end-of-life treatments. The Committee noted from the clinical trial that normal life expectancy with best supportive care alone was unlikely to be greater than 24\xa0months and was potentially as low as 14\xa0weeks. It also noted that oral topotecan extended survival by approximately 12\xa0weeks in the clinical trial and 17\xa0weeks in the Assessment Group's model. The Committee noted that median overall survival of 25.9\xa0weeks for patients receiving oral topotecan compared with 13.9\xa0weeks receiving best supportive care alone had been seen in a clinical trial. The Committee concluded that the evidence in support of extended survival with oral topotecan was sufficiently robust. The Committee was aware that the number of patients with relapsed small-cell lung cancer in England and Wales was between 800 and 1600. Although the Committee noted that topotecan is licensed for other indications than for which it is being appraised, the Committee considered topotecan to fulfil the small population criterion for an end-of-life treatment. The Committee agreed that the evidence for oral topotecan for people in whom treatment with CAV is contraindicated and who would otherwise receive only best supportive care satisfied the criteria for end-of-life treatments.\n\nThe Committee next considered the cost-effectiveness estimate for oral topotecan calculated by the Assessment Group, in light of the appraisal of a life-extending, end-of-life treatment. It considered the impact of giving a greater weight to QALYs achieved in the later stages of terminal diseases, using the assumption that the extended survival period is experienced at the full quality of life anticipated for a healthy person of the same age and the magnitude of additional weight that would need to be assigned to the original QALY benefits in this patient group for the cost effectiveness of the drug to fall within the current threshold range. Although the best estimate of the ICER for oral topotecan plus best supportive care compared with best supportive care alone was in excess of the normal range for cost effectiveness for the NHS, the Committee concluded that oral topotecan should be recommended for patients with relapsed small-cell lung cancer for whom re-treatment with the first-line regimen is not considered appropriate, and for whom treatment with CAV is contraindicated. (For details of the contraindications to CAV see the summary of product characteristics for each of the component drugs.)\n\nThe Committee then considered the role of oral topotecan for patients who were able to receive CAV. The Committee heard from the clinical specialist that most patients who were well enough to receive chemotherapy of any kind would be able to receive CAV. The Committee considered that although there were no clinical data available that directly compared oral topotecan with CAV, it was reasonable to assume equivalence in effectiveness from the trial comparing intravenous topotecan with CAV. The clinical specialist and the patient expert stated that even when CAV was appropriate, some patients might prefer treatment with oral topotecan because it is more convenient to take treatment at home rather than attending hospital for intravenous treatment. However, the Committee noted that no consultees or commentators suggested that oral topotecan had a place when CAV was appropriate. Furthermore the Committee noted that neither the manufacturer nor the Assessment Group provided a detailed economic analysis comparing oral topotecan with CAV. It discussed the detailed cost comparison provided by the Assessment Group and noted the higher total treatment costs associated with oral topotecan compared with CAV. The Committee also considered the threshold analysis that calculated the minimum QALY gains required for oral topotecan to be cost effective compared with CAV, and the associated utility gains needed to achieve the minimum QALY gain. The Committee agreed that it was unlikely that the actual utility differences between the two treatments would be large enough to achieve the minimum QALY gains required for oral topotecan to be cost effective compared with CAV. The Committee therefore concluded that it could not recommend oral topotecan as an alternative treatment to CAV for the treatment of relapsed small-cell lung cancer.", 'Ongoing research': 'The Committee noted the following ongoing clinical trials related to this appraisal.\n\nNCT00547651 is a phase III, randomised controlled trial comparing intravenous amrubicin (40\xa0mg/m2) with intravenous topotecan (1.5\xa0mg/m2) in adults with extensive-stage or limited-stage small-cell lung cancer sensitive or refractory to first-line (platinum-based) chemotherapy. Estimated study completion date: March 2011.', 'Related NICE guidance': 'Lung cancer. NICE clinical guideline 121 (2011).', 'Review of guidance': 'The guidance on this technology will be considered for review by the Guidance Executive in November 2012.\n\nAndrew DillonChief ExecutiveNovember 2009', 'Changes after publication': 'February 2014: implementation section updated to clarify that topotecan is recommended as an option for treating relapsed small-cell lung cancer. Additional minor maintenance update also carried out.\n\nMarch 2012: minor maintenance', 'About this guidance': 'NICE technology appraisal guidance is about the use of new and existing medicines and treatments in the NHS in England and Wales.\n\nThis guidance was developed using the NICE multiple technology appraisal process.\n\nWe have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available.\n\nYour responsibility\n\nThis guidance represents the views of NICE and was arrived at after careful consideration of the evidence available. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. However, the guidance does not override the individual responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.\n\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.\n\nCopyright\n\n© National Institute for Health and Clinical Excellence 2009. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.'}	https://www.nice.org.uk/guidance/ta184	Evidence-based recommendations on topotecan for treating relapsed small-cell cancer in adults.
cc21ddaf4c0232fcfb4d44574c95dfda49665b4f	nice	Topotecan for the treatment of recurrent and stage IVB cervical cancer	Topotecan for the treatment of recurrent and stage IVB cervical cancer Evidence-based recommendations on topotecan for treating recurrent and stage IVB cervical cancer in adults. # Guidance Topotecan in combination with cisplatin is recommended as a treatment option for women with recurrent or stage IVB cervical cancer only if they have not previously received cisplatin. Women who have previously received cisplatin and are currently being treated with topotecan in combination with cisplatin for recurrent and stage IVB cervical cancer should have the option to continue their therapy until they and their clinicians consider it appropriate to stop.# The technology Topotecan (Hycamtin, GlaxoSmithKline) prevents DNA replication in cancer cells by inhibiting the enzyme topoisomerase I. Topotecan in combination with cisplatin has a marketing authorisation for patients with carcinoma of the cervix recurrent after radiotherapy and for patients with stage IVB disease. The summary of product characteristics (SPC) states that patients with prior exposure to cisplatin require a sustained treatment-free interval to justify treatment with topotecan in combination with cisplatin. The recommended dosage is 0.75 mg/m2/day topotecan, administered as a 30-minute intravenous infusion on days 1, 2 and 3 of each cycle. Cisplatin is administered after topotecan as an intravenous infusion on day 1 at a dosage of 50 mg/m2/day. Treatment should be repeated every 21 days for six cycles or until disease progresses. Topotecan should only be readministered if the neutrophil count is at least 1.5 x 109 per litre, the platelet count is at least 100 x 109 per litre, and the haemoglobin level is at least 9 g/100 ml (after transfusion if necessary). The SPC states that topotecan should only be used in units specialised in the administration of cytotoxic chemotherapy and it should only be administered under the supervision of a physician experienced in the use of chemotherapy. Adverse effects commonly associated with topotecan include nausea, vomiting, neutropenia, leukopenia, anaemia, fatigue and alopecia. Topotecan is not recommended in patients with severe renal or hepatic impairment. Cisplatin causes nausea and vomiting in the majority of patients. Serious toxic effects of cisplatin on the kidneys, bone marrow and hearing function are common. Serum electrolyte disturbances, hyperuricaemia, allergic reactions and cardiovascular abnormalities have also been reported. For full details of adverse effects and contraindications, see the SPC. The acquisition cost of topotecan is £97.65 for a 1-mg vial or £290.62 for a 4-mg vial (excluding VAT; 'British national formulary' edition 57). The acquisition cost of cisplatin is £24.50 for a 50-mg vial or £50.22 for a 100-mg vial (excluding VAT; BNF edition 57). Assuming a body surface area of 1.7 m2, the total dose per cycle would be 3.825 mg topotecan (that is, 1.275 mg/day). Assuming excess topotecan is wasted after each dose, a total of six 1-mg vials would be required at a cost of £585.90. For cisplatin, the cost for the required 85 mg would be £49 for two 50-mg vials. The cost of topotecan for a full course of six cycles is £3515.40. Costs may vary in different settings because of negotiated procurement discounts.# The manufacturer's submission The Appraisal Committee (appendix A) considered evidence submitted by the manufacturer of topotecan and a review of this submission by the Evidence Review Group (ERG; appendix B). In the submission, the manufacturer compared topotecan plus cisplatin with cisplatin alone. The manufacturer also compared topotecan plus cisplatin with paclitaxel plus cisplatin. The manufacturer justified their choice of comparator with data from the IMS Oncology Analyzer database from 2004 to 2008 to show that cisplatin alone is the most frequently used therapy in the group of women for whom topotecan plus cisplatin is licensed (39%). A more recent breakdown of the IMS Oncology Analyzer database from 2006 to 2008 indicates that 27% of patients receive cisplatin alone; 23% receive carboplatin plus paclitaxel. There are a range of other combination therapies, each of which is given to fewer than 10% of patients. In total 57% of patients receive some form of combination therapy. The manufacturer identified one phase III, open-label randomised controlled trial (GOG-0179; n = 293) that included women with persistent, recurrent or stage IVB cervical cancer and compared topotecan plus cisplatin with cisplatin alone. These women were followed up for a maximum of 36 months. The trial reported increased median overall survival for topotecan plus cisplatin compared with cisplatin alone: 9.4 versus 6.5 months, respectively (hazard ratio 0.76; 95% confidence interval 0.59 to 0.98; p = 0.033), and increased median progression-free survival for topotecan plus cisplatin compared with cisplatin alone: 4.6 versus 2.9 months, respectively (HR 0.76; 95% CI 0.60 to 0.97; p = 0.027). The manufacturer reported that the safety profile for topotecan plus cisplatin was predictable and manageable. However, there were four treatment-related deaths in the topotecan plus cisplatin group compared with none in the cisplatin group. Febrile neutropenia occurred in 17.7% of women treated with topotecan plus cisplatin and in 7.5% of women treated with cisplatin alone. Serious adverse events occurred in 10% of women treated with cisplatin alone compared with 14% of women treated with topotecan plus cisplatin. The manufacturer presented data on subpopulations of the GOG-0179 trial. The 'licensed population', which consisted of 222 women, was defined as the population for whom topotecan is indicated in the marketing authorisation. Data from the other 71 women in the trial were excluded because they had cervical cancer that was not covered by the marketing authorisation (32 women had persistent disease and in 39 women the sustained cisplatin-free interval was less than 180 days). The median overall survival estimates for the licensed population were 11.9 months for topotecan plus cisplatin (n = 107) and 7.3 months for cisplatin alone (n = 115) (HR 0.65; 95% CI 0.49 to 0.88; p = 0.0041). The manufacturer completed further subgroup analyses of the licensed population to consider the benefits of topotecan in women who had never had cisplatin (cisplatin naive; n = 120) and those with a sustained cisplatin-free interval longer than 180 days (n = 102). The median overall survival in the cisplatin-naive group was 14.5 months for topotecan plus cisplatin and 8.5 months for cisplatin alone (HR 0.59; 95% CI 0.39 to 0.88; p = 0.0098). The median overall survival in the sustained cisplatin-free interval group was 9.9 months for topotecan plus cisplatin and 6.3 months for cisplatin alone (HR 0.75; 95% CI 0.49 to 1.16; p = 0.1912). The manufacturer identified a trial (GOG-0204) that was not formally included in the clinical-effectiveness review. An abstract reported on this trial, which included a head-to-head comparison of four cisplatin-containing combinations: paclitaxel (n = 103), vinorelbine (n = 108), gemcitabine (n = 112) and topotecan (n = 111). A planned interim analysis recommended early closure of GOG-0204 because the comparator groups were unlikely to demonstrate a statistically significant benefit compared with paclitaxel plus cisplatin. For the comparison of cisplatin plus topotecan with cisplatin plus paclitaxel, the trial reported a hazard ratio for progression-free survival of 1.268 and for overall survival of 1.255. The differences favoured the paclitaxel combination but were not statistically significant. The manufacturer identified another trial (GOG-0169) which was used in an indirect comparison of topotecan plus cisplatin and paclitaxel plus cisplatin. This phase III study compared paclitaxel plus cisplatin (n = 130) with cisplatin alone (n = 134) in women with stage IVB, recurrent, or persistent squamous cell cervical cancer. The trial duration was 24 months. The median overall survival was 9.7 months for paclitaxel plus cisplatin and 8.8 months for cisplatin alone. The median progression-free survival was 4.8 months for paclitaxel plus cisplatin and 2.8 months for cisplatin alone. The manufacturer submitted two separate cost-effectiveness analyses: A within-trial comparison between topotecan plus cisplatin and cisplatin alone using a time horizon of 36 months and patient-level data from the GOG-0179 trial. A model-based comparison of topotecan plus cisplatin and paclitaxel plus cisplatin, using a time horizon of 24 months and data from the GOG-0179 and GOG-0169 trials.In the submission the results of the within-trial comparison were reported as cost per quality-adjusted life year (QALY) gained and in the model-based comparison as cost per life year gained. In response to a request from the ERG, an additional model-based comparison was presented expressing outcomes in terms of both life years gained and QALYs gained. For the within-trial comparison the manufacturer performed separate analyses for the licensed population and subgroups of this population. The subgroups were women who were cisplatin naive and women who had had a sustained cisplatin-free period. The manufacturer stated that the least potentially biased analysis in the model-based comparison would be between the cisplatin-naive population of GOG-0179, including women with persistent disease, and the overall intention-to-treat population of GOG-0169. The manufacturer considered the within-trial comparison to be the primary analysis within their submission. The model-based comparison was presented as a secondary analysis to include alternative comparators used in England and Wales. In the within-trial comparison, the manufacturer included patient-level data for clinical efficacy, safety and quality of life from the GOG-0179 trial. Data on resource use were based on clinical events occurring in the trial supplemented by data from external sources, including expert opinion. Costs were obtained from published sources, including NHS Reference Costs 2006/07. The manufacturer did not give a breakdown of the costs for the within-trial comparison. It was assumed that the cost of topotecan was £488.25 per cycle and the cost of cisplatin was £50.74 per cycle. The cost of topotecan was varied in a sensitivity analysis from £390.60 to £585.90 to reflect minimum wastage of unused topotecan (when vials were reused over the 3-day dosing schedule) and maximum wastage (when vials were discarded immediately after use). The cost of administering topotecan was assumed to be £277 for the first dose of each cycle and £51 for each subsequent dose in each cycle. The manufacturer incorporated quality-of-life benefits into the within-trial comparison using an algorithm linking a disease-specific measure of quality of life (Functional Assessment of Cancer Therapy – General ) to utility. Utility values differed depending on whether a woman was treated with cisplatin alone or topotecan plus cisplatin. Values also differed according to the treatment phase: prior to randomisation, prior to cycle 2, prior to cycle 5 and 9 months after randomisation. The values for the cisplatin-alone group were 0.79, 0.73, 0.58 and 0.33, for these four treatment phases respectively. The corresponding values for the topotecan plus cisplatin group were 0.79, 0.72, 0.66 and 0.45. The manufacturer also included a review of the literature of alternative utility data associated with cervical cancer and other gynaecological cancers (including breast cancer). The utility values used in the sensitivity analysis were identified from a study of breast cancer (Brown and Hutton 1998) and were 0.64 at the start of treatment, 0.81 to reflect response to treatment, 0.39 following progression of disease and 0.16 during the last week of life. In the model-based comparison the manufacturer based the key analysis on aggregate data from indirectly comparing the GOG-0179 and GOG-0169 trials. GOG-0169 did not report the hazard ratio for overall survival, therefore the manufacturer estimated the hazard ratio from the survival curves (HR = 0.87; 95% CI 0.68 to 1.11). The estimated hazard ratio was then applied to the observed overall survival for the cisplatin group of GOG-0179 to estimate the overall survival for paclitaxel plus cisplatin in the model-based comparison. The hazard ratio for the compared trials was 0.72 (95% CI 0.46 to 1.15). An additional sensitivity analysis included direct data on this comparison from the GOG-0204 trial. Resource use in the model-based comparison was based on the costing algorithms developed for the within-trial comparison. The utility values from the literature review were included in the cost per QALY analyses. In the within-trial comparison, the base-case results for the licensed population were an incremental QALY gain of 0.23 at an incremental cost of £4122, giving an incremental cost-effectiveness ratio (ICER) of £17,974 per QALY gained. Probabilistic sensitivity analysis suggested that the probability of topotecan being cost effective at £20,000 and £30,000 per QALY gained was 50% and 88% respectively. For the cisplatin-naive population (including women with stage IVB cervical cancer) the incremental QALY gain was 0.32 at an incremental cost of £3521, giving an ICER of £10,928 per QALY gained. Probabilistic sensitivity analysis suggested that the probability of topotecan being cost effective at £20,000 and £30,000 per QALY gained was 89% and 98% respectively. For the sustained cisplatin-free interval population the incremental QALY gain was 0.13 at an incremental cost of £4145, giving an ICER of £32,463 per QALY gained. Probabilistic sensitivity analysis suggested that the probability of topotecan being cost effective at £20,000 and £30,000 per QALY gained was 31% and 55% respectively. In the model-based comparison, the manufacturer only presented results for the cisplatin-naive population (including women with persistent disease). In the base-case results topotecan plus cisplatin dominated paclitaxel plus cisplatin (that is, paclitaxel plus cisplatin was less effective and more expensive), and had an ICER of £19,964 per life year gained compared with cisplatin alone. Using the hazard ratio from GOG-0204 (rather than from GOG-0169), paclitaxel plus cisplatin had an ICER of £982 per life year gained compared with topotecan plus cisplatin. In response to a request for clarification from the ERG, the manufacturer submitted a revised model-based comparison incorporating health-related quality of life and a time horizon of 36 months. When the hazard ratio from GOG-0169 was used, topotecan plus cisplatin dominated paclitaxel plus cisplatin; when the hazard ratio from GOG-0204 was used, paclitaxel plus cisplatin had an ICER of £13,260 per QALY gained compared with topotecan plus cisplatin. The ERG identified a number of differences between the inclusion criteria of the clinical trials. GOG-0179 included women who were previously untreated, or had received prior chemotherapy or radiotherapy with or without a radiosensitiser. Approximately 60% of women had received prior cisplatin either as chemotherapy or as a radiosensitiser. GOG-0169 excluded women who had received prior chemotherapy, but included women who had been given chemotherapy as part of radiosensitisation (approximately 30%). However, it was unclear how many women received cisplatin as a radiosensitiser. GOG-0204 also excluded women who had previously received chemotherapy, unless this was given as a radiosensitiser, and the proportion of women who had previously received cisplatin as a radiosensitiser was approximately 70%. The ERG considered that GOG-0204 may be more representative of the UK population than GOG-0169, because of the increasing number of women in the UK who receive cisplatin as first-line treatment or as a radiosensitiser. The ERG stated that the manufacturer had included treatments currently used in the UK, but had not explained why other potentially relevant comparators were not included such as cisplatin plus 5-fluorouracil and cisplatin plus mitoxantrone. The ERG stated that it was unclear from the manufacturer's submission whether a complete network of evidence had been identified and investigated. GOG-0179 was a well-conducted randomised controlled trial and it was reasonable for the manufacturer to use this as the direct comparison. However, head-to-head comparisons were also available from GOG-0204. The ERG considered such a direct comparison of topotecan plus cisplatin and paclitaxel plus cisplatin would have been preferable to the indirect comparison used, particularly given the differences in populations between GOG-0169 and GOG-0179. The inclusion of GOG-0204 would also have increased the number of potential comparators and expanded the network of indirect evidence. The ERG stated that a complete validation of the within-trial comparison was not possible because complete data sets and coding had not been provided within the timelines of the ERG critique. In addition, the ERG raised concerns about the external validity of this comparison. When comparing the two economic analyses, the ERG noted a difference in the mean costs obtained from the within-trial comparison and the model-based comparison. The ERG was unable to fully investigate the difference because a breakdown of the costs was not provided for the within-trial comparison. The ERG noted that the utility estimates did not appear to have been derived accurately from the trial because of incorrect mapping of FACT-G data to utility values. In addition, there were concerns about the imputation methods and that the impact of mortality may have been double counted. Furthermore, the ERG questioned the appropriateness of the utility values used in the model-based comparison and sensitivity analysis because they were from a study on metastatic breast cancer and not cervical cancer. The ERG raised concerns about the costing in both analyses, particularly costs relating to administration and adverse events. The ERG undertook a number of exploratory analyses for both the cisplatin-naive and the licensed populations using the model-based comparison. The ERG amended the utility values, the costs of administering topotecan and the assumed number of vials of topotecan used per treatment cycle. The ERG also performed exploratory analyses that considered dose reduction. To address the limitations in the utility values available, the ERG considered three scenarios. The first used the manufacturer's starting utility value (Brown and Hutton 1998; 0.64) adopted for the model-based comparison. The second used a slightly higher starting utility value of 0.67 taken from literature estimates of mean utility values associated with cervical cancer, weighted according to the proportion of patients with each stage of disease in GOG-0179. Values for subsequent health states were calculated using the Brown and Hutton 1998 utility values. This second scenario assumed that utility remained constant from starting treatment to disease progression. The third scenario was the same as the second but used a starting utility value of 0.72 derived from the FACT-G data collected in GOG-0179. The ICERs for topotecan plus cisplatin compared with cisplatin alone for the cisplatin-naive population for the three utility scenarios were £25,309, £26,156 and £24,513 per QALY gained respectively. The ICERs for the licensed population for the three utility scenarios were £55,926, £59,406 and £54,352 per QALY gained respectively. The ERG used the third scenario in all subsequent exploratory analyses because they considered it the most appropriate. The ERG considered that the costs of administering topotecan may have been underestimated. The ERG stated that more appropriate estimates of the administration costs for each treatment could be taken from the health resource group code SB14Z for the delivery of complex chemotherapy, including prolonged infusion treatment at first attendance, and code SB15Z for the delivery of subsequent elements of a chemotherapy cycle, given in NHS Reference Costs 2006/07. The cost code SB14Z (£289, inflated to £299 at 2007/08 prices) was assumed to reflect the administration of cisplatin, paclitaxel plus cisplatin, or the first administration of topotecan plus cisplatin. The cost code SB15Z (£189, inflated to £195 at 2007/08 prices) was assumed to reflect the second and third administration of topotecan for each cycle. The total cost of administering topotecan plus cisplatin was £689 per cycle, while the cost of administering cisplatin alone or paclitaxel plus cisplatin was £299 per cycle. The ICER for topotecan plus cisplatin compared with cisplatin alone (including the amended utilities) was £31,831 per QALY gained in the cisplatin-naive population and £68,885 per QALY gained in the licensed population. The revised administration costs were used in subsequent exploratory analyses. The ERG had concerns about the number of topotecan vials used and the amount of wastage in the manufacturer's analysis. In the cisplatin-naive population the ICERs for topotecan plus cisplatin compared with cisplatin alone (including the amended utilities and administration costs) were £26,778 and £34,327 per QALY gained, for minimum and maximum wastage respectively. For the licensed population the ICERs were £58,872 and £73,833 per QALY gained respectively. The ERG considered that the differences in costs between the within-trial comparison and the model-based comparison may have been because of dose reduction. The ERG therefore calculated the difference in costs between the manufacturer's model-based comparison and the ERG's revised cost estimates. The differences were then applied to the absolute estimates of costs in the within-trial analysis. Both minimum and maximum wastage of vials were considered. When wastage was minimised, the ICER for topotecan plus cisplatin compared with cisplatin alone was £19,815 per QALY gained in the cisplatin-naive population and £53,868 per QALY gained in the licensed population. When maximum wastage of topotecan was assumed, the ICERs were £27,362 and £68,826 per QALY gained respectively. The manufacturer's model-based comparison did not report an ICER for any treatment in comparison with cisplatin alone. The ERG integrated the cost and QALY values for cisplatin into the manufacturer's model-based comparison so that cisplatin could be considered as a comparator alongside topotecan plus cisplatin and paclitaxel plus cisplatin. This allowed for a simultaneous incremental analysis to be carried out between the three treatments. The ERG presented two separate scenarios, one using the hazard ratio from the indirect comparison of GOG-0169 and GOG-0179 and another using the hazard ratio from GOG-0204. Both included the amended utility values and administration costs, but neither included dose reduction. When the hazard ratio from the indirect comparison of GOG-0169 and GOG-0179 was used and minimum wastage assumed, the ICER was £26,778 per QALY gained for topotecan plus cisplatin compared with cisplatin alone in the cisplatin-naive population and £58,872 per QALY gained in the licensed population. When maximum wastage was assumed, the ICER was £34,327 per QALY gained for topotecan plus cisplatin compared with cisplatin alone for the cisplatin-naive population. In this scenario paclitaxel plus cisplatin was extendedly dominated (that is, the ICER was higher than that of the next, more effective, alternative). For the licensed population the ICER for topotecan plus cisplatin compared with paclitaxel plus cisplatin was £116,788 per QALY gained, and the ICER for paclitaxel plus cisplatin in comparison with cisplatin alone was £64,865 per QALY gained. When the GOG-0204 hazard ratio was used, topotecan plus cisplatin was dominated by paclitaxel plus cisplatin regardless of the assumption about topotecan wastage (that is topotecan plus cisplatin was more expensive and less effective than paclitaxel plus cisplatin). The ICER for paclitaxel plus cisplatin compared with cisplatin alone was £17,021 per QALY gained for the cisplatin-naive population and £21,926 per QALY gained for the licensed population. Following consultation on the appraisal consultation document, the manufacturer of topotecan provided a network meta-analysis of clinical-effectiveness data and further economic analyses. The network meta-analysis pooled estimates of effectiveness derived from direct and indirect comparisons of the three relevant clinical trials for cisplatin, paclitaxel plus cisplatin and topotecan plus cisplatin: GOG-0179, GOG-0169 and GOG-0204. The overall survival hazard ratios for the comparison of cisplatin plus paclitaxel with cisplatin alone were 0.83 (95% CI 0.68 to 1.08) for the cisplatin-naive population and 0.81 (95% CI 0.67 to 1.03) for the licensed population, favouring the paclitaxel combination. The corresponding hazard ratios for the comparison of cisplatin plus topotecan with cisplatin alone were 0.75 (95% CI 0.53 to 0.97) and 0.81 (95% CI 0.62 to 0.98), favouring the topotecan combination. For the comparison of cisplatin plus topotecan with cisplatin plus paclitaxel the hazard ratio for the cisplatin-naive population was 0.98 (95% CI 0.73 to 1.23). A hazard ratio was not presented for the licensed population. The manufacturer included the hazard ratios obtained from the network meta-analysis in a revised economic analysis. A further economic analysis was also presented that used the hazard ratio for topotecan from GOG-0179, but data from the meta-analysis for the cisplatin survival curves. In addition, the economic model was updated to provide fully incremental analyses (that is, to provide a simultaneous comparison of all three treatment options) and to include a probabilistic function, to capture the uncertainty of the results. Revised parameter assumptions were also incorporated to include the ERG's preferred utility values, preferred administration costs and assumptions of maximum and minimum wastage. Results were presented for both the licensed population and the cisplatin-naive population. For the licensed population, using the hazard ratios from the meta-analysis and assuming maximum wastage, the ICER for topotecan plus cisplatin was £81,756 per QALY gained in comparison with cisplatin alone and was dominated by paclitaxel plus cisplatin. If minimum wastage of topotecan was assumed, the ICER for topotecan plus cisplatin was £63,913 per QALY gained in comparison with cisplatin alone and was dominated by paclitaxel plus cisplatin. For the licensed population, using the hazard ratios from GOG-0179 for topotecan survival and hazard ratios from the meta-analysis for the cisplatin survival curves, and assuming maximum wastage, the ICER for topotecan plus cisplatin was £60,903 per QALY gained in comparison with cisplatin alone and £65,364 per QALY gained in comparison with paclitaxel plus cisplatin. If minimum wastage of topotecan was assumed, the ICER was £47,616 per QALY gained in comparison with cisplatin alone, and £7142 per QALY gained in comparison with paclitaxel plus cisplatin. For the cisplatin-naive subgroup, using the hazard ratios from the meta-analysis and assuming maximum wastage of topotecan, the ICER for topotecan plus cisplatin was £58,911 per QALY gained in comparison with cisplatin alone, and £49,964 in comparison with paclitaxel plus cisplatin. If minimum wastage of topotecan was assumed, the ICER for topotecan plus cisplatin was £46,054 per QALY gained in comparison with cisplatin alone and £5459 per QALY gained in comparison with paclitaxel plus cisplatin. For the cisplatin-naive subgroup, using the hazard ratios from GOG-0179 for topotecan survival and hazard ratios from the meta-analysis for the cisplatin survival curves, and assuming maximum wastage, the ICER for topotecan plus cisplatin was £30,171 per QALY gained in comparison with cisplatin alone and £11,627 in comparison with paclitaxel plus cisplatin. If minimum wastage of topotecan was assumed, the ICER was £23,586 per QALY gained in comparison with cisplatin alone and £1270 in comparison with paclitaxel plus cisplatin. Full details of all the evidence are in the manufacturer's submission and the ERG report.# Consideration of the evidence The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of topotecan, having considered evidence on the nature of recurrent and stage IVB cervical cancer and the value placed on the benefits of topotecan by women with the condition, those who represent them, and clinical specialists. It also took into account the effective use of NHS resources. # Clinical effectiveness The Committee considered current clinical practice for treating recurrent and stage IVB cervical cancer. The Committee heard from clinical specialists that there is currently no nationally agreed standard treatment for women with this condition. Treatment may consist of topotecan plus cisplatin, cisplatin alone, or paclitaxel plus either carboplatin or cisplatin. The clinical specialists considered that combination therapies were generally more effective than single-agent therapies. They also stated that the main reason for there being no single established treatment regimen is because clinical trials in the past had not shown clinically significant advantages in terms of response rates or overall survival for any single regimen in this patient group. The Committee heard from patient experts that they considered it was important to have a number of treatment options because one may be more suitable than others for the individual patient. For example, the choice of treatment may be influenced by comorbidities such as renal dysfunction. Patient experts also highlighted that for some women topotecan plus cisplatin may be considered a final treatment option. The Committee specifically considered the use of cisplatin to treat recurrent and stage IVB cervical cancer. It heard from clinical specialists that approximately 90–95% of women within the licensed population will have previously received cisplatin because it is standard UK clinical practice to use cisplatin either with radiotherapy or as chemotherapy alone as first-line treatment for cervical cancer. It heard how cervical screening in the UK enables early identification of disease and so initial presentation with stage IVB disease is unusual. The Committee also heard that the dose of cisplatin used in chemotherapy and in chemoradiotherapy is the same. The Committee heard from clinical specialists that previous cisplatin use has a significant effect on response rates to subsequent cisplatin-containing chemotherapy regimens. In cisplatin-naive women, response rates to cisplatin were approximately 45%, which could be higher if combination therapy was used. However, for women who had previously received cisplatin, response rates could be as low as 10%. In addition, the response rates were found to increase as the duration of remission after initial cisplatin treatment increased. The Committee discussed the clinical effectiveness of topotecan plus cisplatin compared with cisplatin alone presented in the main trial. The Committee considered that combination therapy was shown to be more effective than cisplatin alone in the GOG-0179 trial population. The Committee noted the results from the subgroup analyses suggesting that topotecan plus cisplatin was more clinically effective in women who were cisplatin naive than in women who had previously received cisplatin. The Committee considered that the reduced response to topotecan plus cisplatin was evident even when the sustained cisplatin-free interval was longer than 180 days. The Committee examined the trial comparing four combination treatments (GOG-0204), including topotecan plus cisplatin. The Committee was aware that the trial had closed early because none of the other treatment combinations were likely to show a significant benefit over paclitaxel plus cisplatin. The Committee noted that hazard ratios from this trial suggested that paclitaxel plus cisplatin was more effective than the other cisplatin combination therapies, but this difference did not reach statistical significance. The Committee heard from clinical specialists that they did not consider there to be any differences in effectiveness between the different combinations that had been used in this trial. The Committee noted that in this trial approximately 70% of women had received cisplatin as prior chemoradiotherapy. The Committee understood that no specific data for cisplatin-naive women from this trial had been provided. It noted that the manufacturer had also included an indirect comparison of topotecan plus cisplatin with paclitaxel plus cisplatin. The Committee recognised that this comparison suggested that topotecan plus cisplatin was more effective than paclitaxel plus cisplatin, but again the difference did not reach statistical significance. The Committee concluded that there was uncertainty about the differences in effectiveness among combination chemotherapy regimens. When considering the comparative evidence the Committee was aware that there were differences in the trial populations. The Committee considered that the trial of combination therapies (GOG-0204) appropriately reflected the majority of the clinical population in England and Wales, where women often received chemoradiotherapy that included cisplatin. However, the Committee noted that for the subgroup of women who were cisplatin naive, the trial of combination therapies was not representative of this population. The Committee concluded that there was additional uncertainty about the efficacy of topotecan in comparison with paclitaxel and other combination regimens for this subgroup. The Committee discussed the manufacturer's network meta-analysis that was provided after consultation on the appraisal consultation document. The Committee noted that the meta-analysis combined direct and indirect evidence that, when considered individually, did not show consistent effects. In addition, there were differences in the trial populations in terms of prior cisplatin exposure, performance status and disease stage. The Committee heard from the ERG that they did not consider that the data from the trials were exchangeable, and therefore it was inappropriate to carry out a meta-analysis of the data. The Committee also heard from the ERG that the manufacturer's analyses that pooled the data for paclitaxel suggested an estimate of effect similar for both the licensed population and the cisplatin-naive population that was not consistent with the clinical trial or clinical specialists' evidence or biological plausibility. The Committee concluded that in principle a network meta-analysis was an appropriate method of calculating efficacy, but the nature of the evidence available in this situation meant that it could not be considered appropriate as a basis on which to make a decision about the cost effectiveness of topotecan. The Committee considered the adverse event profile of topotecan and recognised that women receiving topotecan plus cisplatin may have more adverse events compared with those receiving cisplatin alone. The Committee heard from clinical specialists specifically about neutropenia and febrile neutropenia. It heard how febrile neutropenia may lead to hospital admission, and may be a more frequent occurrence than for other regimens such as paclitaxel plus cisplatin. However, patient experts mentioned that they considered the safety profile of topotecan plus cisplatin to be manageable, although they were concerned about reported deaths following chemotherapy. They also indicated that quality of life may not be worse for women receiving combination therapy than for women receiving monotherapy, although they were specifically concerned about fatigue. # Cost effectiveness The Committee considered the evidence on the cost effectiveness of topotecan plus cisplatin presented in the manufacturer's submission. The Committee recognised that the manufacturer considered their main analysis to be the within-trial comparison and not the model-based comparison. The Committee noted that the ERG could not completely validate the within-trial comparison and that they considered the manufacturer's model-based comparison to have greater external validity. The ERG had therefore used the model-based comparison as the basis for their exploratory analyses. The Committee noted that in the within-trial comparison the base-case ICER provided by the manufacturer for topotecan plus cisplatin compared with cisplatin alone was £18,000 per QALY gained in the licensed population, £11,000 per QALY gained in the cisplatin-naive population and £32,500 per QALY gained in the sustained cisplatin-free interval population. The Committee noted that the results of the model-based comparison using the hazard ratio derived from the indirect comparison suggested that topotecan plus cisplatin had greater efficacy and lower costs than paclitaxel plus cisplatin. However, when the hazard ratio from the trial comparing different combination therapies directly was used, paclitaxel plus cisplatin was more effective and less costly than topotecan plus cisplatin. The Committee considered the utility estimates provided by the manufacturer. The Committee heard from the ERG that the manufacturer had incorrectly mapped disease-specific quality of life to utility and that correcting this led to a lower starting utility of 0.72 instead of 0.79. The ERG also expressed concerns about the mapping equation used in the base-case analysis, including the transparency of the analysis and imputation methods. The ERG suggested that combining their amended starting utility from the main clinical trial with data identified by the manufacturer from a study of metastatic breast cancer could be more appropriate. The Committee recognised that neither approach to estimating utilities reflected the reference case and considered that both sets of utility estimates were associated with uncertainty. However, on balance the Committee considered that utility values suggested by the ERG, which led to more favourable ICERs, may be more appropriate than those provided by the manufacturer. The Committee considered the manufacturer's assumptions about the number of topotecan vials required in clinical practice and the administration costs. The Committee heard that the manufacturer may have underestimated the administration costs for topotecan on days 2 and 3 because they had used an assessment report from a previous appraisal that had built up the costs without the appropriate health resource group codes being available. The ERG stated that these codes were now available and that the cost for administering the second and third infusion of topotecan would be £195 rather than £51. The Committee considered that the revised administration costs proposed by the ERG were appropriate. The Committee also heard from the ERG that the manufacturer had not assumed minimum or maximum wastage of excess topotecan, but used a midpoint. The ERG considered that an assumption of maximum wastage may be more consistent with the SPC. The Committee heard from clinical specialists that although women were grouped so that drug wastage could be reduced, there was less opportunity to group women receiving topotecan because of the small number of women who receive the drug. The Committee considered that although there was uncertainty about the manufacturer's estimate of topotecan wastage, assumptions of either minimum or maximum wastage may also not be accurate. The Committee noted that there appeared to be inconsistencies between the mean cost estimates in the within-trial comparison and the model-based comparison. The Committee heard from the ERG that this may be because dose reduction related to adverse events was included in the within-trial comparison but not in the model-based comparison. However, without a breakdown of costs, the ERG was unable to confirm this. In addition, there were no data on how the use of paclitaxel may be affected by dose reduction. The Committee considered that dose reduction could be important and the ERG's exploratory analyses showed that dose reduction could lower the ICER. However, the Committee was not persuaded that the cost estimates including dose reduction were sufficiently robust for these to form the basis of their examination of the cost effectiveness of topotecan. The Committee considered how adverse events had been included in the model-based comparison. The Committee heard from clinical specialists that the manufacturer's assumption that an adverse event lasted only a week was appropriate. The Committee noted that only the most severe adverse event was taken into account in the manufacturer's analysis even if two or more adverse events were experienced concurrently. The clinical specialists agreed that there may be a further negative impact on quality of life for women who have two concurrent adverse events. Overall the Committee considered that the manufacturer may have underestimated the reduction in quality of life associated with multiple adverse events. The Committee first considered the fully incremental exploratory analysis for the licensed population undertaken by the ERG that incorporated amended administration costs and utility values. The Committee noted that, for the licensed population, using the hazard ratio from the indirect comparison, the ICER for topotecan plus cisplatin compared with cisplatin alone was £59,000 per QALY gained when minimum wastage was assumed, and the ICER for topotecan plus cisplatin compared with paclitaxel plus cisplatin was £117,000 per QALY gained when maximum wastage was assumed. The Committee was also aware that when the hazard ratio derived from the trial of different combination therapies was used, topotecan plus cisplatin was dominated by paclitaxel plus cisplatin. The Committee considered that the trial of different combination therapies (GOG-0204) was more representative of the patient population in England and Wales than the other available evidence. The Committee therefore concluded that for the licensed population, the cost-effectiveness data suggested that topotecan in combination with cisplatin was not a cost-effective use of NHS resources. The Committee considered supplementary advice from NICE that should be taken into account when appraising treatments which may extend the life of patients with a short life expectancy and which are licensed for indications that affect small numbers of people with incurable illnesses. For this advice to be applied, all the following criteria must be met: The treatment is indicated for patients with a short life expectancy, normally less than 24 months. There is sufficient evidence to indicate that the treatment offers an extension to life, normally of at least an additional 3 months, compared with current NHS treatment. The treatment is licensed or otherwise indicated for small patient populations.In addition, when taking these into account the Committee must be persuaded that the estimates of the extension to life are robust and the assumptions used in the reference-case economic modelling are plausible, objective and robust. The Committee considered that the life expectancy for women with recurrent and stage IVB cervical cancer would normally be less than 24 months. The Committee noted that topotecan was licensed for multiple indications, but it could still be considered to be indicated for a small patient population. The Committee discussed the additional benefits provided by topotecan in comparison with other therapies available on the NHS. It noted the clinical trial results from GOG-0179 and agreed that for the licensed population topotecan plus cisplatin had demonstrated a gain in life expectancy of more than 3 months in comparison with cisplatin alone. However, the Committee was aware that the majority of women receive combination therapies in the NHS. The Committee noted the results of the trial of combination therapies (GOG-0204), which had closed early because none of the treatments including topotecan were likely to show a significant benefit over paclitaxel plus cisplatin. The Committee also noted the clinical specialists' comments that they considered there to be equal efficacy among the different combination treatments in GOG-0204. On balance, the Committee considered that, for the licensed population, topotecan plus cisplatin compared with other combination therapies currently available in the NHS had not shown an additional benefit of 3 months. The Committee therefore concluded that topotecan plus cisplatin did not fulfil the criteria for consideration of NICE's supplementary advice on end of life and agreed that topotecan in combination with cisplatin could not be recommended as a cost-effective use of NHS resources. The Committee then considered the subgroup of women who had not previously received cisplatin. The Committee noted that the manufacturer's estimates suggested topotecan plus cisplatin may be cost effective in this group. The Committee considered the ERG's exploratory analyses for this subgroup. When the hazard ratios from the indirect comparison were used the ICER for topotecan plus cisplatin compared with cisplatin alone was £26,800 per QALY gained assuming minimum wastage, and £34,000 per QALY gained assuming maximum wastage. The Committee recognised that this did not include dose reduction, which the ERG had suggested could further reduce these ICERs. The Committee was aware that when the hazard ratios from the trial of different combination therapies were used, topotecan plus cisplatin was dominated by paclitaxel plus cisplatin, but that this evidence was predominantly from a population who had received cisplatin as a radiosensitiser before. Because the indirect comparison was the only data available in which the majority of women were cisplatin naive, the Committee was persuaded that topotecan plus cisplatin could be considered an appropriate use of NHS resources for the treatment of women who have not previously received cisplatin. In light of the duty to have due regard to the need to eliminate unlawful discrimination and promote equality, the Committee discussed the higher prevalence of cervical cancer among women living in the most socioeconomically deprived areas, as outlined by the patient expert statements. It also discussed comments received during consultation on the appraisal consultation document. The Committee noted that a negative recommendation for topotecan in combination with cisplatin for the group of women with prior exposure to cisplatin does not impact particularly on any group protected by the equalities legislation. In addition, given the uncertainty about whether topotecan in combination with cisplatin is more clinically effective than other combination therapies for the treatment of cervical cancer in women with prior exposure to cisplatin, and the availability of alternative treatment options, the Committee was satisfied that its recommendation was consistent with NICE's obligations under the equalities legislation and the requirement for fairness.# Related NICE guidance High dose rate brachytherapy for carcinoma of the cervix. NICE interventional procedure guidance 160 (2006). Guidance on the use of liquid-based cytology for cervical screening (review). NICE technology appraisal guidance 69 (2003).# Review of guidance NICE proposes that the guidance on this technology is considered for review by the Guidance Executive in September 2012. NICE welcomes comment on this proposed date. The Guidance Executive will decide whether the technology should be reviewed based on information gathered by NICE, and in consultation with consultees and commentators. Andrew DillonChief ExecutiveOctober 2009# Changes after publication February 2014: implementation section updated to clarify that topotecan is recommended as an option for treating recurrent or stage IVB cervical cancer. Additional minor maintenance update also carried out. March 2012: minor maintenance# About this guidance NICE technology appraisal guidance is about the use of new and existing medicines and treatments in the NHS in England and Wales. This guidance was developed using the NICE single technology appraisal process. We have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available. Your responsibility This guidance represents the views of NICE and was arrived at after careful consideration of the evidence available. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. However, the guidance does not override the individual responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or guardian or carer. Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties. Copyright © National Institute for Health and Clinical Excellence 2009. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.	{'Guidance': 'Topotecan in combination with cisplatin is recommended as a treatment option for women with recurrent or stage IVB cervical cancer only if they have not previously received cisplatin.\n\nWomen who have previously received cisplatin and are currently being treated with topotecan in combination with cisplatin for recurrent and stage IVB cervical cancer should have the option to continue their therapy until they and their clinicians consider it appropriate to stop.', 'The technology': "Topotecan (Hycamtin, GlaxoSmithKline) prevents DNA replication in cancer cells by inhibiting the enzyme topoisomerase I. Topotecan in combination with cisplatin has a marketing authorisation for patients with carcinoma of the cervix recurrent after radiotherapy and for patients with stage IVB disease. The summary of product characteristics (SPC) states that patients with prior exposure to cisplatin require a sustained treatment-free interval to justify treatment with topotecan in combination with cisplatin.\n\nThe recommended dosage is 0.75\xa0mg/m2/day topotecan, administered as a 30-minute intravenous infusion on days 1, 2 and 3 of each cycle. Cisplatin is administered after topotecan as an intravenous infusion on day 1 at a dosage of 50\xa0mg/m2/day. Treatment should be repeated every 21\xa0days for six cycles or until disease progresses. Topotecan should only be readministered if the neutrophil count is at least 1.5\xa0x\xa0109 per litre, the platelet count is at least 100\xa0x\xa0109 per litre, and the haemoglobin level is at least 9\xa0g/100\xa0ml (after transfusion if necessary). The SPC states that topotecan should only be used in units specialised in the administration of cytotoxic chemotherapy and it should only be administered under the supervision of a physician experienced in the use of chemotherapy.\n\nAdverse effects commonly associated with topotecan include nausea, vomiting, neutropenia, leukopenia, anaemia, fatigue and alopecia. Topotecan is not recommended in patients with severe renal or hepatic impairment. Cisplatin causes nausea and vomiting in the majority of patients. Serious toxic effects of cisplatin on the kidneys, bone marrow and hearing function are common. Serum electrolyte disturbances, hyperuricaemia, allergic reactions and cardiovascular abnormalities have also been reported. For full details of adverse effects and contraindications, see the SPC.\n\nThe acquisition cost of topotecan is £97.65 for a 1-mg vial or £290.62 for a 4-mg vial (excluding VAT; 'British national formulary' [BNF] edition 57). The acquisition cost of cisplatin is £24.50 for a 50-mg vial or £50.22 for a 100-mg vial (excluding VAT; BNF edition 57). Assuming a body surface area of 1.7\xa0m2, the total dose per cycle would be 3.825\xa0mg topotecan (that is, 1.275\xa0mg/day). Assuming excess topotecan is wasted after each dose, a total of six 1-mg vials would be required at a cost of £585.90. For cisplatin, the cost for the required 85\xa0mg would be £49 for two 50-mg vials. The cost of topotecan for a full course of six cycles is £3515.40. Costs may vary in different settings because of negotiated procurement discounts.", "The manufacturer's submission": "The Appraisal Committee (appendix A) considered evidence submitted by the manufacturer of topotecan and a review of this submission by the Evidence Review Group (ERG; appendix B).\n\nIn the submission, the manufacturer compared topotecan plus cisplatin with cisplatin alone. The manufacturer also compared topotecan plus cisplatin with paclitaxel plus cisplatin. The manufacturer justified their choice of comparator with data from the IMS Oncology Analyzer database from 2004 to 2008 to show that cisplatin alone is the most frequently used therapy in the group of women for whom topotecan plus cisplatin is licensed (39%). A more recent breakdown of the IMS Oncology Analyzer database from 2006 to 2008 indicates that 27% of patients receive cisplatin alone; 23% receive carboplatin plus paclitaxel. There are a range of other combination therapies, each of which is given to fewer than 10% of patients. In total 57% of patients receive some form of combination therapy.\n\nThe manufacturer identified one phase III, open-label randomised controlled trial (GOG-0179; n\xa0=\xa0293) that included women with persistent, recurrent or stage IVB cervical cancer and compared topotecan plus cisplatin with cisplatin alone. These women were followed up for a maximum of 36\xa0months. The trial reported increased median overall survival for topotecan plus cisplatin compared with cisplatin alone: 9.4 versus 6.5\xa0months, respectively (hazard ratio [HR] 0.76; 95% confidence interval [CI] 0.59 to 0.98; p\xa0=\xa00.033), and increased median progression-free survival for topotecan plus cisplatin compared with cisplatin alone: 4.6 versus 2.9\xa0months, respectively (HR 0.76; 95% CI 0.60 to 0.97; p\xa0=\xa00.027).\n\nThe manufacturer reported that the safety profile for topotecan plus cisplatin was predictable and manageable. However, there were four treatment-related deaths in the topotecan plus cisplatin group compared with none in the cisplatin group. Febrile neutropenia occurred in 17.7% of women treated with topotecan plus cisplatin and in 7.5% of women treated with cisplatin alone. Serious adverse events occurred in 10% of women treated with cisplatin alone compared with 14% of women treated with topotecan plus cisplatin.\n\nThe manufacturer presented data on subpopulations of the GOG-0179 trial. The 'licensed population', which consisted of 222\xa0women, was defined as the population for whom topotecan is indicated in the marketing authorisation. Data from the other 71\xa0women in the trial were excluded because they had cervical cancer that was not covered by the marketing authorisation (32\xa0women had persistent disease and in 39\xa0women the sustained cisplatin-free interval was less than 180\xa0days). The median overall survival estimates for the licensed population were 11.9\xa0months for topotecan plus cisplatin (n\xa0=\xa0107) and 7.3\xa0months for cisplatin alone (n\xa0=\xa0115) (HR 0.65; 95% CI 0.49 to 0.88; p\xa0=\xa00.0041).\n\nThe manufacturer completed further subgroup analyses of the licensed population to consider the benefits of topotecan in women who had never had cisplatin (cisplatin naive; n\xa0=\xa0120) and those with a sustained cisplatin-free interval longer than 180\xa0days (n\xa0=\xa0102). The median overall survival in the cisplatin-naive group was 14.5\xa0months for topotecan plus cisplatin and 8.5\xa0months for cisplatin alone (HR 0.59; 95% CI 0.39 to 0.88; p\xa0=\xa00.0098). The median overall survival in the sustained cisplatin-free interval group was 9.9\xa0months for topotecan plus cisplatin and 6.3\xa0months for cisplatin alone (HR 0.75; 95% CI 0.49 to 1.16; p\xa0=\xa00.1912).\n\nThe manufacturer identified a trial (GOG-0204) that was not formally included in the clinical-effectiveness review. An abstract reported on this trial, which included a head-to-head comparison of four cisplatin-containing combinations: paclitaxel (n\xa0=\xa0103), vinorelbine (n\xa0=\xa0108), gemcitabine (n\xa0=\xa0112) and topotecan (n\xa0=\xa0111). A planned interim analysis recommended early closure of GOG-0204 because the comparator groups were unlikely to demonstrate a statistically significant benefit compared with paclitaxel plus cisplatin. For the comparison of cisplatin plus topotecan with cisplatin plus paclitaxel, the trial reported a hazard ratio for progression-free survival of 1.268 and for overall survival of 1.255. The differences favoured the paclitaxel combination but were not statistically significant.\n\nThe manufacturer identified another trial (GOG-0169) which was used in an indirect comparison of topotecan plus cisplatin and paclitaxel plus cisplatin. This phase III study compared paclitaxel plus cisplatin (n\xa0=\xa0130) with cisplatin alone (n\xa0=\xa0134) in women with stage IVB, recurrent, or persistent squamous cell cervical cancer. The trial duration was 24\xa0months. The median overall survival was 9.7\xa0months for paclitaxel plus cisplatin and 8.8\xa0months for cisplatin alone. The median progression-free survival was 4.8\xa0months for paclitaxel plus cisplatin and 2.8\xa0months for cisplatin alone.\n\nThe manufacturer submitted two separate cost-effectiveness analyses:\n\nA within-trial comparison between topotecan plus cisplatin and cisplatin alone using a time horizon of 36\xa0months and patient-level data from the GOG-0179 trial.\n\nA model-based comparison of topotecan plus cisplatin and paclitaxel plus cisplatin, using a time horizon of 24\xa0months and data from the GOG-0179 and GOG-0169 trials.In the submission the results of the within-trial comparison were reported as cost per quality-adjusted life year (QALY) gained and in the model-based comparison as cost per life year gained. In response to a request from the ERG, an additional model-based comparison was presented expressing outcomes in terms of both life years gained and QALYs gained.\n\nFor the within-trial comparison the manufacturer performed separate analyses for the licensed population and subgroups of this population. The subgroups were women who were cisplatin naive and women who had had a sustained cisplatin-free period. The manufacturer stated that the least potentially biased analysis in the model-based comparison would be between the cisplatin-naive population of GOG-0179, including women with persistent disease, and the overall intention-to-treat population of GOG-0169. The manufacturer considered the within-trial comparison to be the primary analysis within their submission. The model-based comparison was presented as a secondary analysis to include alternative comparators used in England and Wales.\n\nIn the within-trial comparison, the manufacturer included patient-level data for clinical efficacy, safety and quality of life from the GOG-0179 trial. Data on resource use were based on clinical events occurring in the trial supplemented by data from external sources, including expert opinion. Costs were obtained from published sources, including NHS Reference Costs 2006/07. The manufacturer did not give a breakdown of the costs for the within-trial comparison. It was assumed that the cost of topotecan was £488.25 per cycle and the cost of cisplatin was £50.74 per cycle. The cost of topotecan was varied in a sensitivity analysis from £390.60 to £585.90 to reflect minimum wastage of unused topotecan (when vials were reused over the 3-day dosing schedule) and maximum wastage (when vials were discarded immediately after use). The cost of administering topotecan was assumed to be £277 for the first dose of each cycle and £51 for each subsequent dose in each cycle.\n\nThe manufacturer incorporated quality-of-life benefits into the within-trial comparison using an algorithm linking a disease-specific measure of quality of life (Functional Assessment of Cancer Therapy – General [FACT-G]) to utility. Utility values differed depending on whether a woman was treated with cisplatin alone or topotecan plus cisplatin. Values also differed according to the treatment phase: prior to randomisation, prior to cycle 2, prior to cycle 5 and 9\xa0months after randomisation. The values for the cisplatin-alone group were 0.79, 0.73, 0.58 and 0.33, for these four treatment phases respectively. The corresponding values for the topotecan plus cisplatin group were 0.79, 0.72, 0.66 and 0.45. The manufacturer also included a review of the literature of alternative utility data associated with cervical cancer and other gynaecological cancers (including breast cancer). The utility values used in the sensitivity analysis were identified from a study of breast cancer (Brown and Hutton 1998) and were 0.64 at the start of treatment, 0.81 to reflect response to treatment, 0.39 following progression of disease and 0.16 during the last week of life.\n\nIn the model-based comparison the manufacturer based the key analysis on aggregate data from indirectly comparing the GOG-0179 and GOG-0169 trials. GOG-0169 did not report the hazard ratio for overall survival, therefore the manufacturer estimated the hazard ratio from the survival curves (HR\xa0=\xa00.87; 95% CI 0.68 to 1.11). The estimated hazard ratio was then applied to the observed overall survival for the cisplatin group of GOG-0179 to estimate the overall survival for paclitaxel plus cisplatin in the model-based comparison. The hazard ratio for the compared trials was 0.72 (95% CI 0.46 to 1.15). An additional sensitivity analysis included direct data on this comparison from the GOG-0204 trial. Resource use in the model-based comparison was based on the costing algorithms developed for the within-trial comparison. The utility values from the literature review were included in the cost per QALY analyses.\n\nIn the within-trial comparison, the base-case results for the licensed population were an incremental QALY gain of 0.23 at an incremental cost of £4122, giving an incremental cost-effectiveness ratio (ICER) of £17,974 per QALY gained. Probabilistic sensitivity analysis suggested that the probability of topotecan being cost effective at £20,000 and £30,000 per QALY gained was 50% and 88% respectively. For the cisplatin-naive population (including women with stage IVB cervical cancer) the incremental QALY gain was 0.32 at an incremental cost of £3521, giving an ICER of £10,928 per QALY gained. Probabilistic sensitivity analysis suggested that the probability of topotecan being cost effective at £20,000 and £30,000 per QALY gained was 89% and 98% respectively. For the sustained cisplatin-free interval population the incremental QALY gain was 0.13 at an incremental cost of £4145, giving an ICER of £32,463 per QALY gained. Probabilistic sensitivity analysis suggested that the probability of topotecan being cost effective at £20,000 and £30,000 per QALY gained was 31% and 55% respectively.\n\nIn the model-based comparison, the manufacturer only presented results for the cisplatin-naive population (including women with persistent disease). In the base-case results topotecan plus cisplatin dominated paclitaxel plus cisplatin (that is, paclitaxel plus cisplatin was less effective and more expensive), and had an ICER of £19,964 per life year gained compared with cisplatin alone. Using the hazard ratio from GOG-0204 (rather than from GOG-0169), paclitaxel plus cisplatin had an ICER of £982 per life year gained compared with topotecan plus cisplatin. In response to a request for clarification from the ERG, the manufacturer submitted a revised model-based comparison incorporating health-related quality of life and a time horizon of 36\xa0months. When the hazard ratio from GOG-0169 was used, topotecan plus cisplatin dominated paclitaxel plus cisplatin; when the hazard ratio from GOG-0204 was used, paclitaxel plus cisplatin had an ICER of £13,260 per QALY gained compared with topotecan plus cisplatin.\n\nThe ERG identified a number of differences between the inclusion criteria of the clinical trials. GOG-0179 included women who were previously untreated, or had received prior chemotherapy or radiotherapy with or without a radiosensitiser. Approximately 60% of women had received prior cisplatin either as chemotherapy or as a radiosensitiser. GOG-0169 excluded women who had received prior chemotherapy, but included women who had been given chemotherapy as part of radiosensitisation (approximately 30%). However, it was unclear how many women received cisplatin as a radiosensitiser. GOG-0204 also excluded women who had previously received chemotherapy, unless this was given as a radiosensitiser, and the proportion of women who had previously received cisplatin as a radiosensitiser was approximately 70%. The ERG considered that GOG-0204 may be more representative of the UK population than GOG-0169, because of the increasing number of women in the UK who receive cisplatin as first-line treatment or as a radiosensitiser. The ERG stated that the manufacturer had included treatments currently used in the UK, but had not explained why other potentially relevant comparators were not included such as cisplatin plus 5-fluorouracil and cisplatin plus mitoxantrone.\n\nThe ERG stated that it was unclear from the manufacturer's submission whether a complete network of evidence had been identified and investigated. GOG-0179 was a well-conducted randomised controlled trial and it was reasonable for the manufacturer to use this as the direct comparison. However, head-to-head comparisons were also available from GOG-0204. The ERG considered such a direct comparison of topotecan plus cisplatin and paclitaxel plus cisplatin would have been preferable to the indirect comparison used, particularly given the differences in populations between GOG-0169 and GOG-0179. The inclusion of GOG-0204 would also have increased the number of potential comparators and expanded the network of indirect evidence.\n\nThe ERG stated that a complete validation of the within-trial comparison was not possible because complete data sets and coding had not been provided within the timelines of the ERG critique. In addition, the ERG raised concerns about the external validity of this comparison. When comparing the two economic analyses, the ERG noted a difference in the mean costs obtained from the within-trial comparison and the model-based comparison. The ERG was unable to fully investigate the difference because a breakdown of the costs was not provided for the within-trial comparison. The ERG noted that the utility estimates did not appear to have been derived accurately from the trial because of incorrect mapping of FACT-G data to utility values. In addition, there were concerns about the imputation methods and that the impact of mortality may have been double counted. Furthermore, the ERG questioned the appropriateness of the utility values used in the model-based comparison and sensitivity analysis because they were from a study on metastatic breast cancer and not cervical cancer. The ERG raised concerns about the costing in both analyses, particularly costs relating to administration and adverse events.\n\nThe ERG undertook a number of exploratory analyses for both the cisplatin-naive and the licensed populations using the model-based comparison. The ERG amended the utility values, the costs of administering topotecan and the assumed number of vials of topotecan used per treatment cycle. The ERG also performed exploratory analyses that considered dose reduction.\n\nTo address the limitations in the utility values available, the ERG considered three scenarios. The first used the manufacturer's starting utility value (Brown and Hutton 1998; 0.64) adopted for the model-based comparison. The second used a slightly higher starting utility value of 0.67 taken from literature estimates of mean utility values associated with cervical cancer, weighted according to the proportion of patients with each stage of disease in GOG-0179. Values for subsequent health states were calculated using the Brown and Hutton 1998 utility values. This second scenario assumed that utility remained constant from starting treatment to disease progression. The third scenario was the same as the second but used a starting utility value of 0.72 derived from the FACT-G data collected in GOG-0179. The ICERs for topotecan plus cisplatin compared with cisplatin alone for the cisplatin-naive population for the three utility scenarios were £25,309, £26,156 and £24,513 per QALY gained respectively. The ICERs for the licensed population for the three utility scenarios were £55,926, £59,406 and £54,352 per QALY gained respectively. The ERG used the third scenario in all subsequent exploratory analyses because they considered it the most appropriate.\n\nThe ERG considered that the costs of administering topotecan may have been underestimated. The ERG stated that more appropriate estimates of the administration costs for each treatment could be taken from the health resource group code SB14Z for the delivery of complex chemotherapy, including prolonged infusion treatment at first attendance, and code SB15Z for the delivery of subsequent elements of a chemotherapy cycle, given in NHS Reference Costs 2006/07. The cost code SB14Z (£289, inflated to £299 at 2007/08 prices) was assumed to reflect the administration of cisplatin, paclitaxel plus cisplatin, or the first administration of topotecan plus cisplatin. The cost code SB15Z (£189, inflated to £195 at 2007/08 prices) was assumed to reflect the second and third administration of topotecan for each cycle. The total cost of administering topotecan plus cisplatin was £689 per cycle, while the cost of administering cisplatin alone or paclitaxel plus cisplatin was £299 per cycle. The ICER for topotecan plus cisplatin compared with cisplatin alone (including the amended utilities) was £31,831 per QALY gained in the cisplatin-naive population and £68,885 per QALY gained in the licensed population. The revised administration costs were used in subsequent exploratory analyses.\n\nThe ERG had concerns about the number of topotecan vials used and the amount of wastage in the manufacturer's analysis. In the cisplatin-naive population the ICERs for topotecan plus cisplatin compared with cisplatin alone (including the amended utilities and administration costs) were £26,778 and £34,327 per QALY gained, for minimum and maximum wastage respectively. For the licensed population the ICERs were £58,872 and £73,833 per QALY gained respectively.\n\nThe ERG considered that the differences in costs between the within-trial comparison and the model-based comparison may have been because of dose reduction. The ERG therefore calculated the difference in costs between the manufacturer's model-based comparison and the ERG's revised cost estimates. The differences were then applied to the absolute estimates of costs in the within-trial analysis. Both minimum and maximum wastage of vials were considered. When wastage was minimised, the ICER for topotecan plus cisplatin compared with cisplatin alone was £19,815 per QALY gained in the cisplatin-naive population and £53,868 per QALY gained in the licensed population. When maximum wastage of topotecan was assumed, the ICERs were £27,362 and £68,826 per QALY gained respectively.\n\nThe manufacturer's model-based comparison did not report an ICER for any treatment in comparison with cisplatin alone. The ERG integrated the cost and QALY values for cisplatin into the manufacturer's model-based comparison so that cisplatin could be considered as a comparator alongside topotecan plus cisplatin and paclitaxel plus cisplatin. This allowed for a simultaneous incremental analysis to be carried out between the three treatments. The ERG presented two separate scenarios, one using the hazard ratio from the indirect comparison of GOG-0169 and GOG-0179 and another using the hazard ratio from GOG-0204. Both included the amended utility values and administration costs, but neither included dose reduction. When the hazard ratio from the indirect comparison of GOG-0169 and GOG-0179 was used and minimum wastage assumed, the ICER was £26,778 per QALY gained for topotecan plus cisplatin compared with cisplatin alone in the cisplatin-naive population and £58,872 per QALY gained in the licensed population. When maximum wastage was assumed, the ICER was £34,327 per QALY gained for topotecan plus cisplatin compared with cisplatin alone for the cisplatin-naive population. In this scenario paclitaxel plus cisplatin was extendedly dominated (that is, the ICER was higher than that of the next, more effective, alternative). For the licensed population the ICER for topotecan plus cisplatin compared with paclitaxel plus cisplatin was £116,788 per QALY gained, and the ICER for paclitaxel plus cisplatin in comparison with cisplatin alone was £64,865 per QALY gained. When the GOG-0204 hazard ratio was used, topotecan plus cisplatin was dominated by paclitaxel plus cisplatin regardless of the assumption about topotecan wastage (that is topotecan plus cisplatin was more expensive and less effective than paclitaxel plus cisplatin). The ICER for paclitaxel plus cisplatin compared with cisplatin alone was £17,021 per QALY gained for the cisplatin-naive population and £21,926 per QALY gained for the licensed population.\n\nFollowing consultation on the appraisal consultation document, the manufacturer of topotecan provided a network meta-analysis of clinical-effectiveness data and further economic analyses. The network meta-analysis pooled estimates of effectiveness derived from direct and indirect comparisons of the three relevant clinical trials for cisplatin, paclitaxel plus cisplatin and topotecan plus cisplatin: GOG-0179, GOG-0169 and GOG-0204. The overall survival hazard ratios for the comparison of cisplatin plus paclitaxel with cisplatin alone were 0.83 (95% CI 0.68 to 1.08) for the cisplatin-naive population and 0.81 (95% CI 0.67 to 1.03) for the licensed population, favouring the paclitaxel combination. The corresponding hazard ratios for the comparison of cisplatin plus topotecan with cisplatin alone were 0.75 (95% CI 0.53 to 0.97) and 0.81 (95% CI 0.62 to 0.98), favouring the topotecan combination. For the comparison of cisplatin plus topotecan with cisplatin plus paclitaxel the hazard ratio for the cisplatin-naive population was 0.98 (95% CI 0.73 to 1.23). A hazard ratio was not presented for the licensed population.\n\nThe manufacturer included the hazard ratios obtained from the network meta-analysis in a revised economic analysis. A further economic analysis was also presented that used the hazard ratio for topotecan from GOG-0179, but data from the meta-analysis for the cisplatin survival curves. In addition, the economic model was updated to provide fully incremental analyses (that is, to provide a simultaneous comparison of all three treatment options) and to include a probabilistic function, to capture the uncertainty of the results. Revised parameter assumptions were also incorporated to include the ERG's preferred utility values, preferred administration costs and assumptions of maximum and minimum wastage. Results were presented for both the licensed population and the cisplatin-naive population.\n\nFor the licensed population, using the hazard ratios from the meta-analysis and assuming maximum wastage, the ICER for topotecan plus cisplatin was £81,756 per QALY gained in comparison with cisplatin alone and was dominated by paclitaxel plus cisplatin. If minimum wastage of topotecan was assumed, the ICER for topotecan plus cisplatin was £63,913 per QALY gained in comparison with cisplatin alone and was dominated by paclitaxel plus cisplatin.\n\nFor the licensed population, using the hazard ratios from GOG-0179 for topotecan survival and hazard ratios from the meta-analysis for the cisplatin survival curves, and assuming maximum wastage, the ICER for topotecan plus cisplatin was £60,903 per QALY gained in comparison with cisplatin alone and £65,364 per QALY gained in comparison with paclitaxel plus cisplatin. If minimum wastage of topotecan was assumed, the ICER was £47,616 per QALY gained in comparison with cisplatin alone, and £7142 per QALY gained in comparison with paclitaxel plus cisplatin.\n\nFor the cisplatin-naive subgroup, using the hazard ratios from the meta-analysis and assuming maximum wastage of topotecan, the ICER for topotecan plus cisplatin was £58,911 per QALY gained in comparison with cisplatin alone, and £49,964 in comparison with paclitaxel plus cisplatin. If minimum wastage of topotecan was assumed, the ICER for topotecan plus cisplatin was £46,054 per QALY gained in comparison with cisplatin alone and £5459 per QALY gained in comparison with paclitaxel plus cisplatin.\n\nFor the cisplatin-naive subgroup, using the hazard ratios from GOG-0179 for topotecan survival and hazard ratios from the meta-analysis for the cisplatin survival curves, and assuming maximum wastage, the ICER for topotecan plus cisplatin was £30,171 per QALY gained in comparison with cisplatin alone and £11,627 in comparison with paclitaxel plus cisplatin. If minimum wastage of topotecan was assumed, the ICER was £23,586 per QALY gained in comparison with cisplatin alone and £1270 in comparison with paclitaxel plus cisplatin.\n\nFull details of all the evidence are in the manufacturer's submission and the ERG report.", 'Consideration of the evidence': "The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of topotecan, having considered evidence on the nature of recurrent and stage IVB cervical cancer and the value placed on the benefits of topotecan by women with the condition, those who represent them, and clinical specialists. It also took into account the effective use of NHS resources.\n\n# Clinical effectiveness\n\nThe Committee considered current clinical practice for treating recurrent and stage IVB cervical cancer. The Committee heard from clinical specialists that there is currently no nationally agreed standard treatment for women with this condition. Treatment may consist of topotecan plus cisplatin, cisplatin alone, or paclitaxel plus either carboplatin or cisplatin. The clinical specialists considered that combination therapies were generally more effective than single-agent therapies. They also stated that the main reason for there being no single established treatment regimen is because clinical trials in the past had not shown clinically significant advantages in terms of response rates or overall survival for any single regimen in this patient group. The Committee heard from patient experts that they considered it was important to have a number of treatment options because one may be more suitable than others for the individual patient. For example, the choice of treatment may be influenced by comorbidities such as renal dysfunction. Patient experts also highlighted that for some women topotecan plus cisplatin may be considered a final treatment option.\n\nThe Committee specifically considered the use of cisplatin to treat recurrent and stage IVB cervical cancer. It heard from clinical specialists that approximately 90–95% of women within the licensed population will have previously received cisplatin because it is standard UK clinical practice to use cisplatin either with radiotherapy or as chemotherapy alone as first-line treatment for cervical cancer. It heard how cervical screening in the UK enables early identification of disease and so initial presentation with stage IVB disease is unusual. The Committee also heard that the dose of cisplatin used in chemotherapy and in chemoradiotherapy is the same.\n\nThe Committee heard from clinical specialists that previous cisplatin use has a significant effect on response rates to subsequent cisplatin-containing chemotherapy regimens. In cisplatin-naive women, response rates to cisplatin were approximately 45%, which could be higher if combination therapy was used. However, for women who had previously received cisplatin, response rates could be as low as 10%. In addition, the response rates were found to increase as the duration of remission after initial cisplatin treatment increased.\n\nThe Committee discussed the clinical effectiveness of topotecan plus cisplatin compared with cisplatin alone presented in the main trial. The Committee considered that combination therapy was shown to be more effective than cisplatin alone in the GOG-0179 trial population. The Committee noted the results from the subgroup analyses suggesting that topotecan plus cisplatin was more clinically effective in women who were cisplatin naive than in women who had previously received cisplatin. The Committee considered that the reduced response to topotecan plus cisplatin was evident even when the sustained cisplatin-free interval was longer than 180\xa0days.\n\nThe Committee examined the trial comparing four combination treatments (GOG-0204), including topotecan plus cisplatin. The Committee was aware that the trial had closed early because none of the other treatment combinations were likely to show a significant benefit over paclitaxel plus cisplatin. The Committee noted that hazard ratios from this trial suggested that paclitaxel plus cisplatin was more effective than the other cisplatin combination therapies, but this difference did not reach statistical significance. The Committee heard from clinical specialists that they did not consider there to be any differences in effectiveness between the different combinations that had been used in this trial. The Committee noted that in this trial approximately 70% of women had received cisplatin as prior chemoradiotherapy. The Committee understood that no specific data for cisplatin-naive women from this trial had been provided. It noted that the manufacturer had also included an indirect comparison of topotecan plus cisplatin with paclitaxel plus cisplatin. The Committee recognised that this comparison suggested that topotecan plus cisplatin was more effective than paclitaxel plus cisplatin, but again the difference did not reach statistical significance. The Committee concluded that there was uncertainty about the differences in effectiveness among combination chemotherapy regimens.\n\nWhen considering the comparative evidence the Committee was aware that there were differences in the trial populations. The Committee considered that the trial of combination therapies (GOG-0204) appropriately reflected the majority of the clinical population in England and Wales, where women often received chemoradiotherapy that included cisplatin. However, the Committee noted that for the subgroup of women who were cisplatin naive, the trial of combination therapies was not representative of this population. The Committee concluded that there was additional uncertainty about the efficacy of topotecan in comparison with paclitaxel and other combination regimens for this subgroup.\n\nThe Committee discussed the manufacturer's network meta-analysis that was provided after consultation on the appraisal consultation document. The Committee noted that the meta-analysis combined direct and indirect evidence that, when considered individually, did not show consistent effects. In addition, there were differences in the trial populations in terms of prior cisplatin exposure, performance status and disease stage. The Committee heard from the ERG that they did not consider that the data from the trials were exchangeable, and therefore it was inappropriate to carry out a meta-analysis of the data. The Committee also heard from the ERG that the manufacturer's analyses that pooled the data for paclitaxel suggested an estimate of effect similar for both the licensed population and the cisplatin-naive population that was not consistent with the clinical trial or clinical specialists' evidence or biological plausibility. The Committee concluded that in principle a network meta-analysis was an appropriate method of calculating efficacy, but the nature of the evidence available in this situation meant that it could not be considered appropriate as a basis on which to make a decision about the cost effectiveness of topotecan.\n\nThe Committee considered the adverse event profile of topotecan and recognised that women receiving topotecan plus cisplatin may have more adverse events compared with those receiving cisplatin alone. The Committee heard from clinical specialists specifically about neutropenia and febrile neutropenia. It heard how febrile neutropenia may lead to hospital admission, and may be a more frequent occurrence than for other regimens such as paclitaxel plus cisplatin. However, patient experts mentioned that they considered the safety profile of topotecan plus cisplatin to be manageable, although they were concerned about reported deaths following chemotherapy. They also indicated that quality of life may not be worse for women receiving combination therapy than for women receiving monotherapy, although they were specifically concerned about fatigue.\n\n# Cost effectiveness\n\nThe Committee considered the evidence on the cost effectiveness of topotecan plus cisplatin presented in the manufacturer's submission. The Committee recognised that the manufacturer considered their main analysis to be the within-trial comparison and not the model-based comparison. The Committee noted that the ERG could not completely validate the within-trial comparison and that they considered the manufacturer's model-based comparison to have greater external validity. The ERG had therefore used the model-based comparison as the basis for their exploratory analyses.\n\nThe Committee noted that in the within-trial comparison the base-case ICER provided by the manufacturer for topotecan plus cisplatin compared with cisplatin alone was £18,000 per QALY gained in the licensed population, £11,000 per QALY gained in the cisplatin-naive population and £32,500 per QALY gained in the sustained cisplatin-free interval population. The Committee noted that the results of the model-based comparison using the hazard ratio derived from the indirect comparison suggested that topotecan plus cisplatin had greater efficacy and lower costs than paclitaxel plus cisplatin. However, when the hazard ratio from the trial comparing different combination therapies directly was used, paclitaxel plus cisplatin was more effective and less costly than topotecan plus cisplatin.\n\nThe Committee considered the utility estimates provided by the manufacturer. The Committee heard from the ERG that the manufacturer had incorrectly mapped disease-specific quality of life to utility and that correcting this led to a lower starting utility of 0.72 instead of 0.79. The ERG also expressed concerns about the mapping equation used in the base-case analysis, including the transparency of the analysis and imputation methods. The ERG suggested that combining their amended starting utility from the main clinical trial with data identified by the manufacturer from a study of metastatic breast cancer could be more appropriate. The Committee recognised that neither approach to estimating utilities reflected the reference case and considered that both sets of utility estimates were associated with uncertainty. However, on balance the Committee considered that utility values suggested by the ERG, which led to more favourable ICERs, may be more appropriate than those provided by the manufacturer.\n\nThe Committee considered the manufacturer's assumptions about the number of topotecan vials required in clinical practice and the administration costs. The Committee heard that the manufacturer may have underestimated the administration costs for topotecan on days 2 and 3 because they had used an assessment report from a previous appraisal that had built up the costs without the appropriate health resource group codes being available. The ERG stated that these codes were now available and that the cost for administering the second and third infusion of topotecan would be £195 rather than £51. The Committee considered that the revised administration costs proposed by the ERG were appropriate. The Committee also heard from the ERG that the manufacturer had not assumed minimum or maximum wastage of excess topotecan, but used a midpoint. The ERG considered that an assumption of maximum wastage may be more consistent with the SPC. The Committee heard from clinical specialists that although women were grouped so that drug wastage could be reduced, there was less opportunity to group women receiving topotecan because of the small number of women who receive the drug. The Committee considered that although there was uncertainty about the manufacturer's estimate of topotecan wastage, assumptions of either minimum or maximum wastage may also not be accurate.\n\nThe Committee noted that there appeared to be inconsistencies between the mean cost estimates in the within-trial comparison and the model-based comparison. The Committee heard from the ERG that this may be because dose reduction related to adverse events was included in the within-trial comparison but not in the model-based comparison. However, without a breakdown of costs, the ERG was unable to confirm this. In addition, there were no data on how the use of paclitaxel may be affected by dose reduction. The Committee considered that dose reduction could be important and the ERG's exploratory analyses showed that dose reduction could lower the ICER. However, the Committee was not persuaded that the cost estimates including dose reduction were sufficiently robust for these to form the basis of their examination of the cost effectiveness of topotecan.\n\nThe Committee considered how adverse events had been included in the model-based comparison. The Committee heard from clinical specialists that the manufacturer's assumption that an adverse event lasted only a week was appropriate. The Committee noted that only the most severe adverse event was taken into account in the manufacturer's analysis even if two or more adverse events were experienced concurrently. The clinical specialists agreed that there may be a further negative impact on quality of life for women who have two concurrent adverse events. Overall the Committee considered that the manufacturer may have underestimated the reduction in quality of life associated with multiple adverse events.\n\nThe Committee first considered the fully incremental exploratory analysis for the licensed population undertaken by the ERG that incorporated amended administration costs and utility values. The Committee noted that, for the licensed population, using the hazard ratio from the indirect comparison, the ICER for topotecan plus cisplatin compared with cisplatin alone was £59,000 per QALY gained when minimum wastage was assumed, and the ICER for topotecan plus cisplatin compared with paclitaxel plus cisplatin was £117,000 per QALY gained when maximum wastage was assumed. The Committee was also aware that when the hazard ratio derived from the trial of different combination therapies was used, topotecan plus cisplatin was dominated by paclitaxel plus cisplatin. The Committee considered that the trial of different combination therapies (GOG-0204) was more representative of the patient population in England and Wales than the other available evidence. The Committee therefore concluded that for the licensed population, the cost-effectiveness data suggested that topotecan in combination with cisplatin was not a cost-effective use of NHS resources.\n\nThe Committee considered supplementary advice from NICE that should be taken into account when appraising treatments which may extend the life of patients with a short life expectancy and which are licensed for indications that affect small numbers of people with incurable illnesses. For this advice to be applied, all the following criteria must be met:\n\nThe treatment is indicated for patients with a short life expectancy, normally less than 24\xa0months.\n\nThere is sufficient evidence to indicate that the treatment offers an extension to life, normally of at least an additional 3\xa0months, compared with current NHS treatment.\n\nThe treatment is licensed or otherwise indicated for small patient populations.In addition, when taking these into account the Committee must be persuaded that the estimates of the extension to life are robust and the assumptions used in the reference-case economic modelling are plausible, objective and robust.\n\nThe Committee considered that the life expectancy for women with recurrent and stage IVB cervical cancer would normally be less than 24\xa0months. The Committee noted that topotecan was licensed for multiple indications, but it could still be considered to be indicated for a small patient population. The Committee discussed the additional benefits provided by topotecan in comparison with other therapies available on the NHS. It noted the clinical trial results from GOG-0179 and agreed that for the licensed population topotecan plus cisplatin had demonstrated a gain in life expectancy of more than 3\xa0months in comparison with cisplatin alone. However, the Committee was aware that the majority of women receive combination therapies in the NHS. The Committee noted the results of the trial of combination therapies (GOG-0204), which had closed early because none of the treatments including topotecan were likely to show a significant benefit over paclitaxel plus cisplatin. The Committee also noted the clinical specialists' comments that they considered there to be equal efficacy among the different combination treatments in GOG-0204. On balance, the Committee considered that, for the licensed population, topotecan plus cisplatin compared with other combination therapies currently available in the NHS had not shown an additional benefit of 3\xa0months. The Committee therefore concluded that topotecan plus cisplatin did not fulfil the criteria for consideration of NICE's supplementary advice on end of life and agreed that topotecan in combination with cisplatin could not be recommended as a cost-effective use of NHS resources.\n\nThe Committee then considered the subgroup of women who had not previously received cisplatin. The Committee noted that the manufacturer's estimates suggested topotecan plus cisplatin may be cost effective in this group. The Committee considered the ERG's exploratory analyses for this subgroup. When the hazard ratios from the indirect comparison were used the ICER for topotecan plus cisplatin compared with cisplatin alone was £26,800 per QALY gained assuming minimum wastage, and £34,000 per QALY gained assuming maximum wastage. The Committee recognised that this did not include dose reduction, which the ERG had suggested could further reduce these ICERs. The Committee was aware that when the hazard ratios from the trial of different combination therapies were used, topotecan plus cisplatin was dominated by paclitaxel plus cisplatin, but that this evidence was predominantly from a population who had received cisplatin as a radiosensitiser before. Because the indirect comparison was the only data available in which the majority of women were cisplatin naive, the Committee was persuaded that topotecan plus cisplatin could be considered an appropriate use of NHS resources for the treatment of women who have not previously received cisplatin.\n\nIn light of the duty to have due regard to the need to eliminate unlawful discrimination and promote equality, the Committee discussed the higher prevalence of cervical cancer among women living in the most socioeconomically deprived areas, as outlined by the patient expert statements. It also discussed comments received during consultation on the appraisal consultation document. The Committee noted that a negative recommendation for topotecan in combination with cisplatin for the group of women with prior exposure to cisplatin does not impact particularly on any group protected by the equalities legislation. In addition, given the uncertainty about whether topotecan in combination with cisplatin is more clinically effective than other combination therapies for the treatment of cervical cancer in women with prior exposure to cisplatin, and the availability of alternative treatment options, the Committee was satisfied that its recommendation was consistent with NICE's obligations under the equalities legislation and the requirement for fairness.", 'Related NICE guidance': 'High dose rate brachytherapy for carcinoma of the cervix. NICE interventional procedure guidance 160 (2006).\n\nGuidance on the use of liquid-based cytology for cervical screening (review). NICE technology appraisal guidance 69 (2003).', 'Review of guidance': 'NICE proposes that the guidance on this technology is considered for review by the Guidance Executive in September 2012. NICE welcomes comment on this proposed date. The Guidance Executive will decide whether the technology should be reviewed based on information gathered by NICE, and in consultation with consultees and commentators.\n\nAndrew DillonChief ExecutiveOctober 2009', 'Changes after publication': 'February 2014: implementation section updated to clarify that topotecan is recommended as an option for treating recurrent or stage IVB cervical cancer. Additional minor maintenance update also carried out.\n\nMarch 2012: minor maintenance', 'About this guidance': 'NICE technology appraisal guidance is about the use of new and existing medicines and treatments in the NHS in England and Wales.\n\nThis guidance was developed using the NICE single technology appraisal process.\n\nWe have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available.\n\nYour responsibility\n\nThis guidance represents the views of NICE and was arrived at after careful consideration of the evidence available. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. However, the guidance does not override the individual responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.\n\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.\n\nCopyright\n\n© National Institute for Health and Clinical Excellence 2009. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.'}	https://www.nice.org.uk/guidance/ta183	Evidence-based recommendations on topotecan for treating recurrent and stage IVB cervical cancer in adults.
7a5c5760c47b2ac2c6bd3ddb6fdf097cef8bca4d	nice	Depression in adults with a chronic physical health problem: recognition and management	Depression in adults with a chronic physical health problem: recognition and management This guideline covers identifying, treating and managing depression in people aged 18 and over who also have a chronic physical health problem such as cancer, heart disease or diabetes. It aims to improve the care of people with a long-term physical health problem, which can cause or exacerbate depression. This has the potential to increase their quality of life and life expectancy. # Context This guideline makes recommendations on the identification, treatment and management of depression in adults aged 18 years and older who also have a chronic physical health problem (such as cancer, heart disease, diabetes, or a musculoskeletal, respiratory or neurological disorder). Depression is a broad and heterogeneous diagnosis. Central to it is depressed mood and/or loss of pleasure in most activities. A chronic physical health problem can both cause and exacerbate depression: pain, functional impairment and disability associated with chronic physical health problems can greatly increase the risk of depression in people with physical illness, and depression can also exacerbate the pain and distress associated with physical illnesses and adversely affect outcomes, including shortening life expectancy. Furthermore, depression can be a risk factor in the development of a range of physical illnesses, such as cardiovascular disease. When a person has both depression and a chronic physical health problem, functional impairment is likely to be greater than if a person has depression or the physical health problem alone. Depression is approximately 2 to 3 times more common in patients with a chronic physical health problem than in people who have good physical health and occurs in about 20% of people with a chronic physical health problem. Severity of depression is determined by both the number and severity of symptoms, as well as the degree of functional impairment. A formal diagnosis using the ICD‑10 classification system requires at least 4 out of 10 depressive symptoms, whereas the DSM‑IV system requires at least 5 out of 9 for a diagnosis of major depression (referred to in this guideline as 'depression'). Symptoms should be present for at least 2 weeks and each symptom should be present at sufficient severity for most of every day. Both diagnostic systems require at least 1 (DSM‑IV) or 2 (ICD‑10) key symptoms (low mood , loss of interest and pleasure , or loss of energy ) to be present. Increasingly, it is recognised that depressive symptoms below the DSM‑IV and ICD‑10 threshold criteria can be distressing and disabling if persistent. Therefore this guideline covers 'subthreshold depressive symptoms', which fall below the criteria for a diagnosis of major depression, and are defined as at least one key symptom of depression but with insufficient other symptoms and/or functional impairment to meet the criteria for full diagnosis. Symptoms are considered persistent if they continue despite active monitoring and/or low-intensity intervention, or have been present for a considerable time, typically several months. For a diagnosis of dysthymia, symptoms should be present for at least 2 years. Both DSM‑IV and ICD‑10 have the category of dysthymia, which consists of depressive symptoms that are subthreshold for major depression but that persist (by definition for more than 2 years). There appears to be no empirical evidence that dysthymia is distinct from subthreshold depressive symptoms apart from duration of symptoms, and the term 'persistent subthreshold depressive symptoms' is preferred in this guideline. The presence of a physical illness can complicate the assessment of depression and some symptoms, such as fatigue, are common to both mental and physical disorders. It should be noted that classificatory systems are agreed conventions that seek to define different severities of depression in order to guide diagnosis and treatment, and their value is determined by how useful they are in practice. After careful review of the diagnostic criteria and the evidence, the Guideline Development Group decided to adopt DSM‑IV rather than ICD‑10, which was used in the previous depression guideline (the NICE guideline on depression: management of depression in primary and secondary care). This is because DSM‑IV is used in nearly all the evidence reviewed and it provides definitions for atypical symptoms and seasonal depression. Its definition of severity also makes it less likely that a diagnosis of depression will be based solely on symptom counting. In practical terms, clinicians are not expected to switch to DSM‑IV but should be aware that the threshold for mild depression is higher than with ICD‑10 (5 symptoms not 4) and that degree of functional impairment should be routinely assessed before making a diagnosis. Using DSM‑IV enables the guideline to better target the use of specific interventions, such as antidepressants, for more severe degrees of depression. In addition to physical illness, a wide range of psychological and social factors, which are not captured well by current diagnostic systems, have a significant impact on the course of depression and the response to treatment. Therefore it is also important to consider both personal past history and family history of depression when undertaking a diagnostic assessment (see the appendix on assessing depression and its severity for further details). Treating depression in people with a chronic physical health problem has the potential to increase their quality of life and life expectancy. Depression often has a remitting and relapsing course, and symptoms may persist between episodes. Where possible, the key goal of an intervention for depression should be complete relief of symptoms (remission) – this is associated with better functioning and a lower likelihood of relapse than lesser degrees of response, as well as potentially better physical health outcomes. The guideline will assume that prescribers will use a drug's summary of product characteristics (SPC) and the BNF to inform decisions made with individual patients.# Recommendations The following guidance is based on the best available evidence. The full guideline gives details of the methods and the evidence used to develop the guidance. # Box 1 Depression definitions (taken from DSM-IV) Subthreshold depressive symptoms: Fewer than 5 symptoms of depression. Mild depression: Few, if any, symptoms in excess of the 5 required to make the diagnosis, and symptoms result in only minor functional impairment. Moderate depression: Symptoms of functional impairment are between 'mild' and 'severe'. Severe depression: Most symptoms, and the symptoms markedly interfere with functioning. Can occur with or without psychotic symptoms. Not that a comprehensive assessment of depression should not rely simply on a symptom count, but should take into account the degree of functional impairment and/or disability (see section 1.1.3). Throughout this guideline, the term 'patient' is used to denote a person who has both depression and a chronic physical health problem. This guideline is published alongside NICE's guideline on depression in adults: recognition and management, which makes recommendations on the identification, treatment and management of depression in adults aged 18 years and older, in primary and secondary care. People have the right to be involved in discussions and make informed decisions about their care, as described in making decisions about your care. Making decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding. # Care of all people with depression ## Providing information and support, and obtaining informed consent When working with patients with depression and a chronic physical health problem and their families or carers: build a trusting relationship and work in an open, engaging and non-judgemental manner explore treatment options for depression in an atmosphere of hope and optimism, explaining the different courses of depression and that recovery is possible be aware that stigma and discrimination can be associated with a diagnosis of depression and take into account how this may affect the patient with a chronic physical health problem ensure that discussions take place in settings in which confidentiality, privacy and dignity are respected. When working with patients with depression and a chronic physical health problem and their families or carers: provide information appropriate to their level of understanding about the nature of depression and the range of treatments available avoid clinical language without adequate explanation ensure that comprehensive written information is available in the appropriate language and in audio format if possible provide and work proficiently with independent interpreters (that is, someone who is not known to the patient) if needed. Inform patients with depression and a chronic physical health problem about self-help groups, support groups and other local and national resources for people with depression. Make all efforts necessary to ensure that a patient with depression and a chronic physical health problem can give meaningful and informed consent before treatment starts. This is especially important when a patient has severe depression or is subject to the Mental Health Act. Ensure that consent to treatment is based on the provision of clear information (which should also be available in written form) about the intervention, covering: what it comprises what is expected of the patient while having it likely outcomes (including any side effects). ## Supporting families and carers For families or carers who are involved in supporting a patient with severe or chronic (symptoms more or less continuously for 2 years or more) depression and a chronic physical health problem, see recommendations in the NICE guideline on supporting adult carers on identifying, assessing and meeting the caring, physical and mental health needs of families and carers. ## Principles for assessment, coordination of care and choosing treatments When assessing a patient with a chronic physical health problem who may have depression, conduct a comprehensive assessment that does not rely simply on a symptom count. Take into account both the degree of functional impairment and/or disability associated with the possible depression and the duration of the episode. In addition to assessing symptoms and associated functional impairment, consider how the following factors may have affected the development, course and severity of a patient's depression: any history of depression and comorbid mental health or physical disorders any past history of mood elevation (to determine if the depression may be part of bipolar disorder) any past experience of, and response to, treatments the quality of interpersonal relationships living conditions and social isolation. Be respectful of, and sensitive to, diverse cultural, ethnic and religious backgrounds when working with patients with depression and a chronic physical health problem, and be aware of the possible variations in the presentation of depression. Ensure competence in: culturally sensitive assessment using different explanatory models of depression addressing cultural and ethnic differences when developing and implementing treatment plans working with families from diverse ethnic and cultural backgrounds. When assessing a patient with a chronic physical health problem and suspected depression, be aware of any learning disabilities or acquired cognitive impairments, and if necessary consider consulting with a relevant specialist when developing treatment plans and strategies. When providing interventions for patients with a learning disability or acquired cognitive impairment who have a chronic physical health problem and a diagnosis of depression: where possible, provide the same interventions as for other patients with depression if necessary, adjust the method of delivery or duration of the intervention to take account of the disability or impairment. Always ask patients with depression and a chronic physical health problem directly about suicidal ideation and intent. If there is a risk of self-harm or suicide: assess whether the patient has adequate social support and is aware of sources of help arrange help appropriate to the level of risk (see section 1.3.2) advise the patient to seek further help if the situation deteriorates. ## Effective delivery of interventions for depression All interventions for depression should be delivered by competent practitioners. Psychological and psychosocial interventions should be based on the relevant treatment manual(s), which should guide the structure and duration of the intervention. Practitioners should consider using competence frameworks developed from the relevant treatment manual(s) and for all interventions should: receive regular high-quality supervision use routine outcome measures and ensure that the patient with depression is involved in reviewing the efficacy of the treatment engage in monitoring and evaluation of treatment adherence and practitioner competence – for example, by using video and audio tapes, and external audit and scrutiny where appropriate. Consider providing all interventions in the preferred language of the patient with depression and a chronic physical health problem where possible. Where a patient's management is shared between primary and secondary care, there should be clear agreement between practitioners (especially the patient's GP) on the responsibility for the monitoring and treatment of that patient. The treatment plan should be shared with the patient and, where appropriate, with their family or carer. If a patient's chronic physical health problem restricts their ability to engage with a preferred psychosocial or psychological treatment for depression (see sections 1.4.2, 1.5.1 and 1.5.3), consider alternatives in discussion with the patient, such as antidepressants (see section 1.5.2) or delivery of psychosocial or psychological interventions by telephone if mobility or other difficulties prevent face-to face contact. # Stepped care The stepped-care model provides a framework in which to organise the provision of services, and supports patients, carers and practitioners in identifying and accessing the most effective interventions (see figure 1). In stepped care the least intrusive, most effective intervention is provided first; if a patient does not benefit from the intervention initially offered, or declines an intervention, they should be offered an appropriate intervention from the next step. Focus of the intervention Nature of the intervention STEP 4: Severe and complex depression; risk to life; severe self-neglect Medication, high-intensity psychological interventions, electroconvulsive therapy, crisis service, combined treatments, multiprofessional and inpatient care STEP 3: Persistent subthreshold depressive symptoms or mild to moderate depression with inadequate response to initial interventions; moderate and severe depression Medication, high-intensity psychological interventions, combined treatments, collaborative care and referral for further assessment and interventions STEP 2: Persistent subthreshold depressive symptoms; mild to moderate depression Low-intensity psychosocial interventions, psychological interventions, medication and referral for further assessment and interventions STEP 1: All known and suspected presentations of depression Assessment, support, psychoeducation, active monitoring and referral for further assessment and interventions Complex depression includes depression that shows an inadequate response to multiple treatments, is complicated by psychotic symptoms, and/or is associated with significant psychiatric comorbidity or psychosocial factors. Collaborative care for step 3 is only for depression where the person has a chronic physical health problem and associated functional impairment. # Step 1: recognition, assessment and initial management in primary care and general hospital settings The recommendations in this section are primarily for practitioners working in primary care and in general hospital settings. Practitioners should be aware that patients with a chronic physical health problem are at a high risk of depression, particularly where there is functional impairment. ## Case identification and recognition Be alert to possible depression (particularly in patients with a past history of depression or a chronic physical health problem with associated functional impairment) and consider asking patients who may have depression 2 questions, specifically: During the last month, have you often been bothered by feeling down, depressed or hopeless? During the last month, have you often been bothered by having little interest or pleasure in doing things? If a patient with a chronic physical health problem answers 'yes' to either of the depression identification questions (see recommendation 1.3.1.1) but the practitioner is not competent to perform a mental health assessment, they should refer the patient to an appropriate professional. If this professional is not the patient's GP, inform the GP of the referral. If a patient with a chronic physical health problem answers 'yes' to either of the depression identification questions (see recommendation 1.3.1.1), a practitioner who is competent to perform a mental health assessment should: ask 3 further questions to improve the accuracy of the assessment of depression, specifically: during the last month, have you often been bothered by feelings of worthlessness? during the last month, have you often been bothered by poor concentration? during the last month, have you often been bothered by thoughts of death? review the patient's mental state and associated functional, interpersonal and social difficulties consider the role of both the chronic physical health problem and any prescribed medication in the development or maintenance of the depression ascertain that the optimal treatment for the physical health problem is being provided and adhered to, seeking specialist advice if necessary. When assessing a patient with suspected depression, consider using a validated measure (for example, for symptoms, functions and/or disability) to inform and evaluate treatment. For patients with significant language or communication difficulties, for example patients with sensory impairments or a learning disability, consider using the Distress Thermometer and/or asking a family member or carer about the patient's symptoms to identify possible depression. If a significant level of distress is identified, investigate further. ## Risk assessment and monitoring If a patient with depression and a chronic physical health problem presents considerable immediate risk to themselves or others, refer them urgently to specialist mental health services. Advise patients with depression and a chronic physical health problem of the potential for increased agitation, anxiety and suicidal ideation in the initial stages of treatment for depression; actively seek out these symptoms and: ensure that the patient knows how to seek help promptly review the patient's treatment if they develop marked and/or prolonged agitation. Advise a patient with depression and a chronic physical health problem, and their family or carer, to be vigilant for mood changes, negativity and hopelessness, and suicidal ideation, and to contact their practitioner if concerned. This is particularly important during high-risk periods, such as starting or changing treatment and at times of increased personal stress. If a patient with depression and a chronic physical health problem is assessed to be at risk of suicide: take into account toxicity in overdose if an antidepressant is prescribed or the patient is taking other medication; if necessary, limit the amount of drug(s) available consider increasing the level of support, such as more frequent direct or telephone contacts consider referral to specialist mental health services. # Step 2: recognised depression in primary care and general hospital settings – persistent subthreshold depressive symptoms or mild to moderate depression ## General measures When depression is accompanied by symptoms of anxiety, the first priority should usually be to treat the depression. When the patient has an anxiety disorder and comorbid depression or depressive symptoms, consult the NICE guideline for the relevant anxiety disorder (see the NICE webpage on depression) and consider treating the anxiety disorder first (since effective treatment of the anxiety disorder will often improve the depression or the depressive symptoms). Offer patients with depression and a chronic physical health problem advice on sleep hygiene if needed, including: establishing regular sleep and wake times avoiding excess eating, smoking or drinking alcohol before sleep creating a proper environment for sleep taking regular physical exercise where this is possible for the patient. For patients who, in the judgement of the practitioner, may recover with no formal intervention, or patients with mild depression who do not want an intervention, or patients with subthreshold depressive symptoms who request an intervention: discuss the presenting problem(s) and any concerns that the patient may have about them provide information about the nature and course of depression arrange a further assessment, normally within 2 weeks make contact if the patient does not attend follow-up appointments. ## Low-intensity psychosocial interventions For patients with persistent subthreshold depressive symptoms or mild to moderate depression and a chronic physical health problem, and for patients with subthreshold depressive symptoms that complicate the care of the chronic physical health problem, consider offering one or more of the following interventions, guided by the patient's preference: a structured group physical activity programme a group-based peer support (self-help) programme individual guided self-help based on the principles of cognitive behavioural therapy (CBT) computerised cognitive behavioural therapy (CCBT). Physical activity programmes for patients with persistent subthreshold depressive symptoms or mild to moderate depression and a chronic physical health problem, and for patients with subthreshold depressive symptoms that complicate the care of the chronic physical health problem, should: be modified (in terms of the duration of the programme and frequency and length of the sessions) for different levels of physical ability as a result of the particular chronic physical health problem, in liaison with the team providing care for the physical health problem be delivered in groups with support from a competent practitioner consist typically of 2 or 3 sessions per week of moderate duration (45 minutes to 1 hour) over 10 to 14 weeks (average 12 weeks) be coordinated or integrated with any rehabilitation programme for the chronic physical health problem. Group-based peer support (self-help) programmes for patients with persistent subthreshold depressive symptoms or mild to moderate depression and a chronic physical health problem, and for patients with subthreshold depressive symptoms that complicate the care of the chronic physical health problem, should: be delivered to groups of patients with a shared chronic physical health problem focus on sharing experiences and feelings associated with having a chronic physical health problem be supported by practitioners who should: facilitate attendance at the meetings have knowledge of the patients' chronic physical health problem and its relationship to depression review the outcomes of the intervention with the individual patients consist typically of 1 session per week delivered over a period of 8 to 12 weeks. Individual guided self-help programmes based on the principles of CBT (and including behavioural activation and problem-solving techniques) for patients with persistent subthreshold depressive symptoms or mild to moderate depression and a chronic physical health problem, and for patients with subthreshold depressive symptoms that complicate the care of the chronic physical health problem, should: include the provision of written materials of an appropriate reading age (or alternative media to support access) be supported by a trained practitioner, who typically facilitates the self-help programme and reviews progress and outcome consist of up to 6 to 8 sessions (face-to-face and via telephone) normally taking place over 9 to 12 weeks, including follow-up. CCBT for patients with persistent subthreshold depressive symptoms or mild to moderate depression and a chronic physical health problem, and for patients with subthreshold depressive symptoms that complicate the care of the chronic physical health problem, should: be provided via a stand-alone computer-based or web-based programme include an explanation of the CBT model, encourage tasks between sessions, and use thought-challenging and active monitoring of behaviour, thought patterns and outcomes be supported by a trained practitioner, who typically provides limited facilitation of the programme and reviews progress and outcome typically take place over 9 to 12 weeks, including follow-up. ## Drug treatment For guidance on safe prescribing of antidepressants and managing withdrawal, see NICE's guideline on medicines associated with dependence or withdrawal symptoms. Do not use antidepressants routinely to treat subthreshold depressive symptoms or mild depression in patients with a chronic physical health problem (because the risk–benefit ratio is poor), but consider them for patients with: a past history of moderate or severe depression or mild depression that complicates the care of the physical health problem or initial presentation of subthreshold depressive symptoms that have been present for a long period (typically at least 2 years) or subthreshold depressive symptoms or mild depression that persist(s) after other interventions. Although there is evidence that St John's wort may be of benefit in mild or moderate depression, practitioners should: not prescribe or advise its use by patients with depression and a chronic physical health problem because of uncertainty about appropriate doses, persistence of effect, variation in the nature of preparations and potential serious interactions with other drugs (including oral contraceptives, anticoagulants and anticonvulsants) advise patients with depression of the different potencies of the preparations available and of the potential serious interactions of St John's wort with other drugs. # Step 3: recognised depression in primary care and general hospital settings – persistent subthreshold depressive symptoms or mild to moderate depression with inadequate response to initial interventions, and moderate and severe depression ## Treatment options For guidance on safe prescribing of antidepressants and managing withdrawal, see NICE's guideline on medicines associated with dependence or withdrawal symptoms. For patients with persistent subthreshold depressive symptoms or mild to moderate depression and a chronic physical health problem who have not benefited from a low-intensity psychosocial intervention, discuss the relative merits of different interventions with the patient and provide: an antidepressant (normally a selective serotonin reuptake inhibitor ) or -ne of the following high-intensity psychological interventions: group-based CBT or individual CBT for patients who decline group-based CBT or for whom it is not appropriate, or where a group is not available or behavioural couples therapy for people who have a regular partner and where the relationship may contribute to the development or maintenance of depression, or where involving the partner is considered to be of potential therapeutic benefit. For patients with initial presentation of moderate depression and a chronic physical health problem, offer the following choice of high-intensity psychological interventions: group-based CBT or individual CBT for patients who decline group-based CBT or for whom it is not appropriate, or where a group is not available or behavioural couples therapy for people who have a regular partner and where the relationship may contribute to the development or maintenance of depression, or where involving the partner is considered to be of potential therapeutic benefit. For patients with initial presentation of severe depression and a chronic physical health problem, consider offering a combination of individual CBT and an antidepressant. The choice of intervention should be influenced by the: duration of the episode of depression and the trajectory of symptoms previous course of depression and response to treatment likelihood of adherence to treatment and any potential adverse effects course and treatment of the chronic physical health problem patient's treatment preference and priorities. ## Antidepressant drugs For guidance on safe prescribing of antidepressants and managing withdrawal, see NICE's guideline on medicines associated with dependence or withdrawal symptoms. For additional considerations on using antidepressants and other medications (including the assessment of the relative risks and benefits) for women who may become pregnant, please refer to the BNF and individual drug summary of product characteristics. For women in the antenatal and postnatal periods, also see also the NICE guideline on antenatal and postnatal mental health. When an antidepressant is to be prescribed for a patient with depression and a chronic physical health problem, take into account the following: the presence of additional physical health disorders the side effects of antidepressants, which may impact on the underlying physical disease (in particular, SSRIs may result in or exacerbate hyponatraemia, especially in older people) that there is no evidence as yet supporting the use of specific antidepressants for patients with particular chronic physical health problems interactions with other medications. When an antidepressant is to be prescribed, be aware of drug interactions and: refer to appendix 1 of the BNF and the table of interactions in appendix 16 of the full guideline for information seek specialist advice if there is uncertainty if necessary, refer the patient to specialist mental health services for continued prescribing. First prescribe an SSRI in generic form unless there are interactions with other drugs; consider using citalopram or sertraline because they have less propensity for interactions. When prescribing antidepressants, be aware that: dosulepin should not be prescribed non-reversible monoamine oxidase inhibitors (MAOIs; for example, phenelzine), combined antidepressants and lithium augmentation of antidepressants should normally be prescribed only by specialist mental health professionals. Take into account toxicity in overdose when choosing an antidepressant for patients at significant risk of suicide. Be aware that: compared with other equally effective antidepressants recommended for routine use in primary care, venlafaxine is associated with a greater risk of death from overdose tricyclic antidepressants (TCAs), except for lofepramine, are associated with the greatest risk in overdose. Do not normally offer SSRIs to patients taking non-steroidal anti-inflammatory drugs (NSAIDs) because of the increased risk of gastrointestinal bleeding. Consider offering an antidepressant with a lower propensity for, or a different range of, interactions, such as mianserin, mirtazapine, moclobemide, reboxetine or trazodone. If no suitable alternative antidepressant can be identified, SSRIs may be prescribed at the same time as NSAIDs if gastroprotective medicines (for example, proton-pump inhibitors) are also offered. Do not normally offer SSRIs to patients taking warfarin or heparin because of their anti-platelet effect. Use SSRIs with caution in patients taking aspirin. When aspirin is used as a single agent, consider alternatives that may be safer, such as trazodone, mianserin or reboxetine. If no suitable alternative antidepressant can be identified, SSRIs may be prescribed at the same time as aspirin if gastroprotective medicines (for example, proton-pump inhibitors) are also offered. Consider offering mirtazapine to patients taking heparin, aspirin or warfarin (but note that when taken with warfarin, the international normalised ratio may increase slightly). Do not offer SSRIs to patients receiving 'triptan' drugs for migraine. Offer a safer alternative such as mirtazapine, trazodone, mianserin or reboxetine. Do not normally offer SSRIs at the same time as monoamine oxidase B (MAO‑B) inhibitors such as selegiline and rasagiline. Offer a safer alternative such as mirtazapine, trazodone, mianserin or reboxetine. Do not normally offer fluvoxamine to patients taking theophylline, clozapine, methadone or tizamidine. Offer a safer alternative such as sertraline or citalopram. Offer sertraline as the preferred antidepressant for patients taking flecainide or propafenone, although mirtazapine and moclobemide may also be used. Do not offer fluoxetine or paroxetine to patients taking atomoxetine. Offer a different SSRI. When prescribing antidepressants, explore any concerns the patient with depression and a chronic physical health problem has about taking medication, explain fully the reasons for prescribing, and provide information about taking antidepressants, including: the gradual development of the full antidepressant effect the importance of taking medication as prescribed and the need to continue treatment after remission potential side effects the potential for interactions with other medications the risk and nature of discontinuation symptoms with all antidepressants, particularly with drugs with a shorter half-life (such as paroxetine and venlafaxine), and how these symptoms can be minimised the fact that addiction does not occur with antidepressants.Offer written information appropriate to the patient's needs. Prescribe antidepressant medication at a recognised therapeutic dose for patients with depression and a chronic physical health problem (that is, avoid the tendency to prescribe at subtherapeutic doses in these patients). For patients started on antidepressants who are not considered to be at increased risk of suicide, normally see them after 2 weeks. See them regularly thereafter, for example at intervals of 2 to 4 weeks in the first 3 months, and then at longer intervals if response is good. A patient with depression started on antidepressants who is considered to present an increased suicide risk or is younger than 30 years (because of the potential increased prevalence of suicidal thoughts in the early stages of antidepressant treatment for this group) should normally be seen after 1 week and frequently thereafter as appropriate until the risk is no longer considered clinically important. If a patient with depression and a chronic physical health problem develops side effects early in antidepressant treatment, provide appropriate information and consider one of the following strategies: monitor symptoms closely where side effects are mild and acceptable to the patient or stop the antidepressant or change to a different antidepressant if the patient prefers or in discussion with the patient, consider short-term concomitant treatment with a benzodiazepine if anxiety, agitation and/or insomnia are problematic, but: do not offer benzodiazepines to patients with chronic symptoms of anxiety use benzodiazepines with caution in patients at risk of falls in order to prevent the development of dependence, do not use benzodiazepines for longer than 2 weeks. Support and encourage a patient with a chronic physical health problem who has benefited from taking an antidepressant to continue medication for at least 6 months after remission of an episode of depression. Discuss with the patient that: this greatly reduces the risk of relapse antidepressants are not associated with addiction. Review with the patient with depression and a chronic physical health problem the need for continued antidepressant treatment beyond 6 months after remission, taking into account: the number of previous episodes of depression the presence of residual symptoms concurrent physical health problems and psychosocial difficulties. More detailed advice on switching, sequencing, augmenting and combining antidepressants can be found in section 1.8 of the NICE guideline on depression in adults. The recommendations below should be considered alongside recommendations 1.5.2.6 to 1.5.2.16 in the section 'Interactions of SSRIs with other medication' in the current guideline. If the patient's depression shows no improvement after 2 to 4 weeks with the first antidepressant, check that the drug has been taken regularly and in the prescribed dose. If response is absent or minimal after 3 to 4 weeks of treatment with a therapeutic dose of an antidepressant, increase the level of support (for example, by weekly face-to-face or telephone contact) and consider: increasing the dose in line with the summary of product characteristics if there are no significant side effects or switching to another antidepressant as described in section 1.8 of the NICE guideline on depression in adults if there are side effects or if the patient prefers. If the patient's depression shows some improvement by 4 weeks, continue treatment for another 2 to 4 weeks. Consider switching to another antidepressant as described in section 1.8 of the NICE guideline on depression in adults if: response is still not adequate or there are side effects or the patient prefers to change treatment. When switching from 1 antidepressant to another, be aware of: the need for gradual and modest incremental increases in dose interactions between antidepressants the risk of serotonin syndrome (features include confusion, delirium, shivering, sweating, changes in blood pressure and myoclonus) when combinations of serotonergic antidepressants are prescribed. If an antidepressant has not been effective or is poorly tolerated: consider offering other treatment options, including high-intensity psychological treatments (see section 1.5.3) prescribe another single antidepressant (which can be from the same class) if the decision is made to offer a further course of antidepressants. Advise patients with depression and a chronic physical health problem who are taking antidepressants that discontinuation symptoms may occur on stopping, missing doses or, occasionally, on reducing the dose of the drug. These include increased mood change, restlessness, difficulty sleeping, unsteadiness, sweating, abdominal symptoms and altered sensations. Explain that symptoms are usually mild and self-limiting over about 1 week, but can be severe, particularly if the drug is stopped abruptly. When stopping an antidepressant, gradually reduce the dose, normally over a 4‑week period, although some patients may require longer periods, particularly with drugs with a shorter half-life (such as paroxetine and venlafaxine). This is not required with fluoxetine because of its long half-life. Inform the patient that they should seek advice from their practitioner if they experience significant discontinuation symptoms. If discontinuation symptoms occur: monitor symptoms and reassure the patient if symptoms are mild consider reintroducing the original antidepressant at the dose that was effective (or another antidepressant with a longer half-life from the same class) if symptoms are severe, and reduce the dose gradually while monitoring symptoms. ## Psychological interventions Delivering high-intensity psychological interventions For all high-intensity psychological interventions, the duration of treatment should normally be within the limits indicated in this guideline. As the aim of treatment is to obtain significant improvement or remission the duration of treatment may be: reduced if remission has been achieved increased if progress is being made, and there is agreement between the practitioner and the patient with depression that further sessions would be beneficial (for example, if there is a comorbid personality disorder or psychosocial factors that impact on the patient's ability to benefit from treatment). Group-based CBT for patients with depression and a chronic physical health problem should be: delivered in groups (typically of between 6 and 8 patients) with a common chronic physical health problem typically delivered over a period of 6 to 8 weeks. Individual CBT for patients with moderate depression and a chronic physical health problem should be: delivered until the symptoms of depression have remitted (over a period that is typically 6 to 8 weeks and should not normally exceed 16 to 18 weeks) followed up by 2 further sessions in the 6 months after the end of treatment, especially if treatment was extended. Individual CBT for patients with severe depression and a chronic physical health problem should be: delivered until the symptoms of depression have remitted (over a period that is typically 16 to 18 weeks) focused in the initial sessions (which typically should take place twice weekly for the first 2 to 3 weeks) on behavioural activation followed up by 2 or 3 further sessions in the 12 months after the end of treatment. Behavioural couples therapy for depression should normally be based on behavioural principles, and an adequate course of therapy should be 15 to 20 sessions over 5 to 6 months. ## Collaborative care Collaborative care, which should form part of a well-developed stepped-care programme, could be provided at the primary or secondary care level. The interventions, which involve all sectors of care, require a coordinated approach to mental and physical healthcare, as well as a dedicated coordinator of the intervention located in and receiving support from a multi‑professional team, joint determination of the plan of care, and long-term coordination and follow-up. Consider collaborative care for patients with moderate to severe depression and a chronic physical health problem with associated functional impairment whose depression has not responded to initial high-intensity psychological interventions, pharmacological treatment or a combination of psychological and pharmacological interventions. Collaborative care for patients with depression and a chronic physical health problem should normally include: case management which is supervised and has support from a senior mental health professional close collaboration between primary and secondary physical health services and specialist mental health services a range of interventions consistent with those recommended in this guideline, including patient education, psychological and pharmacological interventions, and medication management long-term coordination of care and follow-up. # Step 4: complex and severe depression Practitioners providing treatment in specialist mental health services for patients with complex and severe depression and a chronic physical health problem should: refer to the NICE guideline on depression in adults be aware of the additional drug interactions associated with the treatment of patients with both depression and a chronic physical health problem (see recommendations 1.5.2.6 to 1.5.2.16) work closely and collaboratively with the physical health services.# Recommendations for research The Guideline Development Group has made the following recommendations for research, based on its review of evidence, to improve NICE guidance and patient care in the future. # Combined medication and CBT for patients with moderate to severe depression and a chronic physical health problem What is the clinical and cost effectiveness of combined medication and cognitive behavioural therapy (CBT) compared with antidepressants or CBT alone for patients with moderate to severe depression and a chronic physical health problem? ## Why this is important There is limited evidence for the effectiveness of combined antidepressant treatment and CBT for patients with moderate to severe depression and a chronic physical health problem. Data from studies in patients with depression in the absence of a chronic physical health problem suggest that combined treatment may bring real benefit. However, uncertainty about medium-term outcomes for these patients remains. In addition to uncertainty about the effectiveness of the interventions, the potential for interactions between medication prescribed for depression and for chronic physical health problems is a concern. This needs to be considered in terms of both the difficulties that may arise from drug interactions and the anxieties of individual patients about this, which may reduce the likelihood of them complying with antidepressant medication. The answer to this question has practical implications for service delivery and resource allocation in the NHS. The outcomes for this proposed study should involve both observer-rated and patient-rated assessments of acute and medium-term outcomes for at least 6 months and an assessment of the acceptability and potential burden of the various treatment options. The study should be large enough to determine the presence or absence of any clinically important effects using a non-inferiority design together with robust health economic measures. # Peer support interventions compared with group-based exercise and treatment as usual for patients with mild to moderate depression and a chronic physical health problem What is the clinical and cost effectiveness of group peer support and group-based exercise when compared with treatment as usual for patients with mild to moderate depression and a chronic physical health problem? ## Why this is important There is limited evidence for the effectiveness of peer support and exercise in the treatment of patients with depression and a chronic physical health problem. Although the available data suggest that both are practical and potentially acceptable treatments that may bring real benefit, uncertainty remains about medium-term outcomes. The answer to this question has practical implications for service delivery and resource allocation in the NHS. This question should be answered in an adequately powered 3‑arm randomised controlled trial that examines medium-term outcomes, including cost effectiveness. The outcomes should reflect both observer-rated and patient-rated assessments for acute and medium-term outcomes for 12 months, and an assessment of the acceptability and potential burden of treatment options. The study should be large enough to determine the presence or absence of clinically important effects using a non-inferiority design with robust health economic measures. # Antidepressant medication compared with placebo in patients with depression and COPD What is the clinical and cost effectiveness of antidepressant medication compared with placebo in patients with depression and chronic obstructive pulmonary disease (COPD)? ## Why this is important There is limited evidence for the effectiveness of antidepressant treatment in patients with depression and a chronic physical health problem. Of particular concern to the Guideline Development Group was the high incidence of depression in patients with COPD (which is also known to be associated with a high incidence of anxiety disorders). The Guideline Development Group considered it important to measure the effectiveness of antidepressant medication in the treatment of COPD. The answer to this question has important practical implications for service delivery, particularly for a patient group with mental health needs that are traditionally under-treated within the NHS. The question should be answered using a randomised controlled trial in which patients with moderate depression and COPD receive either placebo or antidepressant medication. The outcomes chosen should reflect both observer-rated and patient-rated assessments for acute and medium-term outcomes for at least 6 months and an assessment of the acceptability and burden of treatment. In addition to the assessment of symptoms of depression, the study should also assess the impact of antidepressant medication on symptoms of anxiety. The study should be large enough to determine the presence or absence of clinically important effects using a non-inferiority design together with robust health economic measures. # Behavioural activation compared with antidepressant medication for patients with moderate to severe depression and a chronic physical health problem What is the clinical and cost effectiveness of behavioural activation compared with antidepressant medication in the treatment of moderate to severe depression in patients with a chronic physical health problem? ## Why this is important There is limited evidence for the effectiveness of high-intensity psychological interventions in the treatment of moderate to severe depression in patients with a chronic physical health problem; the most substantial evidence base is for CBT. Recent developments suggest that behavioural activation may be an effective intervention for depression. In principle, this may be a more feasible treatment to deliver in routine care than CBT and could potentially contribute to increased treatment choice for patients. The answer to this question would have practical implications for service delivery and resource allocation within the NHS. This question should be answered using a randomised controlled trial in which patients with moderate to severe depression and a chronic physical health problem receive either behavioural activation or antidepressant medication. The outcomes should be chosen to reflect both observer-rated and patient-rated assessments for acute and medium-term outcomes for at least 12 months and also assessment of the acceptability and burden of the treatment options. The study needs to be large enough to determine the presence or absence of clinically important effects using a non-inferiority design and robust health economic measures. # The effects of collaborative care on physical health outcomes for patients with moderate to severe depression and a chronic physical health problem What is the clinical and cost effectiveness of collaborative care with regard to physical health outcomes for people with moderate to severe depression and a chronic physical health problem? ## Why this is important There is a reasonable evidence base to support the use of collaborative care in people with moderate to severe depression and a chronic physical health problem. However, the evidence base regarding the effects of collaborative care on physical health outcomes is more limited. Improved depression care is thought to produce other health benefits, such as improved functioning and physical outcomes; this may be particularly significant for people with depression and a chronic physical health problem. This means that interventions that also improve physical health should result in substantial increases in utility and subsequently result in quality-adjusted life year (QALY) gains. Furthermore, the ability to achieve such health gains can potentially reduce the population burden of illness and morbidity within healthcare budgets. There is an association between depression and increased use of medical services, and so it follows that improved treatment of depression could reduce medical expenditure, partially or fully offsetting the costs of treating the depression. The answer to this question has important practical implications for service delivery and resource allocation within the NHS. This question should be answered using a randomised controlled trial design that includes people with moderate to severe depression and a chronic physical health problem. In addition to depression-related outcomes, physical health outcomes such as general physical functioning and pain, as well as outcomes specifically related to the condition (such as HbA1c for diabetes), should be assessed. These outcomes should reflect both observer-rated and patient-rated assessments of medium-term and long-term outcomes for at least 18 months. The study should also include an assessment of the acceptability and burden of treatment options and the impact of the intervention on the overall care system. It should be large enough to determine the presence or absence of clinically important effects using a non-inferiority design together with robust health outcome measures. # The effectiveness of physical rehabilitation programmes for patients with a chronic physical health problem and depression What is the effectiveness of rehabilitation programmes for patients with depression and a chronic physical health problem in terms of improved mood? ## Why this is important Many patients with a chronic physical health problem undergo rehabilitation programmes. There is some suggestion in the literature that these have a beneficial effect on mental health. Understanding and/or enhancing the psychological benefits of these interventions has potentially important cost and service-design implications for the NHS. Given the large data set that already exists, it is important to determine the potential effects of these programmes to date before embarking on any individual studies. The answer to this question has important practical implications for service delivery and resource allocation within the NHS. This question should be answered by an individual patient meta-analysis. There is an existing evidence base showing that programmes specifically designed to treat depression (for example, psychosocial and pharmacological interventions in patients with a chronic physical health problem) are effective. However, many patients with a chronic physical health problem are also undertaking specifically designed rehabilitation programmes (for example, cardiac rehabilitation programmes after myocardial infarction). These interventions are multi-modal and reports indicate that they can have an impact on mental health outcomes, in particular depression. However, it is unclear what the size of this effect may be, which components of the intervention are effective and which specific patient populations may benefit. Therefore an individual patient meta-analysis to examine the impact of rehabilitation programmes on symptoms of depression in patients with a chronic physical health problem should be undertaken before any further research is conducted. # The efficacy of counselling compared with low-intensity cognitive and behavioural interventions and treatment as usual in the treatment of depression in patients with a chronic physical health problem What is the relative efficacy of counselling compared with low-intensity cognitive and behavioural interventions and treatment as usual in patients with depression and a chronic physical health problem? ## Why this is important There is a limited evidence base for counselling compared with treatment as usual in the treatment of patients with depression and a chronic physical health problem. High-intensity cognitive and behavioural interventions have the best evidence base for efficacy but there is limited evidence on the efficacy of low-intensity cognitive and behavioural interventions in patients with depression and a chronic physical health problem. The evidence on low-intensity cognitive and behavioural interventions for this guideline was largely supplemented by the evidence base in the NICE guideline on depression in adults. It is therefore important to establish whether either counselling or low-intensity cognitive and behavioural interventions are effective alternatives to treatment as usual for patients with a chronic physical health problem and should be provided in the NHS. The answer to this question will have important implications for the provision of psychological treatment in the NHS. This question should be answered using a randomised controlled trial design that reports short-term and medium-term outcomes (including cost-effectiveness outcomes) of at least 18 months' duration. Particular attention should be paid to the reproducibility of the treatment model and the training and supervision of the practitioners providing interventions in order to ensure that the treatments are both robust and generalisable. The outcomes chosen should reflect both observer-rated and patient-rated assessments of improvement and an assessment of the acceptability of the treatment options. Particular attention should be given to physical health and quality-of-life outcomes in addition to depression outcomes. The study needs to be large enough to determine the presence or absence of clinically important effects using a non-inferiority design, and mediators and moderators of response should be investigated.# Appendix: Assessing depression and its severity In this guideline, the assessment of depression is based on the criteria in DSM‑IV. Assessment should include the number and severity of symptoms, duration of the current episode, and the course of the illness. Key symptoms: persistent sadness or low mood and/or marked loss of interests or pleasure. At least one of these, most days, most of the time for at least 2 weeks. If any of above present, ask about associated symptoms: disturbed sleep (decreased or increased compared to usual) decreased or increased appetite and/or weight fatigue or loss of energy agitation or slowing of movements poor concentration or indecisiveness feelings of worthlessness or excessive or inappropriate guilt suicidal thoughts or acts. Then ask about duration and associated disability, past and family history of mood disorders, and availability of social support . Factors that favour general advice and active monitoring: four or fewer of the above symptoms with little associated disability symptoms intermittent, or less than 2 weeks' duration recent onset with identified stressor no past or family history of depression social support available lack of suicidal thoughts. . Factors that favour more active treatment in primary care: five or more symptoms with associated disability persistent or long-standing symptoms personal or family history of depression low social support -ccasional suicidal thoughts. . Factors that favour referral to mental health professionals: inadequate or incomplete response to 2 or more interventions recurrent episode within 1 year of last one history suggestive of bipolar disorder patient with depression or relatives request referral more persistent suicidal thoughts self-neglect. . Factors that favour urgent referral to specialist mental health services actively suicidal ideas or plans psychotic symptoms severe agitation accompanying severe symptoms severe self-neglect. Depression definitions Subthreshold depressive symptoms: Fewer than 5 symptoms of depression. Mild depression: Few, if any, symptoms in excess of the 5 required to make the diagnosis, and symptoms result in only minor functional impairment. Moderate depression: Symptoms or functional impairment are between 'mild' and 'severe'. Severe depression: Most symptoms, and the symptoms markedly interfere with functioning. Can occur with or without psychotic features.	{'Context': "This guideline makes recommendations on the identification, treatment and management of depression in adults aged 18\xa0years and older who also have a chronic physical health problem (such as cancer, heart disease, diabetes, or a musculoskeletal, respiratory or neurological disorder).\n\nDepression is a broad and heterogeneous diagnosis. Central to it is depressed mood and/or loss of pleasure in most activities. A chronic physical health problem can both cause and exacerbate depression: pain, functional impairment and disability associated with chronic physical health problems can greatly increase the risk of depression in people with physical illness, and depression can also exacerbate the pain and distress associated with physical illnesses and adversely affect outcomes, including shortening life expectancy. Furthermore, depression can be a risk factor in the development of a range of physical illnesses, such as cardiovascular disease. When a person has both depression and a chronic physical health problem, functional impairment is likely to be greater than if a person has depression or the physical health problem alone.\n\nDepression is approximately 2\xa0to 3\xa0times more common in patients with a chronic physical health problem than in people who have good physical health and occurs in about 20% of people with a chronic physical health problem.\n\nSeverity of depression is determined by both the number and severity of symptoms, as well as the degree of functional impairment. A formal diagnosis using the ICD‑10 classification system requires at least 4 out of 10\xa0depressive symptoms, whereas the DSM‑IV system requires at least 5 out of 9 for a diagnosis of major depression (referred to in this guideline as 'depression'). Symptoms should be present for at least 2\xa0weeks and each symptom should be present at sufficient severity for most of every day. Both diagnostic systems require at least 1 (DSM‑IV) or 2 (ICD‑10) key symptoms (low mood [in both ICD‑10 and DSM‑IV], loss of interest and pleasure [in both ICD‑10 and DSM‑IV], or loss of energy [in ICD‑10 only]) to be present.\n\nIncreasingly, it is recognised that depressive symptoms below the DSM‑IV and ICD‑10 threshold criteria can be distressing and disabling if persistent. Therefore this guideline covers 'subthreshold depressive symptoms', which fall below the criteria for a diagnosis of major depression, and are defined as at least one key symptom of depression but with insufficient other symptoms and/or functional impairment to meet the criteria for full diagnosis. Symptoms are considered persistent if they continue despite active monitoring and/or low-intensity intervention, or have been present for a considerable time, typically several months. For a diagnosis of dysthymia, symptoms should be present for at least 2\xa0years. Both DSM‑IV and ICD‑10 have the category of dysthymia, which consists of depressive symptoms that are subthreshold for major depression but that persist (by definition for more than 2\xa0years). There appears to be no empirical evidence that dysthymia is distinct from subthreshold depressive symptoms apart from duration of symptoms, and the term 'persistent subthreshold depressive symptoms' is preferred in this guideline.\n\nThe presence of a physical illness can complicate the assessment of depression and some symptoms, such as fatigue, are common to both mental and physical disorders.\n\nIt should be noted that classificatory systems are agreed conventions that seek to define different severities of depression in order to guide diagnosis and treatment, and their value is determined by how useful they are in practice. After careful review of the diagnostic criteria and the evidence, the Guideline Development Group decided to adopt DSM‑IV rather than ICD‑10, which was used in the previous depression guideline (the NICE guideline\xa0on depression: management of depression in primary and secondary care). This is because DSM‑IV is used in nearly all the evidence reviewed and it provides definitions for atypical symptoms and seasonal depression. Its definition of severity also makes it less likely that a diagnosis of depression will be based solely on symptom counting. In practical terms, clinicians are not expected to switch to DSM‑IV but should be aware that the threshold for mild depression is higher than with ICD‑10 (5\xa0symptoms not 4) and that degree of functional impairment should be routinely assessed before making a diagnosis. Using DSM‑IV enables the guideline to better target the use of specific interventions, such as antidepressants, for more severe degrees of depression.\n\nIn addition to physical illness, a wide range of psychological and social factors, which are not captured well by current diagnostic systems, have a significant impact on the course of depression and the response to treatment. Therefore it is also important to consider both personal past history and family history of depression when undertaking a diagnostic assessment (see the appendix\xa0on assessing depression and its severity for further details).\n\nTreating depression in people with a chronic physical health problem has the potential to increase their quality of life and life expectancy. Depression often has a remitting and relapsing course, and symptoms may persist between episodes. Where possible, the key goal of an intervention for depression should be complete relief of symptoms (remission) – this is associated with better functioning and a lower likelihood of relapse than lesser degrees of response, as well as potentially better physical health outcomes.\n\nThe guideline will assume that prescribers will use a drug's summary of product characteristics (SPC) and the BNF to inform decisions made with individual patients.", 'Recommendations': "The following guidance is based on the best available evidence. The full guideline gives details of the methods and the evidence used to develop the guidance.\n\n# Box 1 Depression definitions (taken from DSM-IV)\n\nSubthreshold depressive symptoms: Fewer than 5\xa0symptoms of depression.\n\nMild depression: Few, if any, symptoms in excess of the 5 required to make the diagnosis, and symptoms result in only minor functional impairment.\n\nModerate depression: Symptoms of functional impairment are between 'mild' and 'severe'.\n\nSevere depression: Most symptoms, and the symptoms markedly interfere with functioning. Can occur with or without psychotic symptoms.\n\nNot that a comprehensive assessment of depression should not rely simply on a symptom count, but should take into account the degree of functional impairment and/or disability (see section\xa01.1.3).\n\nThroughout this guideline, the term 'patient' is used to denote a person who has both depression and a chronic physical health problem.\n\nThis guideline is published alongside NICE's guideline on depression in adults: recognition and management, which makes recommendations on the identification, treatment and management of depression in adults aged 18\xa0years and older, in primary and secondary care.\n\nPeople have the right to be involved in discussions and make informed decisions about their care, as described in making decisions about your care.\n\nMaking decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.\n\n# Care of all people with depression\n\n## Providing information and support, and obtaining informed consent\n\nWhen working with patients with depression and a chronic physical health problem and their families or carers:\n\nbuild a trusting relationship and work in an open, engaging and non-judgemental manner\n\nexplore treatment options for depression in an atmosphere of hope and optimism, explaining the different courses of depression and that recovery is possible\n\nbe aware that stigma and discrimination can be associated with a diagnosis of depression and take into account how this may affect the patient with a chronic physical health problem\n\nensure that discussions take place in settings in which confidentiality, privacy and dignity are respected.\n\nWhen working with patients with depression and a chronic physical health problem and their families or carers:\n\nprovide information appropriate to their level of understanding about the nature of depression and the range of treatments available\n\navoid clinical language without adequate explanation\n\nensure that comprehensive written information is available in the appropriate language and in audio format if possible\n\nprovide and work proficiently with independent interpreters (that is, someone who is not known to the patient) if needed.\n\nInform patients with depression and a chronic physical health problem about self-help groups, support groups and other local and national resources for people with depression.\n\nMake all efforts necessary to ensure that a patient with depression and a chronic physical health problem can give meaningful and informed consent before treatment starts. This is especially important when a patient has severe depression or is subject to the Mental Health Act.\n\nEnsure that consent to treatment is based on the provision of clear information (which should also be available in written form) about the intervention, covering:\n\nwhat it comprises\n\nwhat is expected of the patient while having it\n\nlikely outcomes (including any side effects).\n\n## Supporting families and carers\n\nFor families or carers who are involved in supporting a patient with severe or chronic (symptoms more or less continuously for 2\xa0years or more) depression and a chronic physical health problem, see recommendations in the NICE guideline on supporting adult carers on identifying, assessing and meeting the caring, physical and mental health needs of families and carers.\n\n## Principles for assessment, coordination of care and choosing treatments\n\nWhen assessing a patient with a chronic physical health problem who may have depression, conduct a comprehensive assessment that does not rely simply on a symptom count. Take into account both the degree of functional impairment and/or disability associated with the possible depression and the duration of the episode.\n\nIn addition to assessing symptoms and associated functional impairment, consider how the following factors may have affected the development, course and severity of a patient's depression:\n\nany history of depression and comorbid mental health or physical disorders\n\nany past history of mood elevation (to determine if the depression may be part of bipolar disorder)\n\nany past experience of, and response to, treatments\n\nthe quality of interpersonal relationships\n\nliving conditions and social isolation.\n\nBe respectful of, and sensitive to, diverse cultural, ethnic and religious backgrounds when working with patients with depression and a chronic physical health problem, and be aware of the possible variations in the presentation of depression. Ensure competence in:\n\nculturally sensitive assessment\n\nusing different explanatory models of depression\n\naddressing cultural and ethnic differences when developing and implementing treatment plans\n\nworking with families from diverse ethnic and cultural backgrounds.\n\nWhen assessing a patient with a chronic physical health problem and suspected depression, be aware of any learning disabilities or acquired cognitive impairments, and if necessary consider consulting with a relevant specialist when developing treatment plans and strategies.\n\nWhen providing interventions for patients with a learning disability or acquired cognitive impairment who have a chronic physical health problem and a diagnosis of depression:\n\nwhere possible, provide the same interventions as for other patients with depression\n\nif necessary, adjust the method of delivery or duration of the intervention to take account of the disability or impairment.\n\nAlways ask patients with depression and a chronic physical health problem directly about suicidal ideation and intent. If there is a risk of self-harm or suicide:\n\nassess whether the patient has adequate social support and is aware of sources of help\n\narrange help appropriate to the level of risk (see section\xa01.3.2)\n\nadvise the patient to seek further help if the situation deteriorates.\n\n## Effective delivery of interventions for depression\n\nAll interventions for depression should be delivered by competent practitioners. Psychological and psychosocial interventions should be based on the relevant treatment manual(s), which should guide the structure and duration of the intervention. Practitioners should consider using competence frameworks developed from the relevant treatment manual(s) and for all interventions should:\n\nreceive regular high-quality supervision\n\nuse routine outcome measures and ensure that the patient with depression is involved in reviewing the efficacy of the treatment\n\nengage in monitoring and evaluation of treatment adherence and practitioner competence – for example, by using video and audio tapes, and external audit and scrutiny where appropriate.\n\nConsider providing all interventions in the preferred language of the patient with depression and a chronic physical health problem where possible.\n\nWhere a patient's management is shared between primary and secondary care, there should be clear agreement between practitioners (especially the patient's GP) on the responsibility for the monitoring and treatment of that patient. The treatment plan should be shared with the patient and, where appropriate, with their family or carer.\n\nIf a patient's chronic physical health problem restricts their ability to engage with a preferred psychosocial or psychological treatment for depression (see sections\xa01.4.2, 1.5.1 and 1.5.3), consider alternatives in discussion with the patient, such as antidepressants (see section\xa01.5.2) or delivery of psychosocial or psychological interventions by telephone if mobility or other difficulties prevent face-to face contact.\n\n# Stepped care\n\nThe stepped-care model provides a framework in which to organise the provision of services, and supports patients, carers and practitioners in identifying and accessing the most effective interventions (see figure\xa01). In stepped care the least intrusive, most effective intervention is provided first; if a patient does not benefit from the intervention initially offered, or declines an intervention, they should be offered an appropriate intervention from the next step.\n\nFocus of the intervention\n\nNature of the intervention\n\nSTEP 4: Severe and complex depression; risk to life; severe self-neglect\n\nMedication, high-intensity psychological interventions, electroconvulsive therapy, crisis service, combined treatments, multiprofessional and inpatient care\n\nSTEP 3: Persistent subthreshold depressive symptoms or mild to moderate depression with inadequate response to initial interventions; moderate and severe depression\n\nMedication, high-intensity psychological interventions, combined treatments, collaborative care and referral for further assessment and interventions\n\nSTEP 2: Persistent subthreshold depressive symptoms; mild to moderate depression\n\nLow-intensity psychosocial interventions, psychological interventions, medication and referral for further assessment and interventions\n\nSTEP 1: All known and suspected presentations of depression\n\nAssessment, support, psychoeducation, active monitoring and referral for further assessment and interventions\n\nComplex depression includes depression that shows an inadequate response to multiple treatments, is complicated by psychotic symptoms, and/or is associated with significant psychiatric comorbidity or psychosocial factors.\n\nCollaborative care for step\xa03 is only for depression where the person has a chronic physical health problem and associated functional impairment.\n\n# Step 1: recognition, assessment and initial management in primary care and general hospital settings\n\nThe recommendations in this section are primarily for practitioners working in primary care and in general hospital settings. Practitioners should be aware that patients with a chronic physical health problem are at a high risk of depression, particularly where there is functional impairment.\n\n## Case identification and recognition\n\nBe alert to possible depression (particularly in patients with a past history of depression or a chronic physical health problem with associated functional impairment) and consider asking patients who may have depression 2\xa0questions, specifically:\n\nDuring the last month, have you often been bothered by feeling down, depressed or hopeless?\n\nDuring the last month, have you often been bothered by having little interest or pleasure in doing things?\n\nIf a patient with a chronic physical health problem answers 'yes' to either of the depression identification questions (see recommendation\xa01.3.1.1) but the practitioner is not competent to perform a mental health assessment, they should refer the patient to an appropriate professional. If this professional is not the patient's GP, inform the GP of the referral.\n\nIf a patient with a chronic physical health problem answers 'yes' to either of the depression identification questions (see recommendation\xa01.3.1.1), a practitioner who is competent to perform a mental health assessment should:\n\nask 3\xa0further questions to improve the accuracy of the assessment of depression, specifically:\n\n\n\nduring the last month, have you often been bothered by feelings of worthlessness?\n\nduring the last month, have you often been bothered by poor concentration?\n\nduring the last month, have you often been bothered by thoughts of death?\n\n\n\nreview the patient's mental state and associated functional, interpersonal and social difficulties\n\nconsider the role of both the chronic physical health problem and any prescribed medication in the development or maintenance of the depression\n\nascertain that the optimal treatment for the physical health problem is being provided and adhered to, seeking specialist advice if necessary.\n\nWhen assessing a patient with suspected depression, consider using a validated measure (for example, for symptoms, functions and/or disability) to inform and evaluate treatment.\n\nFor patients with significant language or communication difficulties, for example patients with sensory impairments or a learning disability, consider using the Distress Thermometer and/or asking a family member or carer about the patient's symptoms to identify possible depression. If a significant level of distress is identified, investigate further.\n\n## Risk assessment and monitoring\n\nIf a patient with depression and a chronic physical health problem presents considerable immediate risk to themselves or others, refer them urgently to specialist mental health services.\n\nAdvise patients with depression and a chronic physical health problem of the potential for increased agitation, anxiety and suicidal ideation in the initial stages of treatment for depression; actively seek out these symptoms and:\n\nensure that the patient knows how to seek help promptly\n\nreview the patient's treatment if they develop marked and/or prolonged agitation.\n\nAdvise a patient with depression and a chronic physical health problem, and their family or carer, to be vigilant for mood changes, negativity and hopelessness, and suicidal ideation, and to contact their practitioner if concerned. This is particularly important during high-risk periods, such as starting or changing treatment and at times of increased personal stress.\n\nIf a patient with depression and a chronic physical health problem is assessed to be at risk of suicide:\n\ntake into account toxicity in overdose if an antidepressant is prescribed or the patient is taking other medication; if necessary, limit the amount of drug(s) available\n\nconsider increasing the level of support, such as more frequent direct or telephone contacts\n\nconsider referral to specialist mental health services.\n\n# Step 2: recognised depression in primary care and general hospital settings – persistent subthreshold depressive symptoms or mild to moderate depression\n\n## General measures\n\nWhen depression is accompanied by symptoms of anxiety, the first priority should usually be to treat the depression. When the patient has an anxiety disorder and comorbid depression or depressive symptoms, consult the NICE guideline for the relevant anxiety disorder (see the NICE webpage on depression) and consider treating the anxiety disorder first (since effective treatment of the anxiety disorder will often improve the depression or the depressive symptoms).\n\nOffer patients with depression and a chronic physical health problem advice on sleep hygiene if needed, including:\n\nestablishing regular sleep and wake times\n\navoiding excess eating, smoking or drinking alcohol before sleep\n\ncreating a proper environment for sleep\n\ntaking regular physical exercise where this is possible for the patient.\n\nFor patients who, in the judgement of the practitioner, may recover with no formal intervention, or patients with mild depression who do not want an intervention, or patients with subthreshold depressive symptoms who request an intervention:\n\ndiscuss the presenting problem(s) and any concerns that the patient may have about them\n\nprovide information about the nature and course of depression\n\narrange a further assessment, normally within 2 weeks\n\nmake contact if the patient does not attend follow-up appointments.\n\n## Low-intensity psychosocial interventions\n\nFor patients with persistent subthreshold depressive symptoms or mild to moderate depression and a chronic physical health problem, and for patients with subthreshold depressive symptoms that complicate the care of the chronic physical health problem, consider offering one or more of the following interventions, guided by the patient's preference:\n\na structured group physical activity programme\n\na group-based peer support (self-help) programme\n\nindividual guided self-help based on the principles of cognitive behavioural therapy (CBT)\n\ncomputerised cognitive behavioural therapy (CCBT).\n\nPhysical activity programmes for patients with persistent subthreshold depressive symptoms or mild to moderate depression and a chronic physical health problem, and for patients with subthreshold depressive symptoms that complicate the care of the chronic physical health problem, should:\n\nbe modified (in terms of the duration of the programme and frequency and length of the sessions) for different levels of physical ability as a result of the particular chronic physical health problem, in liaison with the team providing care for the physical health problem\n\nbe delivered in groups with support from a competent practitioner\n\nconsist typically of 2\xa0or 3\xa0sessions per week of moderate duration (45\xa0minutes to 1\xa0hour) over 10 to 14\xa0weeks (average 12\xa0weeks)\n\nbe coordinated or integrated with any rehabilitation programme for the chronic physical health problem.\n\nGroup-based peer support (self-help) programmes for patients with persistent subthreshold depressive symptoms or mild to moderate depression and a chronic physical health problem, and for patients with subthreshold depressive symptoms that complicate the care of the chronic physical health problem, should:\n\nbe delivered to groups of patients with a shared chronic physical health problem\n\nfocus on sharing experiences and feelings associated with having a chronic physical health problem\n\nbe supported by practitioners who should:\n\n\n\nfacilitate attendance at the meetings\n\nhave knowledge of the patients' chronic physical health problem and its relationship to depression\n\nreview the outcomes of the intervention with the individual patients\n\n\n\nconsist typically of 1\xa0session per week delivered over a period of 8 to 12\xa0weeks.\n\nIndividual guided self-help programmes based on the principles of CBT (and including behavioural activation and problem-solving techniques) for patients with persistent subthreshold depressive symptoms or mild to moderate depression and a chronic physical health problem, and for patients with subthreshold depressive symptoms that complicate the care of the chronic physical health problem, should:\n\ninclude the provision of written materials of an appropriate reading age (or alternative media to support access)\n\nbe supported by a trained practitioner, who typically facilitates the self-help programme and reviews progress and outcome\n\nconsist of up to 6\xa0to 8\xa0sessions (face-to-face and via telephone) normally taking place over 9 to 12\xa0weeks, including follow-up.\n\nCCBT for patients with persistent subthreshold depressive symptoms or mild to moderate depression and a chronic physical health problem, and for patients with subthreshold depressive symptoms that complicate the care of the chronic physical health problem, should:\n\nbe provided via a stand-alone computer-based or web-based programme\n\ninclude an explanation of the CBT model, encourage tasks between sessions, and use thought-challenging and active monitoring of behaviour, thought patterns and outcomes\n\nbe supported by a trained practitioner, who typically provides limited facilitation of the programme and reviews progress and outcome\n\ntypically take place over 9 to 12\xa0weeks, including follow-up.\n\n## Drug treatment\n\nFor guidance on safe prescribing of antidepressants and managing withdrawal, see NICE's guideline on medicines associated with dependence or withdrawal symptoms.\n\nDo not use antidepressants routinely to treat subthreshold depressive symptoms or mild depression in patients with a chronic physical health problem (because the risk–benefit ratio is poor), but consider them for patients with:\n\na past history of moderate or severe depression or\n\nmild depression that complicates the care of the physical health problem or\n\ninitial presentation of subthreshold depressive symptoms that have been present for a long period (typically at least 2 years) or\n\nsubthreshold depressive symptoms or mild depression that persist(s) after other interventions.\n\nAlthough there is evidence that St John's wort may be of benefit in mild or moderate depression, practitioners should:\n\nnot prescribe or advise its use by patients with depression and a chronic physical health problem because of uncertainty about appropriate doses, persistence of effect, variation in the nature of preparations and potential serious interactions with other drugs (including oral contraceptives, anticoagulants and anticonvulsants)\n\nadvise patients with depression of the different potencies of the preparations available and of the potential serious interactions of St John's wort with other drugs.\n\n# Step 3: recognised depression in primary care and general hospital settings – persistent subthreshold depressive symptoms or mild to moderate depression with inadequate response to initial interventions, and moderate and severe depression\n\n## Treatment options\n\nFor guidance on safe prescribing of antidepressants and managing withdrawal, see NICE's guideline on medicines associated with dependence or withdrawal symptoms.\n\nFor patients with persistent subthreshold depressive symptoms or mild to moderate depression and a chronic physical health problem who have not benefited from a low-intensity psychosocial intervention, discuss the relative merits of different interventions with the patient and provide:\n\nan antidepressant (normally a selective serotonin reuptake inhibitor [SSRI]) or\n\none of the following high-intensity psychological interventions:\n\n\n\ngroup-based CBT or\n\nindividual CBT for patients who decline group-based CBT or for whom it is not appropriate, or where a group is not available or\n\nbehavioural couples therapy for people who have a regular partner and where the relationship may contribute to the development or maintenance of depression, or where involving the partner is considered to be of potential therapeutic benefit.\n\n\n\nFor patients with initial presentation of moderate depression and a chronic physical health problem, offer the following choice of high-intensity psychological interventions:\n\ngroup-based CBT or\n\nindividual CBT for patients who decline group-based CBT or for whom it is not appropriate, or where a group is not available or\n\nbehavioural couples therapy for people who have a regular partner and where the relationship may contribute to the development or maintenance of depression, or where involving the partner is considered to be of potential therapeutic benefit.\n\nFor patients with initial presentation of severe depression and a chronic physical health problem, consider offering a combination of individual CBT and an antidepressant.\n\nThe choice of intervention should be influenced by the:\n\nduration of the episode of depression and the trajectory of symptoms\n\nprevious course of depression and response to treatment\n\nlikelihood of adherence to treatment and any potential adverse effects\n\ncourse and treatment of the chronic physical health problem\n\npatient's treatment preference and priorities.\n\n## Antidepressant drugs\n\nFor guidance on safe prescribing of antidepressants and managing withdrawal, see NICE's guideline on medicines associated with dependence or withdrawal symptoms.\n\nFor additional considerations on using antidepressants and other medications (including the assessment of the relative risks and benefits) for women who may become pregnant, please refer to the BNF and individual drug summary of product characteristics. For women in the antenatal and postnatal periods, also see also the NICE guideline on antenatal and postnatal mental health.\n\nWhen an antidepressant is to be prescribed for a patient with depression and a chronic physical health problem, take into account the following:\n\nthe presence of additional physical health disorders\n\nthe side effects of antidepressants, which may impact on the underlying physical disease (in particular, SSRIs may result in or exacerbate hyponatraemia, especially in older people)\n\nthat there is no evidence as yet supporting the use of specific antidepressants for patients with particular chronic physical health problems\n\ninteractions with other medications.\n\nWhen an antidepressant is to be prescribed, be aware of drug interactions and:\n\nrefer to appendix 1 of the BNF and the table of interactions in appendix 16 of the full guideline for information\n\nseek specialist advice if there is uncertainty\n\nif necessary, refer the patient to specialist mental health services for continued prescribing.\n\nFirst prescribe an SSRI in generic form unless there are interactions with other drugs; consider using citalopram or sertraline because they have less propensity for interactions.\n\nWhen prescribing antidepressants, be aware that:\n\ndosulepin should not be prescribed\n\nnon-reversible monoamine oxidase inhibitors (MAOIs; for example, phenelzine), combined antidepressants and lithium augmentation of antidepressants should normally be prescribed only by specialist mental health professionals.\n\nTake into account toxicity in overdose when choosing an antidepressant for patients at significant risk of suicide. Be aware that:\n\ncompared with other equally effective antidepressants recommended for routine use in primary care, venlafaxine is associated with a greater risk of death from overdose\n\ntricyclic antidepressants (TCAs), except for lofepramine, are associated with the greatest risk in overdose.\n\nDo not normally offer SSRIs to patients taking non-steroidal anti-inflammatory drugs (NSAIDs) because of the increased risk of gastrointestinal bleeding. Consider offering an antidepressant with a lower propensity for, or a different range of, interactions, such as mianserin, mirtazapine, moclobemide, reboxetine or trazodone.\n\nIf no suitable alternative antidepressant can be identified, SSRIs may be prescribed at the same time as NSAIDs if gastroprotective medicines (for example, proton-pump inhibitors) are also offered.\n\nDo not normally offer SSRIs to patients taking warfarin or heparin because of their anti-platelet effect.\n\nUse SSRIs with caution in patients taking aspirin. When aspirin is used as a single agent, consider alternatives that may be safer, such as trazodone, mianserin or reboxetine.\n\nIf no suitable alternative antidepressant can be identified, SSRIs may be prescribed at the same time as aspirin if gastroprotective medicines (for example, proton-pump inhibitors) are also offered.\n\nConsider offering mirtazapine to patients taking heparin, aspirin or warfarin (but note that when taken with warfarin, the international normalised ratio [INR] may increase slightly).\n\nDo not offer SSRIs to patients receiving 'triptan' drugs for migraine. Offer a safer alternative such as mirtazapine, trazodone, mianserin or reboxetine.\n\nDo not normally offer SSRIs at the same time as monoamine oxidase B (MAO‑B) inhibitors such as selegiline and rasagiline. Offer a safer alternative such as mirtazapine, trazodone, mianserin or reboxetine.\n\nDo not normally offer fluvoxamine to patients taking theophylline, clozapine, methadone or tizamidine. Offer a safer alternative such as sertraline or citalopram.\n\nOffer sertraline as the preferred antidepressant for patients taking flecainide or propafenone, although mirtazapine and moclobemide may also be used.\n\nDo not offer fluoxetine or paroxetine to patients taking atomoxetine. Offer a different SSRI.\n\nWhen prescribing antidepressants, explore any concerns the patient with depression and a chronic physical health problem has about taking medication, explain fully the reasons for prescribing, and provide information about taking antidepressants, including:\n\nthe gradual development of the full antidepressant effect\n\nthe importance of taking medication as prescribed and the need to continue treatment after remission\n\npotential side effects\n\nthe potential for interactions with other medications\n\nthe risk and nature of discontinuation symptoms with all antidepressants, particularly with drugs with a shorter half-life (such as paroxetine and venlafaxine), and how these symptoms can be minimised\n\nthe fact that addiction does not occur with antidepressants.Offer written information appropriate to the patient's needs.\n\nPrescribe antidepressant medication at a recognised therapeutic dose for patients with depression and a chronic physical health problem (that is, avoid the tendency to prescribe at subtherapeutic doses in these patients).\n\nFor patients started on antidepressants who are not considered to be at increased risk of suicide, normally see them after 2\xa0weeks. See them regularly thereafter, for example at intervals of 2 to 4\xa0weeks in the first 3\xa0months, and then at longer intervals if response is good.\n\nA patient with depression started on antidepressants who is considered to present an increased suicide risk or is younger than 30\xa0years (because of the potential increased prevalence of suicidal thoughts in the early stages of antidepressant treatment for this group) should normally be seen after 1\xa0week and frequently thereafter as appropriate until the risk is no longer considered clinically important.\n\nIf a patient with depression and a chronic physical health problem develops side effects early in antidepressant treatment, provide appropriate information and consider one of the following strategies:\n\nmonitor symptoms closely where side effects are mild and acceptable to the patient or\n\nstop the antidepressant or change to a different antidepressant if the patient prefers or\n\nin discussion with the patient, consider short-term concomitant treatment with a benzodiazepine if anxiety, agitation and/or insomnia are problematic, but:\n\n\n\ndo not offer benzodiazepines to patients with chronic symptoms of anxiety\n\nuse benzodiazepines with caution in patients at risk of falls\n\nin order to prevent the development of dependence, do not use benzodiazepines for longer than 2\xa0weeks.\n\n\n\nSupport and encourage a patient with a chronic physical health problem who has benefited from taking an antidepressant to continue medication for at least 6\xa0months after remission of an episode of depression. Discuss with the patient that:\n\nthis greatly reduces the risk of relapse\n\nantidepressants are not associated with addiction.\n\nReview with the patient with depression and a chronic physical health problem the need for continued antidepressant treatment beyond 6\xa0months after remission, taking into account:\n\nthe number of previous episodes of depression\n\nthe presence of residual symptoms\n\nconcurrent physical health problems and psychosocial difficulties.\n\nMore detailed advice on switching, sequencing, augmenting and combining antidepressants can be found in section\xa01.8 of the NICE guideline on depression in adults. The recommendations below should be considered alongside recommendations\xa01.5.2.6 to 1.5.2.16 in the section 'Interactions of SSRIs with other medication' in the current guideline.\n\nIf the patient's depression shows no improvement after 2 to 4\xa0weeks with the first antidepressant, check that the drug has been taken regularly and in the prescribed dose.\n\nIf response is absent or minimal after 3 to 4\xa0weeks of treatment with a therapeutic dose of an antidepressant, increase the level of support (for example, by weekly face-to-face or telephone contact) and consider:\n\nincreasing the dose in line with the summary of product characteristics if there are no significant side effects or\n\nswitching to another antidepressant as described in section\xa01.8 of the NICE guideline on depression in adults if there are side effects or if the patient prefers.\n\nIf the patient's depression shows some improvement by 4\xa0weeks, continue treatment for another 2 to 4\xa0weeks. Consider switching to another antidepressant as described in section\xa01.8 of the NICE guideline on depression in adults if:\n\nresponse is still not adequate or\n\nthere are side effects or\n\nthe patient prefers to change treatment.\n\nWhen switching from 1\xa0antidepressant to another, be aware of:\n\nthe need for gradual and modest incremental increases in dose\n\ninteractions between antidepressants\n\nthe risk of serotonin syndrome (features include confusion, delirium, shivering, sweating, changes in blood pressure and myoclonus) when combinations of serotonergic antidepressants are prescribed.\n\nIf an antidepressant has not been effective or is poorly tolerated:\n\nconsider offering other treatment options, including high-intensity psychological treatments (see section\xa01.5.3)\n\nprescribe another single antidepressant (which can be from the same class) if the decision is made to offer a further course of antidepressants.\n\nAdvise patients with depression and a chronic physical health problem who are taking antidepressants that discontinuation symptoms may occur on stopping, missing doses or, occasionally, on reducing the dose of the drug. These include increased mood change, restlessness, difficulty sleeping, unsteadiness, sweating, abdominal symptoms and altered sensations. Explain that symptoms are usually mild and self-limiting over about 1\xa0week, but can be severe, particularly if the drug is stopped abruptly.\n\nWhen stopping an antidepressant, gradually reduce the dose, normally over a 4‑week period, although some patients may require longer periods, particularly with drugs with a shorter half-life (such as paroxetine and venlafaxine). This is not required with fluoxetine because of its long half-life.\n\nInform the patient that they should seek advice from their practitioner if they experience significant discontinuation symptoms. If discontinuation symptoms occur:\n\nmonitor symptoms and reassure the patient if symptoms are mild\n\nconsider reintroducing the original antidepressant at the dose that was effective (or another antidepressant with a longer half-life from the same class) if symptoms are severe, and reduce the dose gradually while monitoring symptoms.\n\n## Psychological interventions\n\nDelivering high-intensity psychological interventions\n\nFor all high-intensity psychological interventions, the duration of treatment should normally be within the limits indicated in this guideline. As the aim of treatment is to obtain significant improvement or remission the duration of treatment may be:\n\nreduced if remission has been achieved\n\nincreased if progress is being made, and there is agreement between the practitioner and the patient with depression that further sessions would be beneficial (for example, if there is a comorbid personality disorder or psychosocial factors that impact on the patient's ability to benefit from treatment).\n\nGroup-based CBT for patients with depression and a chronic physical health problem should be:\n\ndelivered in groups (typically of between 6 and 8\xa0patients) with a common chronic physical health problem\n\ntypically delivered over a period of 6 to 8\xa0weeks.\n\nIndividual CBT for patients with moderate depression and a chronic physical health problem should be:\n\ndelivered until the symptoms of depression have remitted (over a period that is typically 6 to 8\xa0weeks and should not normally exceed 16 to 18\xa0weeks)\n\nfollowed up by 2\xa0further sessions in the 6\xa0months after the end of treatment, especially if treatment was extended.\n\nIndividual CBT for patients with severe depression and a chronic physical health problem should be:\n\ndelivered until the symptoms of depression have remitted (over a period that is typically 16 to 18\xa0weeks)\n\nfocused in the initial sessions (which typically should take place twice weekly for the first 2 to 3\xa0weeks) on behavioural activation\n\nfollowed up by 2\xa0or 3\xa0further sessions in the 12\xa0months after the end of treatment.\n\nBehavioural couples therapy for depression should normally be based on behavioural principles, and an adequate course of therapy should be 15 to 20\xa0sessions over 5 to 6\xa0months.\n\n## Collaborative care\n\nCollaborative care, which should form part of a well-developed stepped-care programme, could be provided at the primary or secondary care level. The interventions, which involve all sectors of care, require a coordinated approach to mental and physical healthcare, as well as a dedicated coordinator of the intervention located in and receiving support from a multi‑professional team, joint determination of the plan of care, and long-term coordination and follow-up.\n\nConsider collaborative care for patients with moderate to severe depression and a chronic physical health problem with associated functional impairment whose depression has not responded to initial high-intensity psychological interventions, pharmacological treatment or a combination of psychological and pharmacological interventions.\n\nCollaborative care for patients with depression and a chronic physical health problem should normally include:\n\ncase management which is supervised and has support from a senior mental health professional\n\nclose collaboration between primary and secondary physical health services and specialist mental health services\n\na range of interventions consistent with those recommended in this guideline, including patient education, psychological and pharmacological interventions, and medication management\n\nlong-term coordination of care and follow-up.\n\n# Step 4: complex and severe depression\n\nPractitioners providing treatment in specialist mental health services for patients with complex and severe depression and a chronic physical health problem should:\n\nrefer to the NICE guideline on depression in adults\n\nbe aware of the additional drug interactions associated with the treatment of patients with both depression and a chronic physical health problem (see recommendations 1.5.2.6 to 1.5.2.16)\n\nwork closely and collaboratively with the physical health services.", 'Recommendations for research': "The Guideline Development Group has made the following recommendations for research, based on its review of evidence, to improve NICE guidance and patient care in the future.\n\n# Combined medication and CBT for patients with moderate to severe depression and a chronic physical health problem\n\nWhat is the clinical and cost effectiveness of combined medication and cognitive behavioural therapy (CBT) compared with antidepressants or CBT alone for patients with moderate to severe depression and a chronic physical health problem?\n\n## Why this is important\n\nThere is limited evidence for the effectiveness of combined antidepressant treatment and CBT for patients with moderate to severe depression and a chronic physical health problem. Data from studies in patients with depression in the absence of a chronic physical health problem suggest that combined treatment may bring real benefit. However, uncertainty about medium-term outcomes for these patients remains. In addition to uncertainty about the effectiveness of the interventions, the potential for interactions between medication prescribed for depression and for chronic physical health problems is a concern. This needs to be considered in terms of both the difficulties that may arise from drug interactions and the anxieties of individual patients about this, which may reduce the likelihood of them complying with antidepressant medication. The answer to this question has practical implications for service delivery and resource allocation in the NHS.\n\nThe outcomes for this proposed study should involve both observer-rated and patient-rated assessments of acute and medium-term outcomes for at least 6\xa0months and an assessment of the acceptability and potential burden of the various treatment options. The study should be large enough to determine the presence or absence of any clinically important effects using a non-inferiority design together with robust health economic measures.\n\n# Peer support interventions compared with group-based exercise and treatment as usual for patients with mild to moderate depression and a chronic physical health problem\n\nWhat is the clinical and cost effectiveness of group peer support and group-based exercise when compared with treatment as usual for patients with mild to moderate depression and a chronic physical health problem?\n\n## Why this is important\n\nThere is limited evidence for the effectiveness of peer support and exercise in the treatment of patients with depression and a chronic physical health problem. Although the available data suggest that both are practical and potentially acceptable treatments that may bring real benefit, uncertainty remains about medium-term outcomes. The answer to this question has practical implications for service delivery and resource allocation in the NHS.\n\nThis question should be answered in an adequately powered 3‑arm randomised controlled trial that examines medium-term outcomes, including cost effectiveness. The outcomes should reflect both observer-rated and patient-rated assessments for acute and medium-term outcomes for 12\xa0months, and an assessment of the acceptability and potential burden of treatment options. The study should be large enough to determine the presence or absence of clinically important effects using a non-inferiority design with robust health economic measures.\n\n# Antidepressant medication compared with placebo in patients with depression and COPD\n\nWhat is the clinical and cost effectiveness of antidepressant medication compared with placebo in patients with depression and chronic obstructive pulmonary disease (COPD)?\n\n## Why this is important\n\nThere is limited evidence for the effectiveness of antidepressant treatment in patients with depression and a chronic physical health problem. Of particular concern to the Guideline Development Group was the high incidence of depression in patients with COPD (which is also known to be associated with a high incidence of anxiety disorders). The Guideline Development Group considered it important to measure the effectiveness of antidepressant medication in the treatment of COPD. The answer to this question has important practical implications for service delivery, particularly for a patient group with mental health needs that are traditionally under-treated within the NHS.\n\nThe question should be answered using a randomised controlled trial in which patients with moderate depression and COPD receive either placebo or antidepressant medication. The outcomes chosen should reflect both observer-rated and patient-rated assessments for acute and medium-term outcomes for at least 6\xa0months and an assessment of the acceptability and burden of treatment. In addition to the assessment of symptoms of depression, the study should also assess the impact of antidepressant medication on symptoms of anxiety. The study should be large enough to determine the presence or absence of clinically important effects using a non-inferiority design together with robust health economic measures.\n\n# Behavioural activation compared with antidepressant medication for patients with moderate to severe depression and a chronic physical health problem\n\nWhat is the clinical and cost effectiveness of behavioural activation compared with antidepressant medication in the treatment of moderate to severe depression in patients with a chronic physical health problem?\n\n## Why this is important\n\nThere is limited evidence for the effectiveness of high-intensity psychological interventions in the treatment of moderate to severe depression in patients with a chronic physical health problem; the most substantial evidence base is for CBT. Recent developments suggest that behavioural activation may be an effective intervention for depression. In principle, this may be a more feasible treatment to deliver in routine care than CBT and could potentially contribute to increased treatment choice for patients. The answer to this question would have practical implications for service delivery and resource allocation within the NHS.\n\nThis question should be answered using a randomised controlled trial in which patients with moderate to severe depression and a chronic physical health problem receive either behavioural activation or antidepressant medication. The outcomes should be chosen to reflect both observer-rated and patient-rated assessments for acute and medium-term outcomes for at least 12\xa0months and also assessment of the acceptability and burden of the treatment options. The study needs to be large enough to determine the presence or absence of clinically important effects using a non-inferiority design and robust health economic measures.\n\n# The effects of collaborative care on physical health outcomes for patients with moderate to severe depression and a chronic physical health problem\n\nWhat is the clinical and cost effectiveness of collaborative care with regard to physical health outcomes for people with moderate to severe depression and a chronic physical health problem?\n\n## Why this is important\n\nThere is a reasonable evidence base to support the use of collaborative care in people with moderate to severe depression and a chronic physical health problem. However, the evidence base regarding the effects of collaborative care on physical health outcomes is more limited. Improved depression care is thought to produce other health benefits, such as improved functioning and physical outcomes; this may be particularly significant for people with depression and a chronic physical health problem. This means that interventions that also improve physical health should result in substantial increases in utility and subsequently result in quality-adjusted life year (QALY) gains. Furthermore, the ability to achieve such health gains can potentially reduce the population burden of illness and morbidity within healthcare budgets. There is an association between depression and increased use of medical services, and so it follows that improved treatment of depression could reduce medical expenditure, partially or fully offsetting the costs of treating the depression. The answer to this question has important practical implications for service delivery and resource allocation within the NHS.\n\nThis question should be answered using a randomised controlled trial design that includes people with moderate to severe depression and a chronic physical health problem. In addition to depression-related outcomes, physical health outcomes such as general physical functioning and pain, as well as outcomes specifically related to the condition (such as HbA1c for diabetes), should be assessed. These outcomes should reflect both observer-rated and patient-rated assessments of medium-term and long-term outcomes for at least 18 months. The study should also include an assessment of the acceptability and burden of treatment options and the impact of the intervention on the overall care system. It should be large enough to determine the presence or absence of clinically important effects using a non-inferiority design together with robust health outcome measures.\n\n# The effectiveness of physical rehabilitation programmes for patients with a chronic physical health problem and depression\n\nWhat is the effectiveness of rehabilitation programmes for patients with depression and a chronic physical health problem in terms of improved mood?\n\n## Why this is important\n\nMany patients with a chronic physical health problem undergo rehabilitation programmes. There is some suggestion in the literature that these have a beneficial effect on mental health. Understanding and/or enhancing the psychological benefits of these interventions has potentially important cost and service-design implications for the NHS. Given the large data set that already exists, it is important to determine the potential effects of these programmes to date before embarking on any individual studies. The answer to this question has important practical implications for service delivery and resource allocation within the NHS.\n\nThis question should be answered by an individual patient meta-analysis. There is an existing evidence base showing that programmes specifically designed to treat depression (for example, psychosocial and pharmacological interventions in patients with a chronic physical health problem) are effective. However, many patients with a chronic physical health problem are also undertaking specifically designed rehabilitation programmes (for example, cardiac rehabilitation programmes after myocardial infarction). These interventions are multi-modal and reports indicate that they can have an impact on mental health outcomes, in particular depression. However, it is unclear what the size of this effect may be, which components of the intervention are effective and which specific patient populations may benefit. Therefore an individual patient meta-analysis to examine the impact of rehabilitation programmes on symptoms of depression in patients with a chronic physical health problem should be undertaken before any further research is conducted.\n\n# The efficacy of counselling compared with low-intensity cognitive and behavioural interventions and treatment as usual in the treatment of depression in patients with a chronic physical health problem\n\nWhat is the relative efficacy of counselling compared with low-intensity cognitive and behavioural interventions and treatment as usual in patients with depression and a chronic physical health problem?\n\n## Why this is important\n\nThere is a limited evidence base for counselling compared with treatment as usual in the treatment of patients with depression and a chronic physical health problem. High-intensity cognitive and behavioural interventions have the best evidence base for efficacy but there is limited evidence on the efficacy of low-intensity cognitive and behavioural interventions in patients with depression and a chronic physical health problem. The evidence on low-intensity cognitive and behavioural interventions for this guideline was largely supplemented by the evidence base in the NICE guideline on depression in adults. It is therefore important to establish whether either counselling or low-intensity cognitive and behavioural interventions are effective alternatives to treatment as usual for patients with a chronic physical health problem and should be provided in the NHS. The answer to this question will have important implications for the provision of psychological treatment in the NHS.\n\nThis question should be answered using a randomised controlled trial design that reports short-term and medium-term outcomes (including cost-effectiveness outcomes) of at least 18\xa0months' duration. Particular attention should be paid to the reproducibility of the treatment model and the training and supervision of the practitioners providing interventions in order to ensure that the treatments are both robust and generalisable. The outcomes chosen should reflect both observer-rated and patient-rated assessments of improvement and an assessment of the acceptability of the treatment options. Particular attention should be given to physical health and quality-of-life outcomes in addition to depression outcomes. The study needs to be large enough to determine the presence or absence of clinically important effects using a non-inferiority design, and mediators and moderators of response should be investigated.", 'Appendix: Assessing depression and its severity': "In this guideline, the assessment of depression is based on the criteria in DSM‑IV. Assessment should include the number and severity of symptoms, duration of the current episode, and the course of the illness.\n\nKey symptoms:\n\npersistent sadness or low mood and/or\n\nmarked loss of interests or pleasure.\n\nAt least one of these, most days, most of the time for at least 2\xa0weeks.\n\nIf any of above present, ask about associated symptoms:\n\ndisturbed sleep (decreased or increased compared to usual)\n\ndecreased or increased appetite and/or weight\n\nfatigue or loss of energy\n\nagitation or slowing of movements\n\npoor concentration or indecisiveness\n\nfeelings of worthlessness or excessive or inappropriate guilt\n\nsuicidal thoughts or acts.\n\nThen ask about duration and associated disability, past and family history of mood disorders, and availability of social support\n\n. Factors that favour general advice and active monitoring:\n\nfour or fewer of the above symptoms with little associated disability\n\nsymptoms intermittent, or less than 2\xa0weeks' duration\n\nrecent onset with identified stressor\n\nno past or family history of depression\n\nsocial support available\n\nlack of suicidal thoughts.\n\n. Factors that favour more active treatment in primary care:\n\nfive or more symptoms with associated disability\n\npersistent or long-standing symptoms\n\npersonal or family history of depression\n\nlow social support\n\noccasional suicidal thoughts.\n\n. Factors that favour referral to mental health professionals:\n\ninadequate or incomplete response to 2 or more interventions\n\nrecurrent episode within 1\xa0year of last one\n\nhistory suggestive of bipolar disorder\n\npatient with depression or relatives request referral\n\nmore persistent suicidal thoughts\n\nself-neglect.\n\n. Factors that favour urgent referral to specialist mental health services\n\nactively suicidal ideas or plans\n\npsychotic symptoms\n\nsevere agitation accompanying severe symptoms\n\nsevere self-neglect.\n\nDepression definitions\n\nSubthreshold depressive symptoms: Fewer than 5\xa0symptoms of depression.\n\nMild depression: Few, if any, symptoms in excess of the 5 required to make the diagnosis, and symptoms result in only minor functional impairment.\n\nModerate depression: Symptoms or functional impairment are between 'mild' and 'severe'.\n\nSevere depression: Most symptoms, and the symptoms markedly interfere with functioning. Can occur with or without psychotic features."}	https://www.nice.org.uk/guidance/cg91	This guideline covers identifying, treating and managing depression in people aged 18 and over who also have a chronic physical health problem such as cancer, heart disease or diabetes. It aims to improve the care of people with a long-term physical health problem, which can cause or exacerbate depression. This has the potential to increase their quality of life and life expectancy.
9b4bef0d2c76b326ca2ecf1c72b1db1d72794a25	nice	Guidance on the use of electroconvulsive therapy	Guidance on the use of electroconvulsive therapy Evidence-based recommendations on electroconvulsive therapy (ECT) for treating catatonia, prolonged or severe manic episodes or schizophrenia in adults. # Guidance The recommendations in this technology appraisal relating to the treatment of depression have been replaced by those in the NICE guideline on depression in adults published in October 2009. Note that the recommendations in this technology appraisal relating to the treatment of catatonia-prolonged or severe manic episodes and schizophrenia have not changed. The recommendations relating to depression have been removed from this version. It is recommended that electroconvulsive therapy (ECT) is used only to achieve rapid and short-term improvement of severe symptoms after an adequate trial of other treatment options has proven ineffective and/or when the condition is considered to be potentially life-threatening, in individuals with: catatonia a prolonged or severe manic episode. The decision as to whether ECT is clinically indicated should be based on a documented assessment of the risks and potential benefits to the individual, including: the risks associated with the anaesthetic; current comorbidities; anticipated adverse events, particularly cognitive impairment; and the risks of not having treatment. The risks associated with ECT may be enhanced during pregnancy, in older people, and in children and young people, and therefore clinicians should exercise particular caution when considering ECT treatment in these groups. Valid consent should be obtained in all cases where the individual has the ability to grant or refuse consent. The decision to use ECT should be made jointly by the individual and the clinician(s) responsible for treatment, on the basis of an informed discussion. This discussion should be enabled by the provision of full and appropriate information about the general risks associated with ECT (see section 1.9) and about the risks and potential benefits specific to that individual. Consent should be obtained without pressure or coercion, which may occur as a result of the circumstances and clinical setting, and the individual should be reminded of their right to withdraw consent at any point. There should be strict adherence to recognised guidelines about consent and the involvement of patient advocates and/or carers to facilitate informed discussion is strongly encouraged. In all situations where informed discussion and consent is not possible advance directives should be taken fully into account and the individual's advocate and/or carer should be consulted. Clinical status should be assessed following each ECT session and treatment should be stopped when a response has been achieved, or sooner if there is evidence of adverse effects. Cognitive function should be monitored on an ongoing basis, and at a minimum at the end of each course of treatment. It is recommended that a repeat course of ECT should be considered under the circumstances indicated in section 1.1 only for individuals who have catatonia or mania and who have previously responded well to ECT. In patients who are experiencing an acute episode but have not previously responded, a repeat trial of ECT should be undertaken only after all other options have been considered and following discussion of the risks and benefits with the individual and/or where appropriate their carer/advocate. This recommendation has been updated and replaced by the NICE guideline on depression in adults. The current state of the evidence does not allow the general use of ECT in the management of schizophrenia to be recommended. National information leaflets should be developed through consultation with appropriate professional and user organisations to enable individuals and their carers/advocates to make an informed decision regarding the appropriateness of ECT for their circumstances. The leaflets should be evidence based, include information about the risks of ECT and availability of alternative treatments, and be produced in formats and languages that make them accessible to a wide range of service users.# Clinical need and practice This appraisal considers electroconvulsive therapy (ECT) in the treatment of: depressive illness, schizophrenia, catatonia and mania. Depressive illness is associated with discrete episodes that are characterised by feelings of sadness, despair, loss of interest in daily life and discouragement. The severity of depressive illness is determined by the number, intensity and frequency or persistence of depressive symptoms and the presence of specific symptoms such as delusions, hallucinations and suicidal ideation. Severe depressive illness can deteriorate into a 'depressive stupor' where a person is conscious but is non-responsive to any stimulation. This extreme manifestation of depressive illness has become less frequent because of the advent of modern treatments. Schizophrenia is characterised by a broad range of cognitive, emotional and behavioural problems, which are in general classified into positive and negative symptoms. Individuals with delusions or hallucinations are described as psychotic. Catatonia is a syndrome that is associated with both schizophrenia and affective (mood) disorders. It is characterised by marked changes in muscle tone or activity that may alternate between the extremes of a deficit of movement (catatonic stupor) and excessive movement (catatonic excitement). Mania is characterised by elated, euphoric or irritable mood and increased energy. The term may refer to a mental disorder or to a mood state or symptom, and mania is associated with bipolar disorders. In severe manic episodes, individuals are psychotic and require continual supervision to prevent physical harm to themselves or others. In 2000, the Psychiatric Morbidity Survey conducted by the Office of National Statistics (ONS) found the prevalence of a depressive episode per thousand population to be 25 in England and 37 in Wales. The prevalence of schizophrenia is estimated at between 2 and 10 per 1,000 in the general population, and the incidence of first-onset schizophrenia is approximately 1 per 10,000 population per year. Recent estimates have suggested that bipolar affective disorder has a point prevalence of up to 50 per 1,000 of the general population, of whom 1% are admitted to hospital for mania each year. There are no recent epidemiological studies on the incidence of catatonia. Depressive illness, schizophrenia and mania are frequently chronic, relapsing conditions and are associated with considerable suicide risk. Diagnosable depressive disorders are implicated in between 40% and 60% of suicide attempts. The 2000 ONS Psychiatric Morbidity Survey found that in individuals with a current depressive episode, 5% reported a suicide attempt within the past year. Common estimates are that 10% of people with schizophrenia will eventually have a completed suicide, and that attempts are made at 2 to 5 times that rate. Severe mental health disorders are associated with considerable personal suffering, occupational and social disadvantage and impairment in interpersonal and family relationships in the long term. They also have a high economic impact, with the indirect costs far exceeding the direct costs. Depressive illness is managed with antidepressants, psychotherapy and counselling, either alone or in combination. Although the management of schizophrenia frequently centres on antipsychotic medication, individuals also require substantial clinical, emotional and social support. Catatonia is usually treated with benzodiazepines; the introduction of effective psychotropic agents has led to a marked reduction in its prevalence. Acute manic episodes are treated with antipsychotics, lithium or anticonvulsants. Many individuals with mental health disorders benefit from self-help techniques including support groups. ECT is used in current UK clinical practice as a treatment option for individuals with depressive illness, catatonia and mania. It is also occasionally used to treat schizophrenia. Guidelines for the use of ECT were developed by the Royal College of Psychiatrists in 1995 and are currently undergoing revision. Guidance for nurses has also been produced by the Royal College of Nursing.# The technology During electroconvulsive therapy (ECT), an electric current is passed briefly through the brain, via electrodes applied to the scalp, to induce generalised seizure activity. The individual receiving treatment is placed under general anaesthetic and muscle relaxants are given to prevent body spasms. The ECT electrodes can be placed on both sides of the head (bilateral placement) or on 1 side of the head (unilateral placement). Unilateral placement is usually to the non-dominant side of the brain, with the aim of reducing cognitive side effects. The amount of current required to induce a seizure (the seizure threshold) can vary up to 40‑fold between individuals. Although ECT has been used since the 1930s, there is still no generally accepted theory that explains its mechanism of action. The most prevalent hypothesis is that it causes an alteration in the post-synaptic response to central nervous system neurotransmitters. In recent years, there have been moves to improve standards in the administration of ECT, with the introduction of practice guidelines published by the Royal College of Psychiatrists and the Royal College of Nursing, and the monitoring of the implementation of these guidelines through ongoing audit. However, there is still variation in the use and practice of ECT within England and Wales. ECT administration affects the central nervous system and causes changes in cardiovascular dynamics, which dictates the need for special caution in those individuals who are at increased risk of a cardiovascular event. There are also other immediate potential complications, such as status epilepticus, laryngospasm and peripheral nerve palsy, which overall have an estimated incidence of 1 per 1,300 to 1,400 treatments. The mortality associated with ECT is reported not to be in excess of that associated with the administration of a general anaesthetic for minor surgery. ECT may cause short- or long-term memory impairment for past events (retrograde amnesia) and current events (anterograde amnesia). As this type of cognitive impairment is a feature of many mental health problems it may sometimes be difficult to differentiate the effects of ECT from those associated with the condition itself. In addition there are differences between individuals in the extent of memory loss secondary to ECT and their perception of the loss. However, this should not detract from the fact that a number of individuals find their memory loss extremely damaging and for them this negates any benefit from ECT. Advance directives are statements made by an individual that express decisions about the healthcare they wish to receive, in anticipation of a time when they may not be competent to make or communicate such decisions. Clinicians are legally obliged to take informed and unambiguous advance refusals of treatment made by a competent individual into account unless: (1) it does not apply to the circumstances that have arisen; (2) the Mental Health Act is used to override the individual's intentions about treatment; (3) it requires the clinician to do something illegal; or (4) it requires treatment that the clinician considers not to be in the individual's best interests. Advance consents are not legally binding because specific medical treatment cannot be demanded, but clinicians should generally take such wishes into account. The number of sessions undertaken during a course of ECT usually ranges from 6 to 12, although a substantial minority of patients respond to fewer than 6 sessions. ECT is usually given twice a week; less commonly it is given once a fortnight or once a month as continuation or maintenance therapy to prevent the relapse of symptoms. It can be given on either an inpatient or day patient basis. In England between January and March 1999, there were 16,482 administrations of ECT to 2,835 individuals, 41% of whom were aged 65 years or over. Seventy-five per cent of the individuals were not formally detained under the Mental Health Act 1983, and of the 709 individuals formally detained, 59% did not or were not able to consent to treatment. Six treatment sessions of ECT have been estimated to cost £2,475. This does not include inpatient costs, estimated as £171 per day.# Evidence and interpretation The Appraisal Committee considered evidence from a number of sources. # Clinical effectiveness The evidence presented in the Assessment Report was primarily drawn from a recent Cochrane Review of electroconvulsive therapy (ECT) in schizophrenia and a systematic review commissioned by the Department of Health on the use of ECT in schizophrenia, depressive illness and mania. Both reviews are of high quality and consider a total of 119 randomised controlled trials (RCTs) and a number of observational studies. Evidence submitted by patient and professional groups was also considered. There were problems with the design of many of the RCTs. A large proportion were conducted before the introduction of modern techniques of administering ECT, and therefore do not reflect current practice. There were large variations in the parameters of the ECT administered that included the machine used, the number of sessions, the dosage and wave form, electrode placement, and the type and dosage of concomitant therapy. A number of studies used fixed dosage rather than individual thresholds. There was little evidence to support the routine prescription of a set number of treatment sessions per course of ECT or of the value of continuation (maintenance) ECT. The validity of many of the measurement scales used in the studies to measure outcome has not been clearly established and no study adequately captured either users' views or quality of life. The Assessment Report reviews data from 90 RCTs in individuals with depressive illness, of different grades of clinical severity, who were referred for ECT. Overall, these RCTs provide evidence that real ECT (that is, where an electric current was applied) is more effective than sham ECT (where no electric current was applied) in the short term. The data provide evidence that the stimulus parameters have an important influence on efficacy; at the end of a course of treatment, bilateral ECT was reported to be more effective than unilateral ECT. Raising the electrical stimulus above the individual's seizure threshold was found to increase the efficacy of unilateral ECT at the expense of increased cognitive impairment. In trials comparing ECT with pharmacotherapy, ECT had greater benefit than the use of certain antidepressants but the trials were of variable quality and inadequate doses and durations of drug therapy were frequently used. The combination of ECT with pharmacotherapy was not shown to be superior to ECT alone, although the duration of the RCTs was insufficient to show whether pharmacotherapy was beneficial. Compared with placebo, continuation pharmacotherapy with tricyclic antidepressants and/or lithium reduced the rate of relapses in people who had responded to ECT. Preliminary studies indicate that ECT is more effective than repetitive transcranial magnetic stimulation. Evidence from 25 RCTs suggests that ECT may be effective in acute episodes of certain types of schizophrenia and reduce the occurrence of relapses, although the results are not conclusive and the design of many of the studies did not reflect current practice. The data on differing efficacy related to electrode placement and stimulus parameters are equivocal and firm conclusions could not be drawn. No RCT investigated the use of ECT in comparison with atypical antipsychotics, and the studies that included individuals with treatment-resistant schizophrenia did not consider the use of clozapine. The combined weight of evidence suggests that ECT is not more effective, and may be less effective, than antipsychotic medication. The combination of ECT and pharmacotherapy may be more effective than pharmacotherapy alone, but the evidence is not conclusive. The 4 RCTs reviewed in the Assessment Report suggest that ECT may be of benefit in the rapid control of mania and catatonia and this suggestion is supported by evidence from a number of observational studies and testimony from clinical experts. However, the evidence on which to base any general conclusions about the effectiveness of ECT or to determine the most appropriate therapeutic strategy is weak. There is clear evidence that cognitive impairment occurs both immediately after administration of ECT and following a course of therapy, and this may cause considerable distress to those affected. The impairment is greater in individuals who have had electrodes applied bilaterally than in those who have had them placed unilaterally, and unilateral placement to the dominant hemisphere causes more impairment than placement to the non-dominant hemisphere. A reduction in the risk of cognitive impairment is, however, mirrored by a reduction in efficacy. There is some limited evidence from RCTs to suggest that the effects on cognitive function may not last beyond 6 months, but this has been inadequately researched. There is also evidence to suggest that the impairment of cognitive function associated with ECT differs between individuals and that it is linked to the dose administered, although the relationship with the seizure threshold has not been adequately defined. There is no evidence to suggest that the effect of ECT on cognitive function differs between diagnoses. In addition to testimony from user groups, a systematic review of evidence from non-randomised studies relating to patients' accounts and experiences of ECT was also considered. This provided important evidence on the experiences of individuals receiving ECT, particularly cognitive impairment and its impact, and the validity of neuropsychological instruments used in clinical trials. There was evidence that the measurement scales used in RCTs do not adequately capture the nature and extent of cognitive impairment, and qualitative studies have indicated that the impairment may be prolonged or permanent. Additionally, there was testimony that individuals are not provided with sufficient information on which to base a decision regarding consent. Also, some individuals are unaware of their rights to refuse treatment, or may feel unable to do so because of the perceived threat of detainment under the Mental Health Act. There was no evidence to suggest that the mortality associated with ECT is greater than that associated with minor procedures involving general anaesthetics, and there were limited data on mortality extending beyond the trial periods. The 6 reviewed studies that used brain-scanning techniques did not provide any evidence that ECT causes brain damage. While there is no evidence to suggest that benefits and safety are age-dependent, there are no studies on the impact of ECT on the developing brain. Furthermore, it is likely that comorbidities could increase the risk of harm. The use of ECT during pregnancy is known to cause complications, but the risks associated with ECT need to be balanced against the risks of using alternative (drug) treatments. # Cost effectiveness There are no published economic studies relating to ECT, and none of the submissions from consultees contained any economic analyses. The Assessment Group therefore constructed economic models of ECT for depressive illness and schizophrenia based on a review of published evidence. They were not able to construct robust models for mania and catatonia because of the low volume of data in these areas. The depressive illness model had a 1-year time horizon and compared the cost effectiveness of inpatient ECT with other inpatient treatments for adults with severe depressive illness. The key comparators were different classes of antidepressants, with lithium given in addition for third-line therapy. After 3 drug treatment strategies, non-responders were assumed to receive 8 weeks of psychotherapy and to make a moderate improvement. The results of the depressive illness model showed that, for 8 different scenarios, total costs range from £10,592 to £15,354, and total quality-adjusted life years (QALYs) range from 0.424 to 0.539. Given the small differences in total costs and QALYs between the strategies that included ECT and the 1 that did not, and the uncertainty in the data available, ECT and pharmacotherapy are likely to be equally cost effective. The schizophrenia model also had a 1-year time horizon and compared the cost effectiveness of ECT in combination with a typical antipsychotic with that of (a) clozapine, and (b) chlorpromazine or haloperidol for adults hospitalised with treatment-resistant schizophrenia of moderate symptomatology. The results of the schizophrenia model suggest that ECT is dominated by clozapine – that is, ECT is associated with fewer QALYs (0.842 versus 0.863) at a higher cost (£55,267 versus £34,787). For individuals who do not respond to clozapine, ECT dominates chlorpromazine/haloperidol, resulting in more QALYs (0.842 versus 0.820) at a lower cost (£55,267 versus £58,265). However, these results do not take into account the degree of uncertainty in the estimates of both cost and effectiveness. To summarise, there is no published evidence regarding the cost effectiveness of ECT. The modelling exercises undertaken by the Assessment Group, while fairly crude and based on a number of uncertain assumptions, suggest that – for those with severe depressive illness and treatment-resistant schizophrenia – ECT and pharmacological treatment may be equally cost effective, with no consistent differences in costs or outcomes. # Consideration of the evidence The Committee reviewed the evidence on both the clinical effectiveness and the cost effectiveness of ECT. It considered written and verbal evidence on the nature of the conditions and the experience of people who have received or may be eligible for ECT, those who represent them, and clinical experts. It was also mindful of the need to ensure that its advice took account of the efficient use of NHS resources. The evidence submitted to the Committee, both written and verbal, demonstrated that, on balance, current opinion is that ECT is an effective treatment for certain subgroups of individuals with mental disorders. However, opinion varies from those who consider that its adverse effects are tolerable to those who consider that it is associated with unacceptable side effects including brain damage, severe confusion and considerable cognitive impairment in both the short and longer terms. While some individuals considered ECT to be a beneficial and lifesaving treatment, others reported feelings of terror, shame and distress, and found it positively harmful and an abusive invasion of personal autonomy, especially when it was administered without their consent. In consideration of these extremes of opinion, the Committee concluded that the wishes of the patient must be of paramount importance and that it is essential that all attempts should be made to obtain valid and informed consent, following recognised guidelines. The Committee felt strongly that consent should never be obtained by coercion – either explicit or implicit – through threat of compulsory treatment under the Mental Health Act, and mechanisms to monitor and prevent this from occurring should be developed and implemented, in consultation with appropriate professional and user organisations. Testimony was heard that the information currently given to individuals does not always adequately inform consent, and the Committee discussed the need for nationally agreed evidence-based patient information leaflets. These should be accessible to a wide range of service users (see section 7) and should emphasise the right of the individual to withhold consent or to withdraw it at any point. While the limitations of advance directives were appreciated (see section 3.7), the Committee believed that, whenever possible, they should be developed and documented in individuals' care programmes and be taken into account when considering ECT. The Committee considered that, on the evidence put before it, the short-term effectiveness of ECT in individuals with severe depressive illness has been demonstrated. There is less robust RCT evidence to suggest that it is effective in the acute treatment of catatonia and mania. However, the Committee considered that the data appraised, taken in conjunction with the strength of clinical opinion and the experiences of users, provided a sufficient basis on which to recommend the use of ECT in restricted circumstances when the alternative treatment options have proven ineffective. The evidence for the effectiveness of ECT in schizophrenia in general was not conclusive and therefore ECT is not recommended in this population. Further research is required to establish clearly the benefits in subgroups of individuals with schizophrenia, for example those with severe symptoms of depressive illness or catatonia. The Committee considered that there was no conclusive evidence to support the effectiveness of ECT beyond the short term or that it is more beneficial as a maintenance therapy in depressive illness than currently available pharmacological alternatives. It was particularly concerned that the value of ECT maintenance therapy remained unproven in the context of the lack of information on whether the adverse effects of ECT (for example, on cognitive function) may be cumulative with repeated administration. In appreciation of the special circumstances in which ECT is administered and the recognition that RCTs cannot adequately capture the long-term effects of ECT, the Committee took special note of the evidence from observations of users' experiences relating to the adverse effects of ECT. In particular, the incidence, extent and timescale of cognitive impairment following ECT was discussed in detail. It was apparent that the nature of cognitive impairment experienced by users was variable and often long lasting to such a degree that it outweighed their perception of any benefit from ECT treatment. The Committee considered that further research, both qualitative and quantitative, was needed to define the effect of ECT on cognitive impairment, especially whether the effects are cumulative with repeated administrations. It was also concerned that the potential for cognitive impairment following ECT may not be highlighted during the consent process. These factors featured significantly in the Committee's deliberations, and specifically in its decision to restrict the use of ECT to situations in which all other alternatives had been exhausted or where the nature of the mental illness was considered to be 'life-threatening'. The Committee noted that the efficacy and adverse effects of ECT are clearly linked to the method of delivery, although the optimum technique and stimulus parameters have not been adequately researched; for example, gains in efficacy as a result of modifications to electrode placement and stimulus parameters are achieved at the expense of an increased risk of cognitive side effects. The Committee therefore considered that the evidence was not sufficient to allow conclusions to be drawn. The RCT evidence considered by the Committee also leaves unanswered a number of important questions, and these require further research (see section 5). Consideration was given to the fact that the majority of the RCTs are not applicable to modern practice because of advances in pharmacological management and ECT administration techniques. The outcomes considered in the RCTs also did not adequately capture the experience of service users, and the validity of many of the scales used to measure outcome had not been clearly established. There was insufficient information to allow appropriate risk–benefit assessment for certain groups of individuals, for example during pregnancy, in older individuals, and in children and young people. Of particular concern were the lack of research into the number of treatment sessions that should be given, and the lack of long-term evidence regarding adverse effects on cognitive function and mortality. The Committee could not establish, in the context of the use of appropriate pharmacological treatment, the value of 'maintenance' ECT therapy following its use to achieve rapid and short-term improvement of severe symptoms. The Committee was persuaded on the balance of the evidence received from patients and carers that the practice of 'continuation' of ECT therapy for short periods following the initial control of severe symptoms was only acceptable in the context of sections 1.6 and 1.7 of the guidance. The ongoing deficiencies in current practice were highlighted to the Committee, and the Committee strongly believed that action is required to ensure that appropriate standards of care are enforced whenever ECT is undertaken and that outcomes are continuously monitored. The Committee considered that ECT should be administered only in a suitably equipped unit by professionals who have been trained in its delivery and in the anaesthetic techniques required for the administration of ECT. These professionals should maintain an appropriate level of skill, both through the regular clinical practice of ECT and through undertaking appropriate continuing professional development. Urgent consideration should be given to the establishment of units dedicated to ECT, and of audit networks, which have been shown to be successful in Scotland. Despite the uncertainty in the estimates of clinical effectiveness and the small differences in costs and outcomes generated in the economic models, the Committee considered that ECT is likely to be cost effective in appropriate patient groups. In summary, the Committee considered that the evidence appraised supported the effectiveness of ECT in certain groups of individuals. However, the Committee recognised there remained a number of uncertainties, including a lack of information on longer-term outcomes. The Committee was aware of the negative experiences of some individuals who have undergone ECT. Therefore the Committee considered that, ECT should be used with caution and only in the restricted circumstances recommended in the guidance in section 1. See also NICE's guidelines on bipolar disorder and psychosis and schizophrenia in adults.# Recommendations for further research There are a number of ongoing research projects that include studies of clinical and cost effectiveness in specific groups and an examination of the effects of seizure parameters. Further research is urgently required to examine the long-term efficacy and safety of electroconvulsive therapy (ECT), including its use as a maintenance therapy and its use in particular subgroups who may be at increased risk, for example older people, children and young people, and during pregnancy. This research should reflect modern techniques and the use of ECT in comparison with and in conjunction with the antipsychotic and antidepressant drugs used in current practice. In addition to the use of appropriately validated psychometric scales, outcome measures should include user perspectives on the impact of ECT, the incidence and impact of important side effects such as cognitive functioning, and mortality. Further research into the mechanism of action of ECT is encouraged, because it may provide important information on aetiology and future treatment strategies. It is clear that the stimulus parameters impact on the safety and efficacy of the technique and recent research needs to be augmented. Further evaluation is needed of whether it is necessary to induce a full seizure for therapeutic effect, and how the efficacy and cognitive effects are influenced by the amount by which the applied electrical dose exceeds the seizure threshold. More research is also needed to determine the cost effectiveness of ECT. In particular, better quality-of-life information is needed for people considered for, or who have received, ECT.# Implications for the NHS As this guidance recommends the use of electroconvulsive therapy (ECT) only in certain restricted circumstances, it is not anticipated that the guidance will increase the use of ECT in England and Wales above current levels. As ECT appears to be of similar cost to alternative treatments, it is unlikely that a change in the use of ECT will result in an increase or decrease in NHS expenditure. However, there will undoubtedly be costs associated with addressing the continuing deficiencies in the standards of care that have been highlighted (see section 3.3).# Appendix C. The use of electroconvulsive therapy A summary of this guidance for patients and carers can be found on our website.# Appendix D. Detail on criteria for audit of the use of electroconvulsive therapy # Objectives for an audit An audit on electroconvulsive therapy (ECT) could be carried out to ensure that ECT is used appropriately. # Patients to be included in the audit All individuals who have received ECT in a suitable time period for audit, for example, 6 months or 1 year. Alternatively, the audit could be undertaken concurrently with the provision of ECT treatments. # Measures that can be used as a basis for audit Criterion Standard Exception Definition of terms . The individual receiving electroconvulsive therapy (ECT) has 1 of the following: a. severe depressive illness b. catatonia c. a prolonged or severe manic episode % of individuals receiving ECT None Local clinicians will have to agree on how and where the indications for ECT are documented for audit purposes. . ECT is used to achieve rapid and short-term improvement of severe symptoms when an adequate trial of other treatment options has proven ineffective, and/or the individual has a potentially life-threatening condition % of individuals receiving ECT None Local clinicians will have to agree on how severe symptoms and response to other treatment options and potentially life-threatening conditions are documented for audit purposes. . An assessment of the risks and potential benefits of ECT for the individual is documented % of individuals receiving ECT None The documented assessment before treatment should note: risks associated with the anaesthetic; current comorbidities; anticipated adverse events, including cognitive impairment; and the risks of no treatment. . The individual provides consent for each course of ECT treatment % of individuals receiving ECT A. The individual does not have the ability to grant or refuse consent, in which case advance directives are fully taken into account and the individual's advocate and/or carer are consulted. B. The individual is detained under the Mental Health Act Local clinicians should agree on how consent to ECT is documented for audit purposes. A course of ECT is usually 6 to 12 sessions, usually given at the rate of 2 a week. The individual who has had/is having ECT should be asked for his/her views as to whether or not this criterion is being met. . The consent process provides that the clinician(s) responsible for treatment carries out all of the following: a. involves the individual's advocate and/or carer where possible b. provides full and appropriate information in a suitable format and language to enable an informed discussion c. explains and discusses the general risks of ECT, risks specific to the individual, enhanced risks for individuals in specific groups and potential benefits to the individual d. does not pressure or coerce the individual into consent to the ECT treatment e. reminds the individual that he/she has the right to withdraw consent at any point % of individuals receiving ECT A. The individual is detained under the Mental Health Act B. The individual does not have the ability to grant or refuse consent but is compliant with treatment and 5a-e is carried out with an advocate and/or carer Local clinicians should agree on how the format and language used to communicate the information provided and the involvement of advocates or carers prior to consent to ECT are documented for audit purposes. See 3 above for a list of general risks to be discussed. Groups of people for whom there may be enhanced risks to be discussed include individuals who are pregnant, older or a child or young person. The individual who has had/is having ECT should be asked for his/her views as to whether or not this criterion is being met. . The individual's clinical status is assessed after each ECT session % of individuals receiving ECT None Local clinicians should agree on what constitutes an assessment of clinical status following an ECT session. . The individual's cognitive function is monitored: a. on an ongoing basis and b. at a minimum at the end of each course of treatment % of individuals receiving ECT None Local clinicians should agree on what constitutes monitoring of cognitive function and how monitoring is documented for audit purposes. The individual who has had/is having ECT should be asked for his/her views as to whether or not this criterion is being met. . ECT is stopped if 1 of the following occurs: a. a response is achieved b. there is evidence of adverse effects c. the individual withdraws consent % of individuals receiving ECT None Local clinicians will have to agree on what constitutes a desired response and evidence of adverse effects for audit purposes. The individuals who has had/is having ECT should be asked for his/her views as to whether or not this criterion is being met. . A repeat course of ECT is provided only for an individual in either one of the following circumstances: a. the individual meets criteria 1 and above and has previously responded well to ECT or b. the individual has not responded previously but is experiencing an acute episode and all other options have been considered and following discussion with the individual and/or where appropriate the carer or advocate of the risks and benefits of such a course of action % of individuals receiving a repeat course of ECT None Local clinicians will have to agree on what constitutes a good response to ECT for audit purposes. See 4 above for definition of course of treatment. See 3 and 5 above for reference to risks. .ECT is used as a maintenance therapy in depressive illness % of individuals receiving ECT None .ECT is used for the management of schizophrenia % of individuals receiving ECT None # Calculation of compliance with the measures Compliance with the measures described in the table is calculated as follows. Number of individuals whose care is consistent with the criterion plus the number of individuals who meet an exception Divided by Number of patients to whom the measure applies Multiplied by 100 Clinicians should review the findings of measurement, identify whether practice can be improved, agree on a plan to achieve any desired improvement, and repeat the measurement of actual practice to confirm that the desired improvement is being achieved.	{'Guidance': "The recommendations in this technology appraisal relating to the treatment of depression have been replaced by those in the NICE guideline on depression in adults published in October 2009. Note that the recommendations in this technology appraisal relating to the treatment of catatonia-prolonged or severe manic episodes and schizophrenia have not changed. The recommendations relating to depression have been removed from this version.\n\nIt is recommended that electroconvulsive therapy (ECT) is used only to achieve rapid and short-term improvement of severe symptoms after an adequate trial of other treatment options has proven ineffective and/or when the condition is considered to be potentially life-threatening, in individuals with:\n\ncatatonia\n\na prolonged or severe manic episode.\n\nThe decision as to whether ECT is clinically indicated should be based on a documented assessment of the risks and potential benefits to the individual, including: the risks associated with the anaesthetic; current comorbidities; anticipated adverse events, particularly cognitive impairment; and the risks of not having treatment.\n\nThe risks associated with ECT may be enhanced during pregnancy, in older people, and in children and young people, and therefore clinicians should exercise particular caution when considering ECT treatment in these groups.\n\nValid consent should be obtained in all cases where the individual has the ability to grant or refuse consent. The decision to use ECT should be made jointly by the individual and the clinician(s) responsible for treatment, on the basis of an informed discussion. This discussion should be enabled by the provision of full and appropriate information about the general risks associated with ECT (see section\xa01.9) and about the risks and potential benefits specific to that individual. Consent should be obtained without pressure or coercion, which may occur as a result of the circumstances and clinical setting, and the individual should be reminded of their right to withdraw consent at any point. There should be strict adherence to recognised guidelines about consent and the involvement of patient advocates and/or carers to facilitate informed discussion is strongly encouraged.\n\nIn all situations where informed discussion and consent is not possible advance directives should be taken fully into account and the individual's advocate and/or carer should be consulted.\n\nClinical status should be assessed following each ECT session and treatment should be stopped when a response has been achieved, or sooner if there is evidence of adverse effects. Cognitive function should be monitored on an ongoing basis, and at a minimum at the end of each course of treatment.\n\nIt is recommended that a repeat course of ECT should be considered under the circumstances indicated in section\xa01.1 only for individuals who have catatonia or mania and who have previously responded well to ECT. In patients who are experiencing an acute episode but have not previously responded, a repeat trial of ECT should be undertaken only after all other options have been considered and following discussion of the risks and benefits with the individual and/or where appropriate their carer/advocate.\n\nThis recommendation has been updated and replaced by the NICE guideline on depression in adults.\n\nThe current state of the evidence does not allow the general use of ECT in the management of schizophrenia to be recommended.\n\nNational information leaflets should be developed through consultation with appropriate professional and user organisations to enable individuals and their carers/advocates to make an informed decision regarding the appropriateness of ECT for their circumstances. The leaflets should be evidence based, include information about the risks of ECT and availability of alternative treatments, and be produced in formats and languages that make them accessible to a wide range of service users.", 'Clinical need and practice': "This appraisal considers electroconvulsive therapy (ECT) in the treatment of: depressive illness, schizophrenia, catatonia and mania.\n\nDepressive illness is associated with discrete episodes that are characterised by feelings of sadness, despair, loss of interest in daily life and discouragement. The severity of depressive illness is determined by the number, intensity and frequency or persistence of depressive symptoms and the presence of specific symptoms such as delusions, hallucinations and suicidal ideation. Severe depressive illness can deteriorate into a 'depressive stupor' where a person is conscious but is non-responsive to any stimulation. This extreme manifestation of depressive illness has become less frequent because of the advent of modern treatments.\n\nSchizophrenia is characterised by a broad range of cognitive, emotional and behavioural problems, which are in general classified into positive and negative symptoms. Individuals with delusions or hallucinations are described as psychotic.\n\nCatatonia is a syndrome that is associated with both schizophrenia and affective (mood) disorders. It is characterised by marked changes in muscle tone or activity that may alternate between the extremes of a deficit of movement (catatonic stupor) and excessive movement (catatonic excitement).\n\nMania is characterised by elated, euphoric or irritable mood and increased energy. The term may refer to a mental disorder or to a mood state or symptom, and mania is associated with bipolar disorders. In severe manic episodes, individuals are psychotic and require continual supervision to prevent physical harm to themselves or others.\n\nIn 2000, the Psychiatric Morbidity Survey conducted by the Office of National Statistics (ONS) found the prevalence of a depressive episode per thousand population to be 25 in England and 37 in Wales. The prevalence of schizophrenia is estimated at between 2 and 10 per 1,000 in the general population, and the incidence of first-onset schizophrenia is approximately 1 per 10,000 population per year. Recent estimates have suggested that bipolar affective disorder has a point prevalence of up to 50 per 1,000 of the general population, of whom 1% are admitted to hospital for mania each year. There are no recent epidemiological studies on the incidence of catatonia.\n\nDepressive illness, schizophrenia and mania are frequently chronic, relapsing conditions and are associated with considerable suicide risk. Diagnosable depressive disorders are implicated in between 40% and 60% of suicide attempts. The 2000 ONS Psychiatric Morbidity Survey found that in individuals with a current depressive episode, 5% reported a suicide attempt within the past year. Common estimates are that 10% of people with schizophrenia will eventually have a completed suicide, and that attempts are made at 2\xa0to\xa05\xa0times that rate.\n\nSevere mental health disorders are associated with considerable personal suffering, occupational and social disadvantage and impairment in interpersonal and family relationships in the long term. They also have a high economic impact, with the indirect costs far exceeding the direct costs.\n\nDepressive illness is managed with antidepressants, psychotherapy and counselling, either alone or in combination. Although the management of schizophrenia frequently centres on antipsychotic medication, individuals also require substantial clinical, emotional and social support. Catatonia is usually treated with benzodiazepines; the introduction of effective psychotropic agents has led to a marked reduction in its prevalence. Acute manic episodes are treated with antipsychotics, lithium or anticonvulsants. Many individuals with mental health disorders benefit from self-help techniques including support groups.\n\nECT is used in current UK clinical practice as a treatment option for individuals with depressive illness, catatonia and mania. It is also occasionally used to treat schizophrenia. Guidelines for the use of ECT were developed by the Royal College of Psychiatrists in 1995 and are currently undergoing revision. Guidance for nurses has also been produced by the Royal College of Nursing.", 'The technology': "During electroconvulsive therapy (ECT), an electric current is passed briefly through the brain, via electrodes applied to the scalp, to induce generalised seizure activity. The individual receiving treatment is placed under general anaesthetic and muscle relaxants are given to prevent body spasms. The ECT electrodes can be placed on both sides of the head (bilateral placement) or on 1\xa0side of the head (unilateral placement). Unilateral placement is usually to the non-dominant side of the brain, with the aim of reducing cognitive side effects. The amount of current required to induce a seizure (the seizure threshold) can vary up to 40‑fold between individuals.\n\nAlthough ECT has been used since the 1930s, there is still no generally accepted theory that explains its mechanism of action. The most prevalent hypothesis is that it causes an alteration in the post-synaptic response to central nervous system neurotransmitters.\n\nIn recent years, there have been moves to improve standards in the administration of ECT, with the introduction of practice guidelines published by the Royal College of Psychiatrists and the Royal College of Nursing, and the monitoring of the implementation of these guidelines through ongoing audit. However, there is still variation in the use and practice of ECT within England and Wales.\n\nECT administration affects the central nervous system and causes changes in cardiovascular dynamics, which dictates the need for special caution in those individuals who are at increased risk of a cardiovascular event. There are also other immediate potential complications, such as status epilepticus, laryngospasm and peripheral nerve palsy, which overall have an estimated incidence of 1 per 1,300 to 1,400 treatments. The mortality associated with ECT is reported not to be in excess of that associated with the administration of a general anaesthetic for minor surgery.\n\nECT may cause short- or long-term memory impairment for past events (retrograde amnesia) and current events (anterograde amnesia). As this type of cognitive impairment is a feature of many mental health problems it may sometimes be difficult to differentiate the effects of ECT from those associated with the condition itself. In addition there are differences between individuals in the extent of memory loss secondary to ECT and their perception of the loss. However, this should not detract from the fact that a number of individuals find their memory loss extremely damaging and for them this negates any benefit from ECT.\n\nAdvance directives are statements made by an individual that express decisions about the healthcare they wish to receive, in anticipation of a time when they may not be competent to make or communicate such decisions. Clinicians are legally obliged to take informed and unambiguous advance refusals of treatment made by a competent individual into account unless: (1) it does not apply to the circumstances that have arisen; (2) the Mental Health Act is used to override the individual's intentions about treatment; (3) it requires the clinician to do something illegal; or (4) it requires treatment that the clinician considers not to be in the individual's best interests. Advance consents are not legally binding because specific medical treatment cannot be demanded, but clinicians should generally take such wishes into account.\n\nThe number of sessions undertaken during a course of ECT usually ranges from 6 to 12, although a substantial minority of patients respond to fewer than 6 sessions. ECT is usually given twice a week; less commonly it is given once a fortnight or once a month as continuation or maintenance therapy to prevent the relapse of symptoms. It can be given on either an inpatient or day patient basis. In England between January and March 1999, there were 16,482 administrations of ECT to 2,835 individuals, 41% of whom were aged 65 years or over. Seventy-five per cent of the individuals were not formally detained under the Mental Health Act 1983, and of the 709 individuals formally detained, 59% did not or were not able to consent to treatment.\n\nSix treatment sessions of ECT have been estimated to cost £2,475. This does not include inpatient costs, estimated as £171 per day.", 'Evidence and interpretation': "The Appraisal Committee considered evidence from a number of sources.\n\n# Clinical effectiveness\n\nThe evidence presented in the Assessment Report was primarily drawn from a recent Cochrane Review of electroconvulsive therapy (ECT) in schizophrenia and a systematic review commissioned by the Department of Health on the use of ECT in schizophrenia, depressive illness and mania. Both reviews are of high quality and consider a total of 119 randomised controlled trials (RCTs) and a number of observational studies. Evidence submitted by patient and professional groups was also considered.\n\nThere were problems with the design of many of the RCTs. A large proportion were conducted before the introduction of modern techniques of administering ECT, and therefore do not reflect current practice. There were large variations in the parameters of the ECT administered that included the machine used, the number of sessions, the dosage and wave form, electrode placement, and the type and dosage of concomitant therapy. A number of studies used fixed dosage rather than individual thresholds. There was little evidence to support the routine prescription of a set number of treatment sessions per course of ECT or of the value of continuation (maintenance) ECT. The validity of many of the measurement scales used in the studies to measure outcome has not been clearly established and no study adequately captured either users' views or quality of life.\n\nThe Assessment Report reviews data from 90 RCTs in individuals with depressive illness, of different grades of clinical severity, who were referred for ECT. Overall, these RCTs provide evidence that real ECT (that is, where an electric current was applied) is more effective than sham ECT (where no electric current was applied) in the short term. The data provide evidence that the stimulus parameters have an important influence on efficacy; at the end of a course of treatment, bilateral ECT was reported to be more effective than unilateral ECT. Raising the electrical stimulus above the individual's seizure threshold was found to increase the efficacy of unilateral ECT at the expense of increased cognitive impairment. In trials comparing ECT with pharmacotherapy, ECT had greater benefit than the use of certain antidepressants but the trials were of variable quality and inadequate doses and durations of drug therapy were frequently used. The combination of ECT with pharmacotherapy was not shown to be superior to ECT alone, although the duration of the RCTs was insufficient to show whether pharmacotherapy was beneficial. Compared with placebo, continuation pharmacotherapy with tricyclic antidepressants and/or lithium reduced the rate of relapses in people who had responded to ECT. Preliminary studies indicate that ECT is more effective than repetitive transcranial magnetic stimulation.\n\nEvidence from 25 RCTs suggests that ECT may be effective in acute episodes of certain types of schizophrenia and reduce the occurrence of relapses, although the results are not conclusive and the design of many of the studies did not reflect current practice. The data on differing efficacy related to electrode placement and stimulus parameters are equivocal and firm conclusions could not be drawn. No RCT investigated the use of ECT in comparison with atypical antipsychotics, and the studies that included individuals with treatment-resistant schizophrenia did not consider the use of clozapine. The combined weight of evidence suggests that ECT is not more effective, and may be less effective, than antipsychotic medication. The combination of ECT and pharmacotherapy may be more effective than pharmacotherapy alone, but the evidence is not conclusive.\n\nThe 4 RCTs reviewed in the Assessment Report suggest that ECT may be of benefit in the rapid control of mania and catatonia and this suggestion is supported by evidence from a number of observational studies and testimony from clinical experts. However, the evidence on which to base any general conclusions about the effectiveness of ECT or to determine the most appropriate therapeutic strategy is weak.\n\nThere is clear evidence that cognitive impairment occurs both immediately after administration of ECT and following a course of therapy, and this may cause considerable distress to those affected. The impairment is greater in individuals who have had electrodes applied bilaterally than in those who have had them placed unilaterally, and unilateral placement to the dominant hemisphere causes more impairment than placement to the non-dominant hemisphere. A reduction in the risk of cognitive impairment is, however, mirrored by a reduction in efficacy. There is some limited evidence from RCTs to suggest that the effects on cognitive function may not last beyond 6\xa0months, but this has been inadequately researched. There is also evidence to suggest that the impairment of cognitive function associated with ECT differs between individuals and that it is linked to the dose administered, although the relationship with the seizure threshold has not been adequately defined. There is no evidence to suggest that the effect of ECT on cognitive function differs between diagnoses.\n\nIn addition to testimony from user groups, a systematic review of evidence from non-randomised studies relating to patients' accounts and experiences of ECT was also considered. This provided important evidence on the experiences of individuals receiving ECT, particularly cognitive impairment and its impact, and the validity of neuropsychological instruments used in clinical trials. There was evidence that the measurement scales used in RCTs do not adequately capture the nature and extent of cognitive impairment, and qualitative studies have indicated that the impairment may be prolonged or permanent. Additionally, there was testimony that individuals are not provided with sufficient information on which to base a decision regarding consent. Also, some individuals are unaware of their rights to refuse treatment, or may feel unable to do so because of the perceived threat of detainment under the Mental Health Act.\n\nThere was no evidence to suggest that the mortality associated with ECT is greater than that associated with minor procedures involving general anaesthetics, and there were limited data on mortality extending beyond the trial periods. The 6\xa0reviewed studies that used brain-scanning techniques did not provide any evidence that ECT causes brain damage. While there is no evidence to suggest that benefits and safety are age-dependent, there are no studies on the impact of ECT on the developing brain. Furthermore, it is likely that comorbidities could increase the risk of harm. The use of ECT during pregnancy is known to cause complications, but the risks associated with ECT need to be balanced against the risks of using alternative (drug) treatments.\n\n# Cost effectiveness\n\nThere are no published economic studies relating to ECT, and none of the submissions from consultees contained any economic analyses. The Assessment Group therefore constructed economic models of ECT for depressive illness and schizophrenia based on a review of published evidence. They were not able to construct robust models for mania and catatonia because of the low volume of data in these areas.\n\nThe depressive illness model had a 1-year time horizon and compared the cost effectiveness of inpatient ECT with other inpatient treatments for adults with severe depressive illness. The key comparators were different classes of antidepressants, with lithium given in addition for third-line therapy. After 3\xa0drug treatment strategies, non-responders were assumed to receive 8\xa0weeks of psychotherapy and to make a moderate improvement.\n\nThe results of the depressive illness model showed that, for 8\xa0different scenarios, total costs range from £10,592 to £15,354, and total quality-adjusted life years (QALYs) range from 0.424 to 0.539. Given the small differences in total costs and QALYs between the strategies that included ECT and the 1\xa0that did not, and the uncertainty in the data available, ECT and pharmacotherapy are likely to be equally cost effective.\n\nThe schizophrenia model also had a 1-year time horizon and compared the cost effectiveness of ECT in combination with a typical antipsychotic with that of (a) clozapine, and (b) chlorpromazine or haloperidol for adults hospitalised with treatment-resistant schizophrenia of moderate symptomatology.\n\nThe results of the schizophrenia model suggest that ECT is dominated by clozapine – that is, ECT is associated with fewer QALYs (0.842 versus 0.863) at a higher cost (£55,267 versus £34,787). For individuals who do not respond to clozapine, ECT dominates chlorpromazine/haloperidol, resulting in more QALYs (0.842 versus 0.820) at a lower cost (£55,267 versus £58,265). However, these results do not take into account the degree of uncertainty in the estimates of both cost and effectiveness.\n\nTo summarise, there is no published evidence regarding the cost effectiveness of ECT. The modelling exercises undertaken by the Assessment Group, while fairly crude and based on a number of uncertain assumptions, suggest that – for those with severe depressive illness and treatment-resistant schizophrenia – ECT and pharmacological treatment may be equally cost effective, with no consistent differences in costs or outcomes.\n\n# Consideration of the evidence\n\nThe Committee reviewed the evidence on both the clinical effectiveness and the cost effectiveness of ECT. It considered written and verbal evidence on the nature of the conditions and the experience of people who have received or may be eligible for ECT, those who represent them, and clinical experts. It was also mindful of the need to ensure that its advice took account of the efficient use of NHS resources.\n\nThe evidence submitted to the Committee, both written and verbal, demonstrated that, on balance, current opinion is that ECT is an effective treatment for certain subgroups of individuals with mental disorders. However, opinion varies from those who consider that its adverse effects are tolerable to those who consider that it is associated with unacceptable side effects including brain damage, severe confusion and considerable cognitive impairment in both the short and longer terms. While some individuals considered ECT to be a beneficial and lifesaving treatment, others reported feelings of terror, shame and distress, and found it positively harmful and an abusive invasion of personal autonomy, especially when it was administered without their consent.\n\nIn consideration of these extremes of opinion, the Committee concluded that the wishes of the patient must be of paramount importance and that it is essential that all attempts should be made to obtain valid and informed consent, following recognised guidelines. The Committee felt strongly that consent should never be obtained by coercion – either explicit or implicit – through threat of compulsory treatment under the Mental Health Act, and mechanisms to monitor and prevent this from occurring should be developed and implemented, in consultation with appropriate professional and user organisations.\n\nTestimony was heard that the information currently given to individuals does not always adequately inform consent, and the Committee discussed the need for nationally agreed evidence-based patient information leaflets. These should be accessible to a wide range of service users (see section\xa07) and should emphasise the right of the individual to withhold consent or to withdraw it at any point.\n\nWhile the limitations of advance directives were appreciated (see section\xa03.7), the Committee believed that, whenever possible, they should be developed and documented in individuals' care programmes and be taken into account when considering ECT.\n\nThe Committee considered that, on the evidence put before it, the short-term effectiveness of ECT in individuals with severe depressive illness has been demonstrated. There is less robust RCT evidence to suggest that it is effective in the acute treatment of catatonia and mania. However, the Committee considered that the data appraised, taken in conjunction with the strength of clinical opinion and the experiences of users, provided a sufficient basis on which to recommend the use of ECT in restricted circumstances when the alternative treatment options have proven ineffective. The evidence for the effectiveness of ECT in schizophrenia in general was not conclusive and therefore ECT is not recommended in this population. Further research is required to establish clearly the benefits in subgroups of individuals with schizophrenia, for example those with severe symptoms of depressive illness or catatonia.\n\nThe Committee considered that there was no conclusive evidence to support the effectiveness of ECT beyond the short term or that it is more beneficial as a maintenance therapy in depressive illness than currently available pharmacological alternatives. It was particularly concerned that the value of ECT maintenance therapy remained unproven in the context of the lack of information on whether the adverse effects of ECT (for example, on cognitive function) may be cumulative with repeated administration.\n\nIn appreciation of the special circumstances in which ECT is administered and the recognition that RCTs cannot adequately capture the long-term effects of ECT, the Committee took special note of the evidence from observations of users' experiences relating to the adverse effects of ECT. In particular, the incidence, extent and timescale of cognitive impairment following ECT was discussed in detail. It was apparent that the nature of cognitive impairment experienced by users was variable and often long lasting to such a degree that it outweighed their perception of any benefit from ECT treatment. The Committee considered that further research, both qualitative and quantitative, was needed to define the effect of ECT on cognitive impairment, especially whether the effects are cumulative with repeated administrations. It was also concerned that the potential for cognitive impairment following ECT may not be highlighted during the consent process. These factors featured significantly in the Committee's deliberations, and specifically in its decision to restrict the use of ECT to situations in which all other alternatives had been exhausted or where the nature of the mental illness was considered to be 'life-threatening'.\n\nThe Committee noted that the efficacy and adverse effects of ECT are clearly linked to the method of delivery, although the optimum technique and stimulus parameters have not been adequately researched; for example, gains in efficacy as a result of modifications to electrode placement and stimulus parameters are achieved at the expense of an increased risk of cognitive side effects. The Committee therefore considered that the evidence was not sufficient to allow conclusions to be drawn.\n\nThe RCT evidence considered by the Committee also leaves unanswered a number of important questions, and these require further research (see section\xa05). Consideration was given to the fact that the majority of the RCTs are not applicable to modern practice because of advances in pharmacological management and ECT administration techniques. The outcomes considered in the RCTs also did not adequately capture the experience of service users, and the validity of many of the scales used to measure outcome had not been clearly established. There was insufficient information to allow appropriate risk–benefit assessment for certain groups of individuals, for example during pregnancy, in older individuals, and in children and young people. Of particular concern were the lack of research into the number of treatment sessions that should be given, and the lack of long-term evidence regarding adverse effects on cognitive function and mortality. The Committee could not establish, in the context of the use of appropriate pharmacological treatment, the value of 'maintenance' ECT therapy following its use to achieve rapid and short-term improvement of severe symptoms. The Committee was persuaded on the balance of the evidence received from patients and carers that the practice of 'continuation' of ECT therapy for short periods following the initial control of severe symptoms was only acceptable in the context of sections 1.6 and 1.7 of the guidance.\n\nThe ongoing deficiencies in current practice were highlighted to the Committee, and the Committee strongly believed that action is required to ensure that appropriate standards of care are enforced whenever ECT is undertaken and that outcomes are continuously monitored. The Committee considered that ECT should be administered only in a suitably equipped unit by professionals who have been trained in its delivery and in the anaesthetic techniques required for the administration of ECT. These professionals should maintain an appropriate level of skill, both through the regular clinical practice of ECT and through undertaking appropriate continuing professional development. Urgent consideration should be given to the establishment of units dedicated to ECT, and of audit networks, which have been shown to be successful in Scotland.\n\nDespite the uncertainty in the estimates of clinical effectiveness and the small differences in costs and outcomes generated in the economic models, the Committee considered that ECT is likely to be cost effective in appropriate patient groups.\n\nIn summary, the Committee considered that the evidence appraised supported the effectiveness of ECT in certain groups of individuals. However, the Committee recognised there remained a number of uncertainties, including a lack of information on longer-term outcomes. The Committee was aware of the negative experiences of some individuals who have undergone ECT. Therefore the Committee considered that, ECT should be used with caution and only in the restricted circumstances recommended in the guidance in section\xa01. See also NICE's guidelines on bipolar disorder and psychosis and schizophrenia in adults.", 'Recommendations for further research': 'There are a number of ongoing research projects that include studies of clinical and cost effectiveness in specific groups and an examination of the effects of seizure parameters.\n\nFurther research is urgently required to examine the long-term efficacy and safety of electroconvulsive therapy (ECT), including its use as a maintenance therapy and its use in particular subgroups who may be at increased risk, for example older people, children and young people, and during pregnancy. This research should reflect modern techniques and the use of ECT in comparison with and in conjunction with the antipsychotic and antidepressant drugs used in current practice. In addition to the use of appropriately validated psychometric scales, outcome measures should include user perspectives on the impact of ECT, the incidence and impact of important side effects such as cognitive functioning, and mortality.\n\nFurther research into the mechanism of action of ECT is encouraged, because it may provide important information on aetiology and future treatment strategies.\n\nIt is clear that the stimulus parameters impact on the safety and efficacy of the technique and recent research needs to be augmented. Further evaluation is needed of whether it is necessary to induce a full seizure for therapeutic effect, and how the efficacy and cognitive effects are influenced by the amount by which the applied electrical dose exceeds the seizure threshold.\n\nMore research is also needed to determine the cost effectiveness of ECT. In particular, better quality-of-life information is needed for people considered for, or who have received, ECT.', 'Implications for the NHS': 'As this guidance recommends the use of electroconvulsive therapy (ECT) only in certain restricted circumstances, it is not anticipated that the guidance will increase the use of ECT in England and Wales above current levels. As ECT appears to be of similar cost to alternative treatments, it is unlikely that a change in the use of ECT will result in an increase or decrease in NHS expenditure. However, there will undoubtedly be costs associated with addressing the continuing deficiencies in the standards of care that have been highlighted (see section\xa03.3).', 'Appendix C. The use of electroconvulsive therapy': 'A summary of this guidance for patients and carers can be found on our website.', 'Appendix D. Detail on criteria for audit of the use of electroconvulsive therapy': "# Objectives for an audit\n\nAn audit on electroconvulsive therapy (ECT) could be carried out to ensure that ECT is used appropriately.\n\n# Patients to be included in the audit\n\nAll individuals who have received ECT in a suitable time period for audit, for example, 6 months or 1 year. Alternatively, the audit could be undertaken concurrently with the provision of ECT treatments.\n\n# Measures that can be used as a basis for audit\n\nCriterion\n\nStandard\n\nException\n\nDefinition of terms\n\n. The individual receiving electroconvulsive therapy (ECT) has 1 of the following:\n\na. severe depressive illness\n\nb. catatonia\n\nc. a prolonged or severe manic episode\n\n% of individuals receiving ECT\n\nNone\n\n\n\nLocal clinicians will have to agree on how and where the indications for ECT are documented for audit purposes.\n\n. ECT is used to achieve rapid and short-term improvement of severe symptoms when an adequate trial of other treatment options has proven ineffective, and/or the individual has a potentially life-threatening condition\n\n% of individuals receiving ECT\n\nNone\n\n\n\nLocal clinicians will have to agree on how severe symptoms and response to other treatment options and potentially life-threatening conditions are documented for audit purposes.\n\n. An assessment of the risks and potential benefits of ECT for the individual is documented\n\n% of individuals receiving ECT\n\nNone\n\nThe documented assessment before treatment should note: risks associated with the anaesthetic; current comorbidities; anticipated adverse events, including cognitive impairment; and the risks of no treatment.\n\n. The individual provides consent for each course of ECT treatment\n\n% of individuals receiving ECT\n\nA. The individual does not have the ability to grant or refuse consent, in which case advance directives are fully taken into account and the individual's advocate and/or carer are consulted.\n\nB. The individual is detained under the Mental Health Act\n\nLocal clinicians should agree on how consent to ECT is documented for audit purposes.\n\nA course of ECT is usually 6 to 12 sessions, usually given at the rate of 2 a week. The individual who has had/is having ECT should be asked for his/her views as to whether or not this criterion is being met.\n\n. The consent process provides that the clinician(s) responsible for treatment carries out all of the following:\n\na. involves the individual's advocate and/or carer where possible\n\nb. provides full and appropriate information in a suitable format and language to enable an informed discussion\n\nc. explains and discusses the general risks of ECT, risks specific to the individual, enhanced risks for individuals in specific groups and potential benefits to the individual\n\nd. does not pressure or coerce the individual into consent to the ECT treatment\n\ne. reminds the individual that he/she has the right to withdraw consent at any point\n\n% of individuals receiving ECT\n\nA. The individual is detained under the Mental Health Act\n\nB. The individual does not have the ability to grant or refuse consent but is compliant with treatment and 5a-e is carried out with an advocate and/or carer\n\nLocal clinicians should agree on how the format and language used to communicate the information provided and the involvement of advocates or carers prior to consent to ECT are documented for audit purposes.\n\nSee 3 above for a list of general risks to be discussed.\n\nGroups of people for whom there may be enhanced risks to be discussed include individuals who are pregnant, older or a child or young person.\n\nThe individual who has had/is having ECT should be asked for his/her views as to whether or not this criterion is being met.\n\n. The individual's clinical status is assessed after each ECT session\n\n% of individuals receiving ECT\n\nNone\n\nLocal clinicians should agree on what constitutes an assessment of clinical status following an ECT session.\n\n. The individual's cognitive function is monitored:\n\na. on an ongoing basis and\n\nb. at a minimum at the end of each course of treatment\n\n% of individuals receiving ECT\n\nNone\n\nLocal clinicians should agree on what constitutes monitoring of cognitive function and how monitoring is documented for audit purposes.\n\nThe individual who has had/is having ECT should be asked for his/her views as to whether or not this criterion is being met.\n\n. ECT is stopped if 1 of the following occurs:\n\na. a response is achieved\n\nb. there is evidence of adverse effects\n\nc. the individual withdraws consent\n\n% of individuals receiving ECT\n\nNone\n\nLocal clinicians will have to agree on what constitutes a desired response and evidence of adverse effects for audit purposes.\n\nThe individuals who has had/is having ECT should be asked for his/her views as to whether or not this criterion is being met.\n\n. A repeat course of ECT is provided only for an individual in either one of the following circumstances:\n\na. the individual meets criteria 1 and\n\nabove and has previously responded well to ECT or\n\nb. the individual has not responded previously but is experiencing an acute episode and all other options have been considered and following discussion with the individual and/or where appropriate the carer or advocate of the risks and benefits of such a course of action\n\n% of individuals receiving a repeat course of ECT\n\nNone\n\nLocal clinicians will have to agree on what constitutes a good response to ECT for audit purposes.\n\nSee 4 above for definition of course of treatment.\n\nSee 3 and 5 above for reference to risks.\n\n.ECT is used as a maintenance therapy in depressive illness\n\n% of individuals receiving ECT\n\nNone\n\n\n\n.ECT is used for the management of schizophrenia\n\n% of individuals receiving ECT\n\nNone\n\n\n\n# Calculation of compliance with the measures\n\nCompliance with the measures described in the table is calculated as follows.\n\nNumber of individuals whose care is consistent with the criterion plus the number of individuals who meet an exception\n\nDivided by\n\nNumber of patients to whom the measure applies\n\nMultiplied by 100\n\nClinicians should review the findings of measurement, identify whether practice can be improved, agree on a plan to achieve any desired improvement, and repeat the measurement of actual practice to confirm that the desired improvement is being achieved."}	https://www.nice.org.uk/guidance/ta59	Evidence-based recommendations on electroconvulsive therapy (ECT) for treating catatonia, prolonged or severe manic episodes or schizophrenia in adults.
f218aebb7176c1cfe292240c28d53e23f1783d5d	nice	Pemetrexed for the first-line treatment of non-small-cell lung cancer	Pemetrexed for the first-line treatment of non-small-cell lung cancer Evidence-based recommendations on pemetrexed for untreated non-small-cell lung cancer in adults. # Guidance Pemetrexed in combination with cisplatin is recommended as an option for the first-line treatment of patients with locally advanced or metastatic non-small-cell lung cancer (NSCLC) only if the histology of the tumour has been confirmed as adenocarcinoma or large-cell carcinoma. People who are currently being treated with pemetrexed for NSCLC but who do not meet the criteria in 1.1 should have the option to continue their therapy until they and their clinicians consider it appropriate to stop.# The technology Pemetrexed disodium (Alimta, Eli Lilly and Company Limited) in combination with cisplatin has a marketing authorisation for the first-line treatment of patients with locally advanced or metastatic non-small-cell lung cancer (NSCLC) other than predominantly squamous cell histology. Pemetrexed is an antifolate agent that works by disrupting folate-dependent metabolic processes essential for cancer cell replication and survival. Cisplatin is a platinum-based chemotherapeutic agent that has antitumour activity in a number of different cancers. The licensed dose of pemetrexed is 500 mg/m² body surface area, administered as a 10-minute intravenous infusion on the first day of each 21-day cycle. It is followed approximately 30 minutes later by 75 mg/m² cisplatin infused over 2 hours. To reduce toxicity, patients treated with pemetrexed should receive folic acid and vitamin B12 supplements. To reduce the incidence and severity of skin reactions, premedication with a corticosteroid is recommended. Adverse effects commonly associated with pemetrexed include nausea, vomiting, fatigue and leukopenia, particularly in the neutrophil component. Skin rash, mucositis and liver function abnormalities have also been reported. Cisplatin causes nausea and vomiting in the majority of patients. These adverse events are controllable in 50–80% of patients. Serious toxic effects of cisplatin on the kidneys, bone marrow and ears are common, and serum electrolyte disturbances, hyperuricaemia, allergic reactions and cardiac abnormalities have also been reported. For full details of side effects and contraindications, see the summaries of product characteristics. The cost of pemetrexed is £800 for a 500-mg vial (excluding VAT, 'British national formulary' 57th edition). The cost per patient, assuming an average of four treatment cycles, is approximately £6400. Costs may vary in different settings because of negotiated procurement discounts.# The manufacturer's submission The Appraisal Committee (appendix A) considered evidence submitted by the manufacturer of pemetrexed and reviews of these submissions by the Evidence Review Group (ERG; appendix B). In the submission the manufacturer compared pemetrexed plus cisplatin (pemetrexed/cisplatin) with gemcitabine plus cisplatin (gemcitabine/cisplatin). The manufacturer justified this choice of comparator with marketing data that suggest gemcitabine plus a platinum drug accounts for 80% of first-line NSCLC treatment, and the fact that according to a meta-analysis and clinical opinion cisplatin is the preferred platinum drug. The manufacturer identified gemcitabine plus carboplatin (gemcitabine/carboplatin) and docetaxel plus cisplatin (docetaxel/cisplatin) as additional comparators. The manufacturer stated that carboplatin is still commonly used in the UK because patients do not need the same hydration that is necessary with cisplatin. It also stated that docetaxel is used occasionally because it requires fewer infusions than gemcitabine. For the comparison of pemetrexed/cisplatin with gemcitabine/cisplatin the manufacturer identified one phase III, open-label, non-inferiority, randomised controlled trial (RCT). This trial (known as JMDB) compared 862 patients given pemetrexed/cisplatin with 863 patients given gemcitabine/cisplatin. It included patients with either squamous or non-squamous NSCLC and subgroups were defined by histology type, including adenocarcinoma, large-cell carcinoma and 'not otherwise specified'. Patients received up to six cycles of chemotherapy and were followed for 2.5 years. The trial results demonstrated overall survival (the primary outcome) of 10.3 months for both pemetrexed/cisplatin and gemcitabine/cisplatin for all randomised patients (hazard ratio 0.94, 95% confidence interval 0.84 to 1.05, p = 0.259). People with NSCLC of non-squamous histology had a greater overall survival with pemetrexed/cisplatin than with gemcitabine/cisplatin, based on median values (11 months versus 10.1 months respectively; HR 0.84, 95% CI 0.74 to 0.96, p = 0.011). A subgroup analysis based on median values showed that for patients with adenocarcinoma and large-cell carcinoma, overall survival was 11.8 months with pemetrexed/cisplatin compared with 10.4 months with gemcitabine/cisplatin (HR 0.81, 95% CI 0.70 to 0.94, p = 0.005). A similar subgroup analysis showed that patients with not otherwise specified histology had overall survival of 8.6 months for pemetrexed/cisplatin compared with 9.2 months for gemcitabine/cisplatin (HR 1.08, 95% CI 0.81 to 1.45, p = 0.586). The manufacturer concluded that these results together proved the hypothesis that pemetrexed/cisplatin was non-inferior to gemcitabine/cisplatin for overall survival in the overall JMDB trial population. It also stated that these results supported targeting pemetrexed/cisplatin treatment to the subgroup of patients with adenocarcinoma and large-cell carcinoma. The difference in median progression-free survival between patients receiving pemetrexed/cisplatin and gemcitabine/cisplatin in all randomised patients was not significant: 4.8 and 5.1 months respectively (HR 1.04, 95% CI 0.94 to 1.15). In patients with non-squamous histology, median progression-free survival was 5.3 months for pemetrexed/cisplatin and 5.0 months for gemcitabine/cisplatin (HR 0.95, 95% CI 0.84 to 1.06). For the manufacturer's target group of patients with adenocarcinoma and large-cell carcinoma the progression-free survival was 5.3 months for pemetrexed/cisplatin and 4.7 months for gemcitabine/cisplatin (HR 0.90, 95% CI 0.79 to 1.02). Pemetrexed/cisplatin was associated with statistically significantly fewer grade 3 and 4 adverse events than gemcitabine/cisplatin, specifically neutropenia, febrile neutropenia, thrombocytopenia, anaemia and alopecia. Patients receiving pemetrexed/cisplatin received fewer red blood cell transfusions, and less granulocyte colony stimulating factor and erythropoietin. Patients randomised to pemetrexed/cisplatin experienced statistically significantly more nausea. No quality of life data were measured in the JMDB clinical trial. The manufacturer carried out an indirect comparison of pemetrexed/cisplatin with other comparators (gemcitabine/carboplatin and docetaxel/cisplatin). The manufacturer identified two phase II, open-label RCTs that could be mapped to the treatment arms of JMDB: Zatloukal et al. (2003) comparing gemcitabine/cisplatin (n = 87) with gemcitabine/carboplatin (n = 89) and Schiller et al. (2002) comparing gemcitabine/cisplatin (n = 301) with docetaxel/cisplatin (n = 304). All treatments were administered within their licensed indications. The trials were relatively homogenous in terms of patient population and when compared with the JMDB trial. The manufacturer noted that the unadjusted comparison suggested that median overall survival and progression-free survival were improved in patients with squamous and non-squamous NSCLC who were given pemetrexed/cisplatin relative to the other comparators. The manufacturer's indirect comparison methodology involved calculating hazard ratios for each of gemcitabine/carboplatin and docetaxel/cisplatin, compared with gemcitabine/cisplatin. The hazard ratios were based on median overall survival and were applied to the hazard rate of the gemcitabine/cisplatin arm in the JMDB trial to produce hazard rates for gemcitabine/carboplatin and docetaxel/cisplatin, adjusted for the JMDB population. This was then used to calculate adjusted median overall survival estimates for the JMDB population. The manufacturer used this method to adjust the hazard rates for the subgroups by using the corresponding hazard rates in JMDB (such as for non-squamous NSCLC). The results of this analysis for the target population of patients with adenocarcinoma and large-cell carcinoma suggested an overall survival advantage for pemetrexed/cisplatin (11.8 months, 95% CI 10.4 to 13.2) versus gemcitabine/carboplatin (9.5 months, 95% CI 8.1 to 13.4) and docetaxel/cisplatin (9.8 months, 95% CI 8.6 to 11.5). Pemetrexed also improved progression-free survival: 5.3 months for pemetrexed/cisplatin compared with 3.8 months for gemcitabine/carboplatin and 4.1 months for docetaxel/cisplatin (no confidence intervals reported). The manufacturer developed a Markov model with a 6-year time horizon that compared pemetrexed/cisplatin, gemcitabine/cisplatin, gemcitabine/carboplatin and docetaxel/cisplatin. The efficacy data from the JMDB trial were used for the comparison of pemetrexed/cisplatin with gemcitabine/cisplatin, and the results of the indirect comparison were used for the other comparators. The adverse event states were built into the model as separate mutually exclusive health states. All clinical events were modelled via transition probabilities. Treatment effects considered included overall survival, progression-free survival, response rates, adverse events and HRQoL. All effectiveness data used in the model, apart from HRQoL, were trial-based. In the model, patients were given a maximum of four cycles of chemotherapy. A continuation rule stipulated that only patients whose disease had responded to pemetrexed/cisplatin after three cycles continued treatment to a fourth cycle. To reflect treatment discontinuation after the third cycle for patients whose disease did not respond, no further chemotherapy costs were incurred. A literature review of utility data for patients with NSCLC identified a number of studies, but the manufacturer considered that none were suitable for inclusion. Instead, a study by Nafees et al. (2008) was used. This was commissioned to study second-line treatment of NSCLC by the manufacturer, but was assumed by the manufacturer to apply to first-line treatment. It involved 100 members of the public interviewed with visual analogue scale and standard gamble techniques to elicit societal values on utilities in lung cancer. The base-case analysis compared pemetrexed/cisplatin with gemcitabine/cisplatin. In the population with non-squamous NSCLC, the analysis resulted in an incremental cost of £1364 and 0.041 incremental quality adjusted life years (QALYs). The incremental cost-effectiveness ratio (ICER) for pemetrexed/cisplatin compared with gemcitabine/cisplatin was £33,065 per QALY gained without the continuation rule (see 3.8). With the continuation rule the incremental cost fell to £1252 and the incremental QALY remained the same, resulting in an ICER of £25,967 per QALY gained. When subgroups according to histology were analysed using the continuation rule, pemetrexed/cisplatin compared with gemcitabine/cisplatin in the adenocarcinoma subgroup gave an ICER of £18,442 per QALY gained, and large-cell carcinoma gave an ICER of £8,056 per QALY gained. The ERG reviewed the evidence submitted for clinical and cost effectiveness. The ERG report concentrated on the exclusion of vinorelbine, the indirect comparison and the suitability of the chosen cost-effectiveness analysis. The ERG noted that vinorelbine had been excluded from the analysis even though the marketing data presented by the manufacturer suggested it accounted for 11% of first-line NSCLC treatment, which was greater than the 4% usage of docetaxel. The ERG considered that vinorelbine should have been included in the manufacturer's decision problem to allow a full assessment of pemetrexed against relevant comparators. The ERG noted that in the JMDB trial, baseline characteristics were well balanced between treatment arms and between histological subgroups. The ERG noted that the findings from the per-protocol analysis requested from the manufacturer did not differ much from the findings from the intention-to-treat analysis. The ERG considered that this made the JMDB trial results considerably more robust. On request, the manufacturer reported the p values for the test for interaction as p = 0.0024 for squamous NSCLC compared with non-squamous NSCLC, and p = 0.0059 across all other subgroups. This makes it more likely that there were real differences between the histological subgroups. The ERG expressed concerns over the trial selection for the indirect comparison. The ERG believed that all the comparators specified in the scope (pemetrexed, docetaxel, gemcitabine, paclitaxel and vinorelbine) should have been included in the indirect comparison analyses. This would have identified five further phase III RCTs for consideration, and improved the subsequent power and validity of the indirect comparison. The ERG also noted that the manufacturer did not assess validity of the included RCTs. The ERG also expressed concern over the statistical approach used in the indirect comparison. It noted that the manufacturer's method may have resulted in under- or overestimation of treatment effects, and loss of statistical power. It also noted that the manufacturer's submission suggested that the treatment-arm-level hazard rates were used; the ERG stated that indirect comparisons should be based on a comparison of relative effects rather than a comparison of single arm estimates, as the former maintains randomisation within a trial. The ERG stated that the key assumption of an indirect comparison is that the relative effects are exchangeable across the trial settings, that is, there are no treatment effect modifiers. Within the JMDB trial, histology is an effect modifier, and this should be accounted for in the indirect comparison. The ERG concluded that, because key comparators were excluded from the indirect comparison analysis, and because of the assumptions underlying the statistical approach used, the findings from this analysis should be interpreted with caution. The ERG commented on the submitted cost-effectiveness analysis. It noted that the chosen Markov model structure did not seem to be appropriate because it did not replicate the trial data, which was used to calibrate the model, to an acceptable level of accuracy. The ERG commented that this was noticeable when calculating response and survival. It considered that because overall survival and progression-free survival were the primary outcomes in the JMDB trial, these two outcomes should be accurately replicated in the economic model for each of the subgroups for the trial period. It noted that the manufacturer's model appeared to overestimate overall survival in both arms and almost all patient groups. For progression-free survival, the ERG commented that the model tended to underestimate in the first 6 months and to overestimate thereafter. In addition, the ERG noted that some survival estimates suggested an error in the model's logic. The ERG commented on the use of response to treatment in the model structure. It is commonly assumed that response leads to a delay in disease progression and therefore to progression-free survival, this becoming the source of survival gain. Following disease progression it is usually assumed that the natural course of the disease will continue. The JMDB trial data suggested that all the reported survival gain occurred after disease progression, with progression-free survival effectively identical between the pemetrexed/cisplatin and gemcitabine/cisplatin arms. The ERG stated that it was not clear whether objective response determined the extent of health gain and whether the survival gain was restricted to patients whose disease has responded to treatment, or to all patients who had treatment. The ERG considered that this had implications for the design of the model; if response doesn't predict progression-free survival or post-progression survival, then its use as a distinct health state is potentially irrelevant, and could generate misleading results. The ERG identified other concerns with the cost-effectiveness analysis, including: All transition probabilities during the trial period were assumed to arise from constant risk processes (that is, exponential survival distributions), without any justification. A half-cycle correction appeared to have been disabled for costs and used incorrectly for outcomes. Cumulative costs and outcome effects of patients having more than one adverse event at any given time (for example, within a single hospital admission) were not taken into account. This omission could have led to overestimation of the costs and harms attributable to treatment. There may have been an overestimation of mortality because of incorrect use of the febrile neutropenia mortality risk. The ERG stated that the evidence submitted by the manufacturer was not sufficiently convincing or robust for it to determine the cost effectiveness of pemetrexed. During the consultation for this appraisal, the manufacturer submitted revised cost-effectiveness estimates for pemetrexed/cisplatin compared with gemcitabine/cisplatin. No other comparators were considered. The primary analysis was a modified version of the previously submitted Markov model, but used Weibull distributions to improve its representation of the outcomes of the JMDB trial. The manufacturer responded to the concerns raised by the Committee concerning the use of response, transition probabilities, half-cycle correction, adverse events and mortality due to febrile neutropenia. It also presented two validation models: a trial-based economic analysis conducted using the individual patient survival outcomes and resource use events from the JMDB clinical trial database, and an economic model used for a submission to the Pharmaceutical Benefits Advisory Committee (PBAC) in Australia. The PBAC model was based on the patient-level data from the clinical trial and used Weibull distributions to extrapolate survival beyond the trial period. The manufacturer stated that validation processes included a 'double-build' process for the trial-based model (in which two researchers independently built and analysed the database to make sure data outputs were consistent), and internal and independent external reviews, for both the modified and clinical trial-based models. The manufacturer's base-case ICER, using the modified Markov model calculated for a maximum of four cycles of treatment, was £27,565 for the population included in the licence (those with non-squamous histology) and £22,202 for patients with adenocarcinoma or large-cell carcinoma. For the trial-based analysis, the ICER calculated for a maximum of four cycles of treatment was £31,157 for the population included in the licence and £24,224 for patients with adenocarcinoma or large-cell carcinoma. When the number of cycles was increased to six, as specified in the trial, the ICERs increased to £42,306 and £33,730 for the two groups respectively. In the PBAC model, the ICER for only four cycles of chemotherapy for patients with adenocarcinoma or large-cell carcinoma was £23,157 per QALY gained. The ERG commented on the manufacturer's additional analysis. It stated that the cost-effectiveness analyses based on the JMDB trial patient-level data without use of projection techniques were very similar to the previous cost-effectiveness models, and used the same unit cost and state utility parameter values. However, the ERG noted several limitations with the submitted analyses. These included restricting the number of cycles and corresponding costs, with no corresponding alteration in effectiveness. Therefore, only the estimates using six cycles were valid trial-based estimates. The ERG further noted that new utility values were used in the revised model without explanation. The ERG considered that, as all survival benefit observed for pemetrexed in the JMDB trial occurred after disease progression, the correct utility value for use with the incremental survival is that of the 'progressive disease' state from the original Markov model (that is, 0.47), not that of the pre-progression states of 'stable' (0.65) and 'responding' (0.67). The ERG noted that the estimates for the cost of chemotherapy did not consider differences in body surface area, or allow for wastage of part-used vials. The ERG suggested that taking these factors into account increased the cost per cycle of pemetrexed/cisplatin chemotherapy by £81.63 and decreased that of gemcitabine/cisplatin by £3.80. The ERG noted that the 'in-trial' analysis did not use discounting on either costs or outcomes, despite trial follow-up extending to more than 2 years for some patients. The ERG stated that this was an important omission, because much of the survival gain occurred after the first 12 months and would therefore be likely to be affected by discounting. Drug costs, however, would be incurred early on. The ERG noted that the 'in-trial' analysis used differential costs per patient for terminal care and for best supportive care (BSC). However, these figures were not derived from an analysis of the trial's individual patient data, but were mean results calculated in the manufacturer's Markov model. This created confusion between observation and modelling, which may have distorted the results of the 'in-trial' analysis. The ERG preferred to include terminal care and BSC costs for all patients, but discounted for a period after the recorded survival date for patients censored in the trial. The combined ERG amendments to the in-trial analysis, using the utility derived from disease progression (0.47) and up to six cycles of chemotherapy, produced an ICER for the population included in the licence of £60,130, and £48,055 for the adenocarcinoma and large-cell carcinoma subgroup. The ERG noted that the manufacturer's modified Markov model addressed a number of the issues identified by the ERG previously. However, it noted that although the Weibull survival models were better than the original exponential models, they were still not adequate. In particular, they were inaccurate for long-term projection. The ERG also noted that patients having more than one adverse event at a time (for example, during one hospital admission) was not addressed, and chemotherapy costs were based on JMDB trial data and were therefore not representative of UK clinical practice. There was also the issue of reducing six cycles to four, and the effects of this on overall efficacy. In addition the ERG identified new errors in the analysis, including the calculation of adverse event costs, and inappropriate response rates used for the whole population. The ERG commented that the PBAC health technology assessment submission was well presented and clearly laid out, thereby simplifying the validation. However, because it was based on the same fundamental assumptions as the manufacturer's Markov analysis, it merely demonstrated that similar assumptions resulted in similar cost-effectiveness results when using a different model structure. The ERG concluded that it did not address some of the major issues with the manufacturer's cost-effectiveness analysis that had been identified previously. The ERG stated that the time available to review the new evidence submitted by the manufacturer did not allow detailed modifications to be made to the modified Markov model. Instead it used the information contained in the 'in-trial' analysis, together with the additional exploratory survival analysis, to generate modified cost-effectiveness results. The ERG noted that an extract of individual patient data from the JMDB trial was included by the manufacturer in the 'in-trial' cost-effectiveness analysis. This was restricted to the population of patients with NSCLC and included only information relating to chemotherapy treatment cycles and overall survival, that is, the timing of death or censoring. No information was provided about response to treatment or the time of confirmed disease progression. This data made it possible for the ERG to consider what was the most appropriate estimate of survival gain and utility gain attributable to pemetrexed within the JMDB trial, and thus whether it was possible to estimate the likely change in patient outcomes when treatment was limited to four cycles instead of the maximum of six cycles used in the trial. The ERG classified patients according to the last cycle in which they received a dose of pemetrexed or gemcitabine. Initial examination of Kaplan-Meier survival charts by the ERG indicated that patients could be classified into three groups that were mainly homogeneous with respect to prognosis: up to two cycles, three to four cycles and five to six cycles of chemotherapy. In the absence of specific information on disease progression or treatment discontinuation, these divisions should reflect the approximate time when patients leave the stable or response states. The ERG considered that this analysis provided a basis for considering the possible effects of limiting treatment duration. The results of the ERG's exploratory analysis suggested that for six cycles of chemotherapy, the ICER for pemetrexed/cisplatin compared with gemcitabine/cisplatin was £28,241 per QALY gained for non-squamous patients and £23,598 per QALY gained for adenocarcinoma and large-cell carcinoma patients. When the number of cycles was reduced to four the ICERs were £20,497 and £17,162 per QALY gained respectively. The ERG explored two scenarios to account for the potential consequences of reducing the number of chemotherapy cycles. First, if overall survival is related to tumour response, the overall survival gain lost when chemotherapy is stopped sooner can be estimated from the response rate difference (19%). Secondly, if overall survival is related to drug exposure, the overall survival gain lost when chemotherapy is stopped sooner can be estimated as the proportion of treatment cycles given beyond four cycles (32%). For four cycles of pemetrexed/cisplatin in the population included in the licence (those with non-squamous histology), the exploratory analyses described in 3.32 led to an ICER of £25,336 for a 19% reduction in the overall survival gain, and £30,142 for a 32% reduction in the overall survival gain. For the treatment of patients with adenocarcinoma and large-cell carcinoma subgroup, the respective ICERs were £21,214 and £25,239. The ERG noted that gemcitabine's patent ended this year (2009), and that generic versions are already being marketed. The ERG explored the potential impact of some market price changes, and noted that they adversely affected the cost-effectiveness estimates for pemetrexed/cisplatin. Full details of all the evidence are in the manufacturer's submission and the ERG report.# Consideration of the evidence The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of pemetrexed, having considered evidence on the nature of NSCLC and the value placed on the benefits of pemetrexed by people with the condition, those who represent them, and clinical specialists. It also took into account the effective use of NHS resources. # Clinical effectiveness The Committee discussed current UK clinical practice for the treatment of NSCLC. It noted that the manufacturer had limited its analysis to comparisons with gemcitabine/cisplatin, gemcitabine/carboplatin and docetaxel/cisplatin. The Committee heard from clinical specialists that current UK clinical practice was to combine gemcitabine with a platinum drug (usually cisplatin) in the majority of cases. It also heard that there were still some centres that used carboplatin as they could not administer cisplatin because of the hydration required, and possibly because some consider carboplatin to be less toxic. The Committee discussed the additional comparator presented by the manufacturer (docetaxel/cisplatin) and the ERG's concern that vinorelbine had been excluded. The Committee heard from clinical specialists that docetaxel and vinorelbine are not widely used in the UK because of their adverse-event profiles, in particular the higher rates of febrile neutropenia compared with those seen with pemetrexed and gemcitabine. However, the Committee heard from clinical specialists that docetaxel requires fewer hospital visits than gemcitabine, and so it is occasionally used in areas where patients have difficulty getting to hospital. The Committee noted market research data presented by the manufacturer that confirmed that gemcitabine was the main treatment regimen used in the UK, with an 85% market share. Vinorelbine was in second place with an 11% market share. The Committee heard from clinical specialists that the 11% market share of vinorelbine could be an overestimate because it could include use in other indications. The Committee concluded that the gemcitabine/cisplatin combination was the principle comparator in UK clinical practice for the first-line treatment of NSCLC. The Committee considered the evidence on the clinical effectiveness of pemetrexed/cisplatin compared with gemcitabine/cisplatin. It noted that the JMDB trial was well conducted and considered its results to be robust. The Committee heard from the clinical specialists that the histological subtyping was an important factor in predicting response to pemetrexed. It also heard that the improved overall survival with pemetrexed/cisplatin seen in the JMDB trial in the adenocarcinoma and large-cell carcinoma subgroups has been replicated in other studies. Additionally the Committee noted that pemetrexed had not been proven to be effective in the non-specified histology subgroup. It was mindful that the p value for interaction (see 3.13) supported the hypothesis that the differences between the subgroups was real and not due to chance. The Committee concluded that there is evidence to support a true difference in response to pemetrexed between histological subtypes, although the pathophysiological basis for this is not known. The Committee then discussed whether the results of the JMDB trial were generalisable to UK clinical practice, with particular reference to routine identification of histological subtypes and numbers of treatment cycles recommended. It heard from clinical specialists that histological identification of patients with non-squamous disease to determine whether they have adenocarcinoma or large-cell carcinoma was not common practice in the UK. However the Committee was satisfied that there would not be problems with doing this in practice because pathology services across the UK can perform such histological diagnoses. The Committee noted that 4 cycles of chemotherapy was considered standard UK clinical practice, whereas the JMDB trial had allowed up to 6, with an average of 4.4 actually being administered. The clinical specialists stated that a reduction in the number of cycles from 4.4 to 4 was unlikely to affect the clinical outcomes of the trial. The Committee concluded that pemetrexed/cisplatin was more clinically effective than gemcitabine/cisplatin in patients with adenocarcinoma and large-cell carcinoma. The Committee considered the indirect comparison of pemetrexed/cisplatin with gemcitabine/carboplatin and docetaxel/cisplatin. It noted the manufacturer's exclusion of comparators such as vinorelbine. It considered that even though its use in the UK was low, the omission was inappropriate because it excluded additional information and data from the analysis. The Committee was also mindful of the concerns of the ERG over the methodology used by the manufacturer, and of the fact that the indirect comparisons presented in the manufacturer's submission were potentially flawed because of the exclusion of relevant comparators and the chosen statistical method. However, the Committee noted that the gemcitabine/cisplatin combination was the principle comparator in UK clinical practice for the first-line treatment of NSCLC. It also noted evidence from the clinical specialists and patient expert that suggested that gemcitabine/cisplatin was as effective or more effective than gemcitabine/carboplatin or docetaxel/cisplatin. The Committee concluded that its concerns about the indirect comparison did not prevent it from concluding that pemetrexed/cisplatin is clinically effective in UK clinical practice. The Committee heard from the patient expert and clinical specialists that pemetrexed was valued by patients because of its favourable adverse-event profile, in particular the lower incidences of febrile neutropenia and alopecia. In addition, patients preferred pemetrexed's shorter infusion time and the fewer hospital visits needed for treatment compared with gemcitabine. The Committee concluded that the increased survival in the adenocarcinoma and large-cell carcinoma subpopulations and lower toxicity demonstrated in the JMDB trial for pemetrexed/cisplatin was clinically significant when compared with gemcitabine/cisplatin, especially when taking into account the overall low survival rates for NSCLC. # Cost effectiveness The Committee considered the manufacturer's original cost-effectiveness analysis and the ERG's critique. The Committee noted that the original model did not replicate the results of the JMDB trial, especially with respect to the three primary clinical outcomes (overall survival, progression-free survival and response rate). The Committee agreed with the ERG that the model should be able to reproduce the JMDB trial results, because the JMDB trial data are the primary source of clinical data used in the model. The Committee also noted the other problems identified by the ERG and was concerned that the submitted model had not been adequately quality assured. The Committee concluded that on the basis of the evidence presented, the cost effectiveness of pemetrexed/cisplatin had not been proven despite the apparently favourable ICERs in the manufacturer's original submission. The Committee subsequently considered the revised analysis submitted by the manufacturer. The Committee considered that reducing the number of cycles to four and therefore diverging from the trial was inappropriate for a trial-based analysis. It also considered that the utility values used for progressive states were not appropriate. The Committee concluded that the ERG's exploratory analysis of the manufacturer's revised analysis produced the most plausible estimates. The Committee noted that the ERG's exploratory analysis resulted in ICERs above £48,000 per QALY gained and therefore suggested that pemetrexed/cisplatin was not cost effective. However, the Committee considered that because this analysis only covered the duration of the trial it was inappropriate to conclude cost ineffectiveness from this, although it provided useful additional validation for the subsequently revised Markov model, and the ERG analyses of that. The Committee considered the manufacturer's modified Markov model and ERG comments on it. The Committee was concerned that some issues of face validity identified by the ERG had not been appropriately addressed. The Committee noted that although reducing the average number of cycles from 4.4 to 4 did not affect the conclusion that pemetrexed was clinically effective, setting a maximum of 4 cycles would affect the conclusions of the cost-effectiveness analysis. It considered that the manufacturer should have taken some account of the probable lower effectiveness. The Committee noted the new errors identified by the ERG that suggested the new analysis had not been sufficiently quality assured. The Committee concluded that the submitted modified Markov model was still not suitable for drawing conclusions because of its inability to replicate the trial results accurately and the lack of quality assurance. The Committee considered the ERG's exploratory analyses based on the manufacturer's modified Markov model. It was mindful that there were limitations with the data available and that the analyses did not consider the inherent uncertainty in the point estimates through probabilistic sensitivity analysis. The Committee noted that the ERG's estimates of survival were based on individual patient data and that they adequately represented the trial results, in particular the long-term extrapolation. The Committee concluded that the ERG's exploratory analyses were sufficiently robust to allow conclusions to be drawn about the cost effectiveness of pemetrexed/cisplatin. The Committee noted that the ICERs estimated by the ERG's exploratory analysis were all under £30,000 per QALY gained regardless of the population examined for six cycles of chemotherapy. The Committee noted that when the number of cycles was reduced to four and the ERG's calculations for reduced effectiveness were included, the ICERs were between £20,000 and £30,000 per QALY gained for non-squamous NSCLC and between £17,000 and £25,000 per QALY gained for adenocarcinoma and large cell carcinoma. The Committee therefore concluded that pemetrexed/cisplatin was a cost-effective use of NHS resources based on the evidence available. The Committee acknowledged that generic versions of gemcitabine have recently become available and that the price was currently subject to change. It noted the ERG's view that when including any substantial price reduction for gemcitabine in the model, pemetrexed/cisplatin was no longer cost-effective compared with gemcitabine/cisplatin. However, it also noted that there was no nationally available price for the generic versions, and that local prices were likely to vary considerably. The Committee concluded that, since the published list price for gemcitabine had not changed, the cost-effectiveness analysis on which it had to base its decision was that described in section 4.13. The Committee considered that the guidance for pemetrexed should be reviewed early if there is a substantial change to the nationally available price of gemcitabine in the NHS. # Conclusion The Committee considered that current UK clinical practice was to use up to four cycles of gemcitabine/cisplatin as first line-chemotherapy for the treatment of NSCLC. Consequently the Committee considered that the clinical-effectiveness evidence from the JMDB trial, the clinical specialists and patient expert was sufficient and robust enough to demonstrate the clinical effectiveness of pemetrexed/cisplatin in patients with adenocarcinoma and large-cell carcinoma. The Committee noted that pemetrexed/cisplatin had not been shown to be any more effective than gemcitabine/cisplatin in patients with non-squamous NSCLC with unspecified histology. The Committee considered that the ERG's exploratory analysis had demonstrated that the ICERs for pemetrexed/cisplatin were between £17,000 and £25,000 per QALY for adenocarcinoma or large-cell carcinoma. It therefore recommended pemetrexed as an option for the first-line treatment of patients with adenocarcinoma or large-cell carcinoma. The Committee considered that this guidance should be reviewed early if there is any significant change in the price of generic gemcitabine.# Related NICE guidance # Published Erlotinib for the treatment of non-small-cell lung cancer.NICE technology appraisal guidance 162 (2008). Bevacizumab for the treatment of non-small-cell lung cancer (terminated appraisal).NICE technology appraisal 148 (2008). Pemetrexed for the treatment of non-small-cell lung cancer.NICE technology appraisal guidance 124 (2007). Lung cancer: the diagnosis and treatment of lung cancer. NICE clinical guideline 24 (2005). Gefitinib for the first-line treatment of locally advanced or metastatic non-small-cell lung cancer. NICE technology appraisal guidance 192 (2010) Erlotinib monotherapy for maintenance treatment of non-small-cell lung cancer. NICE technology appraisal guidance 227 (2011). # Under development NICE is developing the following guidance(details available from the NICE website): Cetuximab for the treatment of advanced non-small-cell lung cancer. NICE technology appraisal guidance(publication date to be confirmed).# Review of guidance The guidance on this technology was reviewed in January 2012. Details are on the NICE website. Andrew DillonChief ExecutiveSeptember 2009# Changes after publication February 2014: implementation section updated to clarify that pemetrexed is recommended as an option for treating non-small-cell lung cancer. Additional minor maintenance update also carried out. March 2012: minor maintenance# About this guidance NICE technology appraisal guidance is about the use of new and existing medicines and treatments in the NHS in England and Wales. This guidance was developed using the NICE single technology appraisal process. We have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available. Your responsibility This guidance represents the views of NICE and was arrived at after careful consideration of the evidence available. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. However, the guidance does not override the individual responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or guardian or carer. Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties. Copyright © National Institute for Health and Clinical Excellence 2009. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.	{'Guidance': 'Pemetrexed in combination with cisplatin is recommended as an option for the first-line treatment of patients with locally advanced or metastatic non-small-cell lung cancer (NSCLC) only if the histology of the tumour has been confirmed as adenocarcinoma or large-cell carcinoma.\n\nPeople who are currently being treated with pemetrexed for NSCLC but who do not meet the criteria in 1.1 should have the option to continue their therapy until they and their clinicians consider it appropriate to stop.', 'The technology ': "Pemetrexed disodium (Alimta, Eli Lilly and Company Limited) in combination with cisplatin has a marketing authorisation for the first-line treatment of patients with locally advanced or metastatic non-small-cell lung cancer (NSCLC) other than predominantly squamous cell histology.\n\nPemetrexed is an antifolate agent that works by disrupting folate-dependent metabolic processes essential for cancer cell replication and survival. Cisplatin is a platinum-based chemotherapeutic agent that has antitumour activity in a number of different cancers.\n\nThe licensed dose of pemetrexed is 500 mg/m² body surface area, administered as a 10-minute intravenous infusion on the first day of each 21-day cycle. It is followed approximately 30\xa0minutes later by 75 mg/m² cisplatin infused over 2\xa0hours. To reduce toxicity, patients treated with pemetrexed should receive folic acid and vitamin B12 supplements. To reduce the incidence and severity of skin reactions, premedication with a corticosteroid is recommended.\n\nAdverse effects commonly associated with pemetrexed include nausea, vomiting, fatigue and leukopenia, particularly in the neutrophil component. Skin rash, mucositis and liver function abnormalities have also been\xa0reported. Cisplatin causes nausea and vomiting in the majority of patients. These adverse events are controllable in 50–80% of patients. Serious toxic effects of cisplatin on the kidneys, bone marrow and ears are common, and serum electrolyte disturbances, hyperuricaemia, allergic reactions and cardiac abnormalities have also been reported. For full details of side effects and contraindications, see the summaries of product characteristics.\n\nThe cost of pemetrexed is £800 for a 500-mg vial (excluding VAT, 'British national formulary' 57th edition). The cost per patient, assuming an average of four treatment cycles, is approximately £6400. Costs may vary in different settings because of negotiated procurement discounts.", "The manufacturer's submission": "The Appraisal Committee (appendix A) considered evidence submitted by the manufacturer of pemetrexed and reviews of these submissions by the Evidence Review Group (ERG; appendix B).\n\nIn the submission the manufacturer compared pemetrexed plus cisplatin (pemetrexed/cisplatin) with gemcitabine plus cisplatin (gemcitabine/cisplatin). The manufacturer justified this choice of comparator with marketing data that suggest gemcitabine plus a platinum drug accounts for 80% of first-line NSCLC treatment, and the fact that according to a meta-analysis and clinical opinion cisplatin is the preferred platinum drug. The manufacturer identified gemcitabine plus carboplatin (gemcitabine/carboplatin) and docetaxel plus cisplatin (docetaxel/cisplatin) as additional comparators. The manufacturer stated that carboplatin is still commonly used in the UK because patients do not need the same hydration that is necessary with cisplatin. It also stated that docetaxel is used occasionally because it requires fewer infusions than gemcitabine.\n\nFor the comparison of pemetrexed/cisplatin with gemcitabine/cisplatin the manufacturer identified one phase III, open-label, non-inferiority, randomised controlled trial (RCT). This trial (known as JMDB) compared 862 patients given pemetrexed/cisplatin with 863 patients given gemcitabine/cisplatin. It included patients with either squamous or non-squamous NSCLC and subgroups were defined by histology type, including adenocarcinoma, large-cell carcinoma and 'not otherwise specified'. Patients received up to six cycles of chemotherapy and were followed for 2.5 years. The trial results demonstrated overall survival (the primary outcome) of 10.3 months for both pemetrexed/cisplatin and gemcitabine/cisplatin for all randomised patients (hazard ratio [HR] 0.94, 95% confidence interval [CI] 0.84 to 1.05, p\xa0= 0.259). People with NSCLC of non-squamous histology had a greater overall survival with pemetrexed/cisplatin than with gemcitabine/cisplatin, based on median values (11 months versus 10.1 months respectively; HR 0.84, 95% CI 0.74 to 0.96, p\xa0=\xa00.011). A subgroup analysis based on median values showed that for patients with adenocarcinoma and large-cell carcinoma, overall survival was 11.8 months with pemetrexed/cisplatin compared with 10.4\xa0months with gemcitabine/cisplatin (HR 0.81, 95% CI 0.70 to 0.94, p\xa0= 0.005). A similar subgroup analysis showed that patients with not otherwise specified histology had overall survival of 8.6\xa0months for pemetrexed/cisplatin compared with 9.2 months for gemcitabine/cisplatin (HR 1.08, 95% CI 0.81 to 1.45, p\xa0= 0.586). The manufacturer concluded that these results together proved the hypothesis that pemetrexed/cisplatin was non-inferior to gemcitabine/cisplatin for overall survival in the overall JMDB trial population. It also stated that these results supported targeting pemetrexed/cisplatin treatment to the subgroup of patients with adenocarcinoma and large-cell carcinoma.\n\nThe difference in median progression-free survival between patients receiving pemetrexed/cisplatin and gemcitabine/cisplatin in all randomised patients was not significant: 4.8 and 5.1 months respectively (HR 1.04, 95% CI 0.94 to 1.15). In patients with non-squamous histology, median progression-free survival was 5.3\xa0months for pemetrexed/cisplatin and 5.0 months for gemcitabine/cisplatin (HR 0.95, 95% CI 0.84 to 1.06). For the manufacturer's target group of patients with adenocarcinoma and large-cell carcinoma the progression-free survival was 5.3 months for pemetrexed/cisplatin and 4.7 months for gemcitabine/cisplatin (HR\xa00.90, 95% CI 0.79 to 1.02).\n\nPemetrexed/cisplatin was associated with statistically significantly fewer grade 3 and 4 adverse events than gemcitabine/cisplatin, specifically neutropenia, febrile neutropenia, thrombocytopenia, anaemia and alopecia. Patients receiving pemetrexed/cisplatin received fewer red blood cell transfusions, and less granulocyte colony stimulating factor and erythropoietin. Patients randomised to pemetrexed/cisplatin experienced statistically significantly more nausea. No quality of life data were measured in the JMDB clinical trial.\n\nThe manufacturer carried out an indirect comparison of pemetrexed/cisplatin with other comparators (gemcitabine/carboplatin and docetaxel/cisplatin). The manufacturer identified two phase II, open-label RCTs that could be mapped to the treatment arms of JMDB: Zatloukal et al. (2003) comparing gemcitabine/cisplatin (n = 87) with gemcitabine/carboplatin (n\xa0=\xa089) and Schiller et al. (2002) comparing gemcitabine/cisplatin (n\xa0=\xa0301) with docetaxel/cisplatin (n\xa0=\xa0304). All treatments were administered within their licensed indications. The trials were relatively homogenous in terms of patient population and when compared with the JMDB trial. The manufacturer noted that the unadjusted comparison suggested that median overall survival and progression-free survival were improved in patients with squamous and non-squamous NSCLC who were given pemetrexed/cisplatin relative to the other comparators.\n\nThe manufacturer's indirect comparison methodology involved calculating hazard ratios for each of gemcitabine/carboplatin and docetaxel/cisplatin, compared with gemcitabine/cisplatin. The hazard ratios were based on median overall survival and were applied to the hazard rate of the gemcitabine/cisplatin arm in the JMDB trial to produce hazard rates for gemcitabine/carboplatin and docetaxel/cisplatin, adjusted for the JMDB population. This was then used to calculate adjusted median overall survival estimates for the JMDB population. The manufacturer used this method to adjust the hazard rates for the subgroups by using the corresponding hazard rates in JMDB (such as for non-squamous NSCLC). The results of this analysis for the target population of patients with adenocarcinoma and large-cell carcinoma suggested an overall survival advantage for pemetrexed/cisplatin (11.8\xa0months, 95% CI 10.4 to 13.2) versus gemcitabine/carboplatin (9.5 months, 95% CI 8.1 to 13.4) and docetaxel/cisplatin (9.8\xa0months, 95% CI 8.6 to 11.5). Pemetrexed also improved progression-free survival: 5.3 months for pemetrexed/cisplatin compared with 3.8 months for gemcitabine/carboplatin and 4.1 months for docetaxel/cisplatin (no confidence intervals reported).\n\nThe manufacturer developed a Markov model with a 6-year time horizon that compared pemetrexed/cisplatin, gemcitabine/cisplatin, gemcitabine/carboplatin and docetaxel/cisplatin. The efficacy data from the JMDB trial were used for the comparison of pemetrexed/cisplatin with gemcitabine/cisplatin, and the results of the indirect comparison were used for the other comparators. The adverse event states were built into the model as separate mutually exclusive health states. All clinical events were modelled via transition probabilities. Treatment effects considered included overall survival, progression-free survival, response rates, adverse events and HRQoL. All effectiveness data used in the model, apart from HRQoL, were trial-based.\n\nIn the model, patients were given a maximum of four cycles of chemotherapy. A continuation rule stipulated that only patients whose disease had responded to pemetrexed/cisplatin after three cycles continued treatment to a fourth cycle. To reflect treatment discontinuation after the third cycle for patients whose disease did not respond, no further chemotherapy costs were incurred.\n\nA literature review of utility data for patients with NSCLC identified a number of studies, but the manufacturer considered that none were suitable for inclusion. Instead, a study by Nafees et al. (2008) was used. This was commissioned to study second-line treatment of NSCLC by the manufacturer, but was assumed by the manufacturer to apply to first-line treatment. It involved 100\xa0members of the public interviewed with visual analogue scale and standard gamble techniques to elicit societal values on utilities in lung cancer.\n\nThe base-case analysis compared pemetrexed/cisplatin with gemcitabine/cisplatin. In the population with non-squamous NSCLC, the analysis resulted in an incremental cost of £1364 and 0.041 incremental quality adjusted life years (QALYs). The incremental cost-effectiveness ratio (ICER) for pemetrexed/cisplatin compared with gemcitabine/cisplatin was £33,065 per QALY gained without the continuation rule (see 3.8). With the continuation rule the incremental cost fell to £1252 and the incremental QALY remained the same, resulting in an ICER of £25,967 per QALY gained. When subgroups according to histology were analysed using the continuation rule, pemetrexed/cisplatin compared with gemcitabine/cisplatin in the adenocarcinoma subgroup gave an ICER of £18,442 per QALY gained, and large-cell carcinoma gave an ICER of £8,056 per QALY gained.\n\nThe ERG reviewed the evidence submitted for clinical and cost effectiveness. The ERG report concentrated on the exclusion of vinorelbine, the indirect comparison and the suitability of the chosen cost-effectiveness analysis.\n\nThe ERG noted that vinorelbine had been excluded from the analysis even though the marketing data presented by the manufacturer suggested it accounted for 11% of first-line NSCLC treatment, which was greater than the 4% usage of docetaxel. The ERG considered that vinorelbine should have been included in the manufacturer's decision problem to allow a full assessment of pemetrexed against relevant comparators.\n\nThe ERG noted that in the JMDB trial, baseline characteristics were well balanced between treatment arms and between histological subgroups. The ERG noted that the findings from the per-protocol analysis requested from the manufacturer did not differ much from the findings from the intention-to-treat analysis. The ERG considered that this made the JMDB trial results considerably more robust. On request, the manufacturer reported the p values for the test for interaction as p = 0.0024 for squamous NSCLC compared with non-squamous NSCLC, and p = 0.0059 across all other subgroups. This makes it more likely that there were real differences between the histological subgroups.\n\nThe ERG expressed concerns over the trial selection for the indirect comparison. The ERG believed that all the comparators specified in the scope (pemetrexed, docetaxel, gemcitabine, paclitaxel and vinorelbine) should have been included in the indirect comparison analyses. This would have identified five further phase III RCTs for consideration, and improved the subsequent power and validity of the indirect comparison. The ERG also noted that the manufacturer did not assess validity of the included RCTs.\n\nThe ERG also expressed concern over the statistical approach used in the indirect comparison. It noted that the manufacturer's method may have resulted in under- or overestimation of treatment effects, and loss of statistical power. It also noted that the manufacturer's submission suggested that the treatment-arm-level hazard rates were used; the ERG stated that indirect comparisons should be based on a comparison of relative effects rather than a comparison of single arm estimates, as the former maintains randomisation within a trial. The ERG stated that the key assumption of an indirect comparison is that the relative effects are exchangeable across the trial settings, that is, there are no treatment effect modifiers. Within the JMDB trial, histology is an effect modifier, and this should be accounted for in the indirect comparison. The ERG concluded that, because key comparators were excluded from the indirect comparison analysis, and because of the assumptions underlying the statistical approach used, the findings from this analysis should be interpreted with caution.\n\nThe ERG commented on the submitted cost-effectiveness analysis. It noted that the chosen Markov model structure did not seem to be appropriate because it did not replicate the trial data, which was used to calibrate the model, to an acceptable level of accuracy. The ERG commented that this was noticeable when calculating response and survival. It considered that because overall survival and progression-free survival were the primary outcomes in the JMDB trial, these two outcomes should be accurately replicated in the economic model for each of the subgroups for the trial period. It noted that the manufacturer's model appeared to overestimate overall survival in both arms and almost all patient groups. For progression-free survival, the ERG commented that the model tended to underestimate in the first 6\xa0months and to overestimate thereafter. In addition, the ERG noted that some survival estimates suggested an error in the model's logic.\n\nThe ERG commented on the use of response to treatment in the model structure. It is commonly assumed that response leads to a delay in disease progression and therefore to progression-free survival, this becoming the source of survival gain. Following disease progression it is usually assumed that the natural course of the disease will continue. The JMDB trial data suggested that all the reported survival gain occurred after disease progression, with progression-free survival effectively identical between the pemetrexed/cisplatin and gemcitabine/cisplatin arms. The ERG stated that it was not clear whether objective response determined the extent of health gain and whether the survival gain was restricted to patients whose disease has responded to treatment, or to all patients who had treatment. The ERG considered that this had implications for the design of the model; if response doesn't predict progression-free survival or post-progression survival, then its use as a distinct health state is potentially irrelevant, and could generate misleading results.\n\nThe ERG identified other concerns with the cost-effectiveness analysis, including:\n\nAll transition probabilities during the trial period were assumed to arise from constant risk processes (that is, exponential survival distributions), without any justification.\n\nA half-cycle correction appeared to have been disabled for costs and used incorrectly for outcomes.\n\nCumulative costs and outcome effects of patients having more than one adverse event at any given time (for example, within a single hospital admission) were not taken into account. This omission could have led to overestimation of the costs and harms attributable to treatment.\n\nThere may have been an overestimation of mortality because of incorrect use of the febrile neutropenia mortality risk.\n\nThe ERG stated that the evidence submitted by the manufacturer was not sufficiently convincing or robust for it to determine the cost effectiveness of pemetrexed.\n\nDuring the consultation for this appraisal, the manufacturer submitted revised cost-effectiveness estimates for pemetrexed/cisplatin compared with gemcitabine/cisplatin. No other comparators were considered. The primary analysis was a modified version of the previously submitted Markov model, but used Weibull distributions to improve its representation of the outcomes of the JMDB trial. The manufacturer responded to the concerns raised by the Committee concerning the use of response, transition probabilities, half-cycle correction, adverse events and mortality due to febrile neutropenia. It also presented two validation models: a trial-based economic analysis conducted using the individual patient survival outcomes and resource use events from the JMDB clinical trial database, and an economic model used for a submission to the Pharmaceutical Benefits Advisory Committee (PBAC) in Australia. The PBAC model was based on the patient-level data from the clinical trial and used Weibull distributions to extrapolate survival beyond the trial period. The manufacturer stated that validation processes included a 'double-build' process for the trial-based model (in which two researchers independently built and analysed the database to make sure data outputs were consistent), and internal and independent external reviews, for both the modified and clinical trial-based models.\n\nThe manufacturer's base-case ICER, using the modified Markov model calculated for a maximum of four cycles of treatment, was £27,565 for the population included in the licence (those with non-squamous histology) and £22,202 for patients with adenocarcinoma or large-cell carcinoma. For the trial-based analysis, the ICER calculated for a maximum of four cycles of treatment was £31,157 for the population included in the licence and £24,224 for patients with adenocarcinoma or large-cell carcinoma. When the number of cycles was increased to six, as specified in the trial, the ICERs increased to £42,306 and £33,730 for the two groups respectively. In the PBAC model, the ICER for only four cycles of chemotherapy for patients with adenocarcinoma or large-cell carcinoma was £23,157 per QALY gained.\n\nThe ERG commented on the manufacturer's additional analysis. It stated that the cost-effectiveness analyses based on the JMDB trial patient-level data without use of projection techniques were very similar to the previous cost-effectiveness models, and used the same unit cost and state utility parameter values.\n\nHowever, the ERG noted several limitations with the submitted analyses. These included restricting the number of cycles and corresponding costs, with no corresponding alteration in effectiveness. Therefore, only the estimates using six cycles were valid trial-based estimates. The ERG further noted that new utility values were used in the revised model without explanation. The ERG considered that, as all survival benefit observed for pemetrexed in the JMDB trial occurred after disease progression, the correct utility value for use with the incremental survival is that of the 'progressive disease' state from the original Markov model (that is, 0.47), not that of the pre-progression states of 'stable' (0.65) and 'responding' (0.67).\n\nThe ERG noted that the estimates for the cost of chemotherapy did not consider differences in body surface area, or allow for wastage of part-used vials. The ERG suggested that taking these factors into account increased the cost per cycle of pemetrexed/cisplatin chemotherapy by £81.63 and decreased that of gemcitabine/cisplatin by £3.80.\n\nThe ERG noted that the 'in-trial' analysis did not use discounting on either costs or outcomes, despite trial follow-up extending to more than 2 years for some patients. The ERG stated that this was an important omission, because much of the survival gain occurred after the first 12 months and would therefore be likely to be affected by discounting. Drug costs, however, would be incurred early on. The ERG noted that the 'in-trial' analysis used differential costs per patient for terminal care and for best supportive care (BSC). However, these figures were not derived from an analysis of the trial's individual patient data, but were mean results calculated in the manufacturer's Markov model. This created confusion between observation and modelling, which may have distorted the results of the 'in-trial' analysis. The ERG preferred to include terminal care and BSC costs for all patients, but discounted for a period after the recorded survival date for patients censored in the trial.\n\nThe combined ERG amendments to the in-trial analysis, using the utility derived from disease progression (0.47) and up to six cycles of chemotherapy, produced an ICER for the population included in the licence of £60,130, and £48,055 for the adenocarcinoma and large-cell carcinoma subgroup.\n\nThe ERG noted that the manufacturer's modified Markov model addressed a number of the issues identified by the ERG previously. However, it noted that although the Weibull survival models were better than the original exponential models, they were still not adequate. In particular, they were inaccurate for long-term projection. The ERG also noted that patients having more than one adverse event at a time (for example, during one hospital admission) was not addressed, and chemotherapy costs were based on JMDB trial data and were therefore not representative of UK clinical practice. There was also the issue of reducing six cycles to four, and the effects of this on overall efficacy. In addition the ERG identified new errors in the analysis, including the calculation of adverse event costs, and inappropriate response rates used for the whole population.\n\nThe ERG commented that the PBAC health technology assessment submission was well presented and clearly laid out, thereby simplifying the validation. However, because it was based on the same fundamental assumptions as the manufacturer's Markov analysis, it merely demonstrated that similar assumptions resulted in similar cost-effectiveness results when using a different model structure. The ERG concluded that it did not address some of the major issues with the manufacturer's cost-effectiveness analysis that had been identified previously.\n\nThe ERG stated that the time available to review the new evidence submitted by the manufacturer did not allow detailed modifications to be made to the modified Markov model. Instead it used the information contained in the 'in-trial' analysis, together with the additional exploratory survival analysis, to generate modified cost-effectiveness results.\n\nThe ERG noted that an extract of individual patient data from the JMDB trial was included by the manufacturer in the 'in-trial' cost-effectiveness analysis. This was restricted to the population of patients with NSCLC and included only information relating to chemotherapy treatment cycles and overall survival, that is, the timing of death or censoring. No information was provided about response to treatment or the time of confirmed disease progression. This data made it possible for the ERG to consider what was the most appropriate estimate of survival gain and utility gain attributable to pemetrexed within the JMDB trial, and thus whether it was possible to estimate the likely change in patient outcomes when treatment was limited to four cycles instead of the maximum of six cycles used in the trial. The ERG classified patients according to the last cycle in which they received a dose of pemetrexed or gemcitabine. Initial examination of Kaplan-Meier survival charts by the ERG indicated that patients could be classified into three groups that were mainly homogeneous with respect to prognosis: up to two cycles, three to four cycles and five to six cycles of chemotherapy. In the absence of specific information on disease progression or treatment discontinuation, these divisions should reflect the approximate time when patients leave the stable or response states. The ERG considered that this analysis provided a basis for considering the possible effects of limiting treatment duration.\n\nThe results of the ERG's exploratory analysis suggested that for six cycles of chemotherapy, the ICER for pemetrexed/cisplatin compared with gemcitabine/cisplatin was £28,241 per QALY gained for non-squamous patients and £23,598 per QALY gained for adenocarcinoma and large-cell carcinoma patients. When the number of cycles was reduced to four the ICERs were £20,497 and £17,162 per QALY gained respectively.\n\nThe ERG explored two scenarios to account for the potential consequences of reducing the number of chemotherapy cycles. First, if overall survival is related to tumour response, the overall survival gain lost when chemotherapy is stopped sooner can be estimated from the response rate difference (19%). Secondly, if overall survival is related to drug exposure, the overall survival gain lost when chemotherapy is stopped sooner can be estimated as the proportion of treatment cycles given beyond four cycles (32%).\n\nFor four cycles of pemetrexed/cisplatin in the population included in the licence (those with non-squamous histology), the exploratory analyses described in 3.32 led to an ICER of £25,336 for a 19% reduction in the overall survival gain, and £30,142 for a 32% reduction in the overall survival gain. For the treatment of patients with adenocarcinoma and large-cell carcinoma subgroup, the respective ICERs were £21,214 and £25,239.\n\nThe ERG noted that gemcitabine's patent ended this year (2009), and that generic versions are already being marketed. The ERG explored the potential impact of some market price changes, and noted that they adversely affected the cost-effectiveness estimates for pemetrexed/cisplatin.\n\nFull details of all the evidence are in the manufacturer's submission and the ERG report.", 'Consideration of the evidence': "The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of pemetrexed, having considered evidence on the nature of NSCLC and the value placed on the benefits of pemetrexed by people with the condition, those who represent them, and clinical specialists. It also took into account the effective use of NHS resources.\n\n# Clinical effectiveness\n\nThe Committee discussed current UK clinical practice for the treatment of NSCLC. It noted that the manufacturer had limited its analysis to comparisons with gemcitabine/cisplatin, gemcitabine/carboplatin and docetaxel/cisplatin. The Committee heard from clinical specialists that current UK clinical practice was to combine gemcitabine with a platinum drug (usually cisplatin) in the majority of cases. It also heard that there were still some centres that used carboplatin as they could not administer cisplatin because of the hydration required, and possibly because some consider carboplatin to be less toxic.\n\nThe Committee discussed the additional comparator presented by the manufacturer (docetaxel/cisplatin) and the ERG's concern that vinorelbine had been excluded. The Committee heard from clinical specialists that docetaxel and vinorelbine are not widely used in the UK because of their adverse-event profiles, in particular the higher rates of febrile neutropenia compared with those seen with pemetrexed and gemcitabine. However, the Committee heard from clinical specialists that docetaxel requires fewer hospital visits than gemcitabine, and so it is occasionally used in areas where patients have difficulty getting to hospital. The Committee noted market research data presented by the manufacturer that confirmed that gemcitabine was the main treatment regimen used in the UK, with an 85% market share. Vinorelbine was in second place with an 11% market share. The Committee heard from clinical specialists that the 11% market share of vinorelbine could be an overestimate because it could include use in other indications. The Committee concluded that the gemcitabine/cisplatin combination was the principle comparator in UK clinical practice for the first-line treatment of NSCLC.\n\nThe Committee considered the evidence on the clinical effectiveness of pemetrexed/cisplatin compared with gemcitabine/cisplatin. It noted that the JMDB trial was well conducted and considered its results to be robust. The Committee heard from the clinical specialists that the histological subtyping was an important factor in predicting response to pemetrexed. It also heard that the improved overall survival with pemetrexed/cisplatin seen in the JMDB trial in the adenocarcinoma and large-cell carcinoma subgroups has been replicated in other studies. Additionally the Committee noted that pemetrexed had not been proven to be effective in the non-specified histology subgroup. It was mindful that the p value for interaction (see 3.13) supported the hypothesis that the differences between the subgroups was real and not due to chance. The Committee concluded that there is evidence to support a true difference in response to pemetrexed between histological subtypes, although the pathophysiological basis for this is not known.\n\nThe Committee then discussed whether the results of the JMDB trial were generalisable to UK clinical practice, with particular reference to routine identification of histological subtypes and numbers of treatment cycles recommended. It heard from clinical specialists that histological identification of patients with non-squamous disease to determine whether they have adenocarcinoma or large-cell carcinoma was not common practice in the UK. However the Committee was satisfied that there would not be problems with doing this in practice because pathology services across the UK can perform such histological diagnoses.\n\nThe Committee noted that 4 cycles of chemotherapy was considered standard UK clinical practice, whereas the JMDB trial had allowed up to 6, with an average of 4.4 actually being administered. The clinical specialists stated that a reduction in the number of cycles from 4.4 to 4 was unlikely to affect the clinical outcomes of the trial. The Committee concluded that pemetrexed/cisplatin was more clinically effective than gemcitabine/cisplatin in patients with adenocarcinoma and large-cell carcinoma.\n\nThe Committee considered the indirect comparison of pemetrexed/cisplatin with gemcitabine/carboplatin and docetaxel/cisplatin. It noted the manufacturer's exclusion of comparators such as vinorelbine. It considered that even though its use in the UK was low, the omission was inappropriate because it excluded additional information and data from the analysis. The Committee was also mindful of the concerns of the ERG over the methodology used by the manufacturer, and of the fact that the indirect comparisons presented in the manufacturer's submission were potentially flawed because of the exclusion of relevant comparators and the chosen statistical method. However, the Committee noted that the gemcitabine/cisplatin combination was the principle comparator in UK clinical practice for the first-line treatment of NSCLC. It also noted evidence from the clinical specialists and patient expert that suggested that gemcitabine/cisplatin was as effective or more effective than gemcitabine/carboplatin or docetaxel/cisplatin. The Committee concluded that its concerns about the indirect comparison did not prevent it from concluding that pemetrexed/cisplatin is clinically effective in UK clinical practice.\n\nThe Committee heard from the patient expert and clinical specialists that pemetrexed was valued by patients because of its favourable adverse-event profile, in particular the lower incidences of febrile neutropenia and alopecia. In addition, patients preferred pemetrexed's shorter infusion time and the fewer hospital visits needed for treatment compared with gemcitabine. The Committee concluded that the increased survival in the adenocarcinoma and large-cell carcinoma subpopulations and lower toxicity demonstrated in the JMDB trial for pemetrexed/cisplatin was clinically significant when compared with gemcitabine/cisplatin, especially when taking into account the overall low survival rates for NSCLC.\n\n# Cost effectiveness\n\nThe Committee considered the manufacturer's original cost-effectiveness analysis and the ERG's critique. The Committee noted that the original model did not replicate the results of the JMDB trial, especially with respect to the three primary clinical outcomes (overall survival, progression-free survival and response rate). The Committee agreed with the ERG that the model should be able to reproduce the JMDB trial results, because the JMDB trial data are the primary source of clinical data used in the model. The Committee also noted the other problems identified by the ERG and was concerned that the submitted model had not been adequately quality assured. The Committee concluded that on the basis of the evidence presented, the cost effectiveness of pemetrexed/cisplatin had not been proven despite the apparently favourable ICERs in the manufacturer's original submission.\n\nThe Committee subsequently considered the revised analysis submitted by the manufacturer. The Committee considered that reducing the number of cycles to four and therefore diverging from the trial was inappropriate for a trial-based analysis. It also considered that the utility values used for progressive states were not appropriate. The Committee concluded that the ERG's exploratory analysis of the manufacturer's revised analysis produced the most plausible estimates. The Committee noted that the ERG's exploratory analysis resulted in ICERs above £48,000 per QALY gained and therefore suggested that pemetrexed/cisplatin was not cost effective. However, the Committee considered that because this analysis only covered the duration of the trial it was inappropriate to conclude cost ineffectiveness from this, although it provided useful additional validation for the subsequently revised Markov model, and the ERG analyses of that.\n\nThe Committee considered the manufacturer's modified Markov model and ERG comments on it. The Committee was concerned that some issues of face validity identified by the ERG had not been appropriately addressed. The Committee noted that although reducing the average number of cycles from 4.4 to 4 did not affect the conclusion that pemetrexed was clinically effective, setting a maximum of 4\xa0cycles would affect the conclusions of the cost-effectiveness analysis. It considered that the manufacturer should have taken some account of the probable lower effectiveness. The Committee noted the new errors identified by the ERG that suggested the new analysis had not been sufficiently quality assured. The Committee concluded that the submitted modified Markov model was still not suitable for drawing conclusions because of its inability to replicate the trial results accurately and the lack of quality assurance.\n\nThe Committee considered the ERG's exploratory analyses based on the manufacturer's modified Markov model. It was mindful that there were limitations with the data available and that the analyses did not consider the inherent uncertainty in the point estimates through probabilistic sensitivity analysis. The Committee noted that the ERG's estimates of survival were based on individual patient data and that they adequately represented the trial results, in particular the long-term extrapolation. The Committee concluded that the ERG's exploratory analyses were sufficiently robust to allow conclusions to be drawn about the cost effectiveness of pemetrexed/cisplatin.\n\nThe Committee noted that the ICERs estimated by the ERG's exploratory analysis were all under £30,000 per QALY gained regardless of the population examined for six cycles of chemotherapy. The Committee noted that when the number of cycles was reduced to four and the ERG's calculations for reduced effectiveness were included, the ICERs were between £20,000 and £30,000 per QALY gained for non-squamous NSCLC and between £17,000 and £25,000 per QALY gained for adenocarcinoma and large cell carcinoma. The Committee therefore concluded that pemetrexed/cisplatin was a cost-effective use of NHS resources based on the evidence available.\n\nThe Committee acknowledged that generic versions of gemcitabine have recently become available and that the price was currently subject to change. It noted the ERG's view that when including any substantial price reduction for gemcitabine in the model, pemetrexed/cisplatin was no longer cost-effective compared with gemcitabine/cisplatin. However, it also noted that there was no nationally available price for the generic versions, and that local prices were likely to vary considerably. The Committee concluded that, since the published list price for gemcitabine had not changed, the cost-effectiveness analysis on which it had to base its decision was that described in section 4.13. The Committee considered that the guidance for pemetrexed should be reviewed early if there is a substantial change to the nationally available price of gemcitabine in the NHS.\n\n# Conclusion\n\nThe Committee considered that current UK clinical practice was to use up to four cycles of gemcitabine/cisplatin as first line-chemotherapy for the treatment of NSCLC. Consequently the Committee considered that the clinical-effectiveness evidence from the JMDB trial, the clinical specialists and patient expert was sufficient and robust enough to demonstrate the clinical effectiveness of pemetrexed/cisplatin in patients with adenocarcinoma and large-cell carcinoma. The Committee noted that pemetrexed/cisplatin had not been shown to be any more effective than gemcitabine/cisplatin in patients with non-squamous NSCLC with unspecified histology. The Committee considered that the ERG's exploratory analysis had demonstrated that the ICERs for pemetrexed/cisplatin were between £17,000 and £25,000 per QALY for adenocarcinoma or large-cell carcinoma. It therefore recommended pemetrexed as an option for the first-line treatment of patients with adenocarcinoma or large-cell carcinoma. The Committee considered that this guidance should be reviewed early if there is any significant change in the price of generic gemcitabine.", 'Related NICE guidance': '# Published\n\nErlotinib for the treatment of non-small-cell lung cancer.NICE technology appraisal guidance 162 (2008).\n\nBevacizumab for the treatment of non-small-cell lung cancer (terminated appraisal).NICE technology appraisal 148 (2008).\n\nPemetrexed for the treatment of non-small-cell lung cancer.NICE technology appraisal guidance 124 (2007).\n\nLung cancer: the diagnosis and treatment of lung cancer. NICE clinical guideline 24 (2005). [Replaced by NICE clinical guideline 121]\n\nGefitinib for the first-line treatment of locally advanced or metastatic non-small-cell lung cancer. NICE technology appraisal guidance 192 (2010)\n\nErlotinib monotherapy for maintenance treatment of non-small-cell lung cancer. NICE technology appraisal guidance 227 (2011).\n\n# Under development\n\nNICE is developing the following guidance(details available from the NICE website):\n\nCetuximab for the treatment of advanced non-small-cell lung cancer. NICE technology appraisal guidance(publication date to be confirmed).', 'Review of guidance': 'The guidance on this technology was reviewed in January 2012. Details are on the NICE website.\n\nAndrew DillonChief ExecutiveSeptember 2009', 'Changes after publication': 'February 2014: implementation section updated to clarify that pemetrexed is recommended as an option for treating non-small-cell lung cancer. Additional minor maintenance update also carried out.\n\nMarch 2012: minor maintenance', 'About this guidance': 'NICE technology appraisal guidance is about the use of new and existing medicines and treatments in the NHS in England and Wales.\n\nThis guidance was developed using the NICE single technology appraisal process.\n\nWe have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available.\n\nYour responsibility\n\nThis guidance represents the views of NICE and was arrived at after careful consideration of the evidence available. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. However, the guidance does not override the individual responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.\n\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.\n\nCopyright\n\n© National Institute for Health and Clinical Excellence 2009. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.'}	https://www.nice.org.uk/guidance/ta181	Evidence-based recommendations on pemetrexed for untreated non-small-cell lung cancer in adults.
5f6406b693215b0a53244dc44747ff29f6c9cdb8	nice	Sunitinib for the treatment of gastrointestinal stromal tumours	Sunitinib for the treatment of gastrointestinal stromal tumours Evidence-based recommendations on sunitinib (Sutent) for treating gastrointestinal stromal tumours in adults. # Guidance Sunitinib is recommended, within its licensed indication, as a treatment option for people with unresectable and/or metastatic malignant gastrointestinal stromal tumours if: imatinib treatment has failed because of resistance or intolerance, and the drug cost of sunitinib (excluding any related costs) for the first treatment cycle will be met by the manufacturer. The use of sunitinib should be supervised by cancer specialists with experience in treating people with unresectable and/or metastatic malignant gastrointestinal stromal tumours after failure of imatinib treatment because of resistance or intolerance.# The technology Sunitinib (Sutent, Pfizer) is one of a group of closely related tyrosine kinase inhibitors. It inhibits vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF) receptors on cancer cells, vascular endothelial cells and pericytes. This reduces tumour cell proliferation and tumour blood vessel development. Sunitinib has a UK marketing authorisation for the treatment of people with unresectable and/or metastatic malignant gastrointestinal stromal tumour (GIST) after failure of imatinib mesilate treatment due to resistance or intolerance. Sunitinib is contraindicated in people who have hypersensitivity to sunitinib malate or to any of the excipients. The summary of product characteristics (SPC) lists the following conditions that may be associated with sunitinib treatment: cardiovascular events, skin and tissue problems, gastrointestinal events, haemorrhage, hypertension, haematological problems, venous thromboembolic events, pulmonary embolism and hypothyroidism. For full details of side effects and contraindications, see the SPC. Sunitinib is administered orally. The recommended dosage is 50 mg once daily, for 4 consecutive weeks, followed by a 2-week rest period (that is, a complete treatment cycle of 6 weeks). The dose may be adjusted in steps of 12.5 mg according to tolerability (within the dose range 25–75 mg). The price for a pack of 50-mg capsules (28 per pack) is £3138.80 (excluding VAT; 'British national formulary' edition 56). The manufacturer of sunitinib has agreed a patient access scheme with the Department of Health for GIST, in which the first treatment cycle of sunitinib is free to the NHS. The Department of Health considered that this patient access scheme does not constitute an excessive administrative burden on the NHS. Costs of subsequent treatment cycles may vary in different settings because of negotiated procurement discounts.# The manufacturer's submission The Appraisal Committee (appendix A) considered evidence submitted by the manufacturer of sunitinib and a review of this submission by the Evidence Review Group (ERG; appendix B). In the submission, the manufacturer presented evidence on the clinical effectiveness of sunitinib for the treatment of unresectable and/or metastatic malignant GIST that was within the marketing authorisation for sunitinib and in line with the appraisal scope. The main clinical-effectiveness evidence came from one randomised controlled trial (RCT). The RCT, A6181004, compared the effect of sunitinib plus best supportive care (n = 207) with placebo plus best supportive care (n = 105). Best supportive care was defined as symptom control, palliative care without active treatment and monitoring of progression. The trial was conducted in people with a good performance status (Eastern Cooperative Oncology Group status 0 or 1). Approximately 4% of people in the trial had initial imatinib intolerance and approximately 80% had received more than 400 mg of imatinib daily before trial entry. People in the trial were stratified according to: best outcome of prior imatinib treatment (progressive disease within 6 months of starting imatinib treatment or progressive disease after 6 months of starting imatinib treatment or imatinib intolerance) and baseline McGill pain questionnaire score (0 versus 1 or more). The primary outcome in the study was time to tumour progression, which was defined as the time from the first dose of study drug to first documentation of progressive disease. The blinded phase of the RCT was stopped early when the first planned interim analysis demonstrated that the time to tumour progression in people randomised to receive sunitinib was statistically significantly longer than in people randomised to receive placebo. A total of 84% of people randomised to receive placebo plus best supportive care crossed over and received sunitinib plus best supportive care. Median time to tumour progression in the intention-to-treat (ITT) population was 27.3 weeks in the sunitinib arm and 6.4 weeks in the placebo arm (hazard ratio 0.33; 95% confidence interval 0.23 to 0.47, p < 0.0001). The median time to tumour progression for the group that crossed over from placebo to sunitinib was similar to that for the group originally randomised to receive sunitinib. During the blinded phase of the study, more than half of the people in both study arms of the trial were alive. However, the interim ITT analysis showed that overall survival was significantly longer for those who received sunitinib compared with those who received placebo (HR 0.491; 95% CI 0.290 to 0.831, p = 0.007). The ITT analysis of the entire study (that is, blinded plus open-label phase) showed that there was no statistically significant difference in overall survival for people who received sunitinib plus best supportive care (overall survival 73 weeks) compared with people who received placebo plus best supportive care (overall survival 65 weeks) (HR 0.876; 95% CI 0.679 to 1.129, p = 0.306). The manufacturer also presented analyses of overall survival using a rank preserved structural failure time (RPSFT) model. This model was a 'post-hoc' approach taken by the manufacturer to control for the crossover from the placebo arm to the sunitinib arm. The RPSFT method estimated the overall survival of people randomised to receive placebo assuming that they had not crossed over; that is, as if they had remained on placebo for the duration of the trial. This method was therefore based on a comparison of the groups according to the way they were randomised. The RPSFT method proportionally 'shrinks' the estimated amount of additional survival conferred to people who crossed over to receive sunitinib, thereby changing the estimate of the hazard ratio in the ITT analysis used later in the economic analyses. The initial RPSFT analysis suggested a statistically significantly longer overall survival for people who received sunitinib plus best supportive care (overall survival 73 weeks) compared with those who received placebo plus best supportive care (overall survival 39 weeks) (HR 0.505; 95% CI 0.388 to 0.658, p < 0.0001) for the entire study. However, following a recommendation from an independent statistician, the manufacturer revised the 95% confidence interval associated with the hazard ratio derived from the RPSFT approach. The revised RPSFT method did not change the significance, which remained that of the unadjusted ITT analysis (p = 0.306). It did, however, provide a lower estimate of the hazard ratio adjusted for crossover and a revised 95% confidence interval for the hazard ratio which, naturally, included one (that is, unity). The revised 95% confidence interval was 0.262 to 1.134. Quality of life was measured in the RCT using the European quality of life (EuroQoL) health state questionnaire (EQ-5D). More than 75% of people completed the EQ-5D questionnaire at each time point and there were no statistically significant differences reported between the treatment groups. Treatment-related adverse events and serious adverse events were more common in the sunitinib arm than in the placebo arm. A total of 83% of people in the sunitinib arm and 59% of people in the placebo arm experienced treatment-related adverse events of any severity. The manufacturer stated that the adverse events reported were generally of mild to moderate intensity and were easily managed by dose reduction, dose interruption or standard supportive medical treatments. A total of 9% of people randomised to sunitinib and 8% of people randomised to receive placebo discontinued treatment because of adverse events. The manufacturer also provided details of an ongoing, open-label expanded access programme (EAP). This cohort study (A6181036) was set up to allow people with GIST, who might not have access to the drug because of study inclusion criteria or lack of regulatory approval where they live, to receive sunitinib. As of December 2007, 1126 people were enrolled in the EAP and the ITT population comprised 1117 people. People in the EAP were of ECOG performance status 0–4 and 68% of people had received dosages of more than 400 mg of imatinib daily before joining the study. In the EAP, sunitinib treatment was given for as long as there was evidence of disease control according to the investigator. The EAP is scheduled to end in December 2009. At the time of data analysis, 50% of the ITT population were alive. The median time to tumour progression was 41 weeks (95% CI 36 to 47) and the median overall survival was 75 weeks (95% CI 68 to 84). The manufacturer developed a Markov model to assess the cost effectiveness of sunitinib compared with best supportive care in people with unresectable and/or metastatic malignant GIST after failure of imatinib therapy because of resistance or intolerance. The model had three distinct health states: progression free, progressive disease (no active therapy) and death. All people entered the progression-free state of the model, assuming that imatinib therapy had failed. The model had a cycle length of 6 weeks and the time horizon was 6 years; the manufacturer stated that this reflected the maximum life expectancy of the population in the model. No subgroup analyses were conducted by the manufacturer. The model used effectiveness data from the RCT (A6181004) described in paragraph 3.1. For progression-free survival, Weibull curves were fitted to the ITT data from the placebo plus best supportive care and sunitinib plus best supportive care arms independently. For overall survival, Weibull curves were fitted to the ITT data from the sunitinib plus best supportive care arm and to the RPSFT-adjusted data from the placebo plus best supportive care arm independently. In a sensitivity analysis, the manufacturer fitted a Weibull curve to the unadjusted ITT data for overall survival with placebo plus best supportive care. The utility values used in the model were taken from the EQ-5D questionnaire used in the RCT. In the progression-free health state, a utility value of 0.731 was assigned to people receiving sunitinib plus best supportive care and a utility value of 0.781 was assigned to people receiving placebo plus best supportive care. In the progressive disease health state, a utility value of 0.577 was assigned to both arms. The manufacturer did not model the effect of adverse events on utility, and stated that the reduced utility values assigned to the sunitinib plus best supportive care arm would account for disutility from adverse events. Resource use was not measured directly in the RCT, although the drug use and relative dose intensity estimates were derived from the RCT. In the model, the manufacturer assumed a relative dose intensity of 88.6% for sunitinib and cost data were taken from the BNF 56. The manufacturer had agreed a patient access scheme with the Department of Health, in which the first cycle of sunitinib is free to the NHS. With discounting at 3.5% per year, sunitinib compared with best supportive care produced a base-case incremental cost-effectiveness ratio (ICER) of £27,365 per QALY gained. One-way sensitivity analyses demonstrated that the ICER was most sensitive to the source of overall survival data for the best supportive care arm. When the ITT data were used to model the placebo plus best supportive care overall survival curve, the ICER increased to £77,107 per QALY gained. Probabilistic sensitivity analyses suggested that sunitinib had a 50% probability of being cost effective compared with best supportive care at a willingness-to-pay threshold of £30,000 per QALY gained. The ERG stated that the manufacturer's submission was generally of good quality and appropriate to the decision problem. Although the clinical-effectiveness evidence was derived from only one RCT, this RCT was of good quality and demonstrated that sunitinib plus best supportive care significantly improved time to tumour progression compared with placebo plus best supportive care. The ERG stated that the economic model developed by the manufacturer was appropriate for the decision problem and appeared to contain no logical errors or internal inconsistencies. The ERG highlighted the following key areas of concern with the manufacturer's submission: the use of the RPSFT method the uncertainty surrounding the cost-effectiveness estimate provided by the manufacturer the cost of sunitinib for people who continued to receive it after disease progression. The ERG stated that the RPSFT method used by the manufacturer to control for the effects of crossover was uncommon and could not determine whether the method had been applied correctly. The ERG also highlighted a number of errors and omissions in the probabilistic sensitivity analyses. In particular, the ERG stated that the uncertainties in the progression-free and overall survival states were not modelled fully, as only the certainty of fit of the Weibull curves was assessed in sensitivity analyses for these parameters. The ERG also noted that the manufacturer had used standard deviations rather than standard errors for the utility values in the sensitivity analyses. The ERG was concerned, given the wide confidence interval around the estimate for the overall survival hazard ratio using the RPSFT method, that the uncertainty in the base-case ICER was substantial and likely to be higher than that presented by the manufacturer in the probabilistic sensitivity analyses. The ERG also highlighted a number of other, more minor, errors and omissions in the manufacturer's probabilistic sensitivity analyses. The ERG noted that the economic model developed by the manufacturer assumed that sunitinib was only given until disease progression. In the RCT, from which the effectiveness of sunitinib was derived, 54 people (22%) received sunitinib after disease progression. The additional cost of sunitinib for these people, as estimated by the ERG, was £2237. This increased the base-case ICER from £27,400 to £31,800 per QALY gained. When the additional costs of sunitinib were incorporated into the sensitivity analyses that used the ITT data, the ICER increased from £77,100 to £90,500 per QALY gained. The ERG also noted that median progression-free survival in the RCT (and thus the progression-free survival used in the manufacturer's economic model) and the EAP differed markedly. When the ERG increased the median progression-free survival to equal that of the EAP (41 weeks), the ICER increased the base-case from £27,400 to £46,300 per QALY gained. The ERG noted that the ICER increased substantially when the progression-free survival was taken from the EAP. It stated that this was because people who experienced longer progression-free survival received more sunitinib, which increased the acquisition costs. After the first Appraisal Committee meeting, the manufacturer presented updated cost-effectiveness analyses incorporating the sunitinib costs after disease progression, as requested by the Committee. The manufacturer confirmed that in the base-case cost-effectiveness estimate, only sunitinib costs incurred in the progression-free health state were taken into account, but that in the RCT a total of 22% of participants randomised to the sunitinib arm did receive sunitinib after disease progression. The manufacturer highlighted that there was insufficient evidence to know whether people with unresectable and/or metastatic malignant GIST would continue to receive sunitinib after disease progression in clinical practice. The manufacturer accepted the ERG's estimate of the additional sunitinib costs incurred after disease progression, and agreed that including these costs increased the base-case ICER from £27,365 to £31,817 per QALY gained. The manufacturer also presented an updated cost-effectiveness analysis incorporating the sunitinib costs based on the sunitinib treatment duration in the EAP, as requested by the Committee. The manufacturer stated that the main value of the EAP was that it confirmed the safety and efficacy of sunitinib as demonstrated in the RCT. The manufacturer highlighted that the rationale for the difference in treatment duration between the EAP and RCT was unclear, pointing to the following factors: The people in the EAP had not been followed up for as long as the people in the RCT. Tumour measurements in the EAP were performed according to local standards of care, and treatment was continued for as long as there was evidence of disease control, unlike the study protocol for the RCT. The EAP included participants who were ineligible for the RCT.The manufacturer's updated cost-effectiveness estimates incorporating the sunitinib treatment duration and costs from the EAP differed slightly from the ERG and increased the base-case ICER from £27,365 to £47,628 per QALY gained. The manufacturer clarified the RPSFT method used to control for crossover and presented updated cost-effectiveness estimates using censoring to control for crossover, as requested by the Committee. The manufacturer restated that the RPSFT method was appropriate as it preserved the randomisation of the trial. However, as the RPSFT method was based on randomisation, it did not change the level of evidence against the null hypothesis and so the 95% confidence interval around the revised RPSFT hazard ratio was wide. The manufacturer also stated that the methods used had been corroborated by an independent statistical expert. The manufacturer highlighted that because of the high level of crossover, which occurred very early in the trial, and the fact that crossover was informative (that is, participants who did not crossover were likely to be different from those who did crossover), traditional approaches to account for crossover were inappropriate. The manufacturer highlighted that censoring the participants at the point at which they crossed over was unreliable because there were only 15 participants who did not crossover to receive sunitinib. Censoring the participants who crossed over to receive sunitinib resulted in an ICER in which best supportive care dominated sunitinib. An additional analysis incorporating data from the 15 participants who did not crossover to sunitinib resulted in an ICER of £20,618 per QALY gained. The manufacturer also presented updated probabilistic sensitivity analyses on all scenarios; these corrected for the errors and omissions that were identified by the ERG. At willingness-to-pay thresholds of £20,000 and £30,000 per QALY gained, the manufacturer's base-case ICER of £27,365 had a 17% and 57% probability of being cost effective, respectively. Incorporating the costs of sunitinib incurred after disease progression from the RCT resulted in a 7% and 42% probability of it being cost effective at willingness-to-pay thresholds of £20,000 and £30,000 per QALY gained, respectively. All the other updated cost-effectiveness analyses (except the £20,618) had a 0% probability of being cost effective at willingness-to-pay thresholds of £20,000 and £30,000 per QALY gained. The ERG considered the updated analyses and clarification provided by the manufacturer. It agreed that the RPSFT method appeared appropriate. The ERG confirmed that the RPSFT method applied a multiplicative factor to the time spent after crossover rather than to the whole of overall survival. The ERG highlighted that the hazard ratio for overall survival produced using the RPSFT method (0.505) was similar to the hazard ratio for overall survival produced at the interim ITT analyses before crossover had occurred (0.49). It stated that this strengthened the confidence it had in the results derived using the RPSFT method. Additionally, the ERG agreed with the manufacturer that censoring the participants at crossover in this instance was an unreliable method for controlling for crossover. The ERG also noted that the first 4 months of the overall survival curve for people who received best supportive care, who were then censored at the point at which they crossed over, was similar to the RPSFT overall survival curve. The ERG stated that this gave further credibility to the results derived using the RPSFT method because there would have been minimal censoring during the first 4 months. Full details of all the evidence are in the manufacturer's submission and the ERG report.# Consideration of the evidence The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of sunitinib for the treatment of GIST, having considered evidence on the nature of the condition and the value placed on the benefits of sunitinib by people with unresectable and/or metastatic malignant GIST, those who represent them, and clinical specialists. It was also mindful of the need to take account of the effective use of NHS resources. The Committee first considered the clinical-effectiveness data presented by the manufacturer. It noted that there were statistically significant improvements in time to tumour progression and progression-free survival for people taking sunitinib plus best supportive care compared with people taking placebo plus best supportive care. The Committee noted that the estimates of time to tumour progression and progression-free survival were obtained at the first interim analysis and so were not confounded by any crossover. The Committee heard from clinical specialists and patient experts that the observed benefits in time to tumour progression and progression-free survival were clinically meaningful. The Committee was aware that, after the interim analysis, people were offered open-label sunitinib and that the ITT analysis was confounded by the crossover. The Committee accepted that the benefits seen in time to tumour progression and progression-free survival were such that a substantial improvement in overall survival with sunitinib treatment was probable. The Committee therefore concluded that sunitinib was a clinically effective treatment for unresectable and/or metastatic malignant GIST which is resistant or intolerant to imatinib. Additionally, the Committee understood that the use of sunitinib should be supervised by cancer specialists with experience in treating people with unresectable and/or metastatic malignant gastrointestinal stromal tumours after failure of imatinib treatment because of resistance or intolerance. The Committee then discussed the cost-effectiveness estimate of sunitinib compared with best supportive care submitted by the manufacturer. The Committee considered the ERG comments that the model structure was appropriate for the decision problem. It also noted the concern raised by the ERG that the utility data supplied by the manufacturer in clarification could not be reconciled with data originally submitted. However, the Committee agreed that the cost-effectiveness estimate was relatively insensitive to variations in the utility values and therefore the utility values used in the base case were appropriate. The Committee discussed the best supportive care effectiveness data that were used in the economic model. It agreed that the high level of crossover in the RCT confounded the ITT data for the best supportive care arm. The Committee therefore agreed that it was appropriate to adjust the best supportive care effectiveness data for the crossover that had occurred. The Committee considered that as censoring of the participants at the point at which they crossed over was based on very early data, the results would be unreliable. The Committee discussed the RPSFT method used by the manufacturer and the clarification provided after the first Appraisal Committee meeting and agreed that it was an acceptable approach. The Committee then discussed the best supportive care costs that were included in the economic model. The Committee noted that the base-case estimate did not include imatinib as part of best supportive care. The Committee heard from clinical specialists that in practice it may be possible that a person would benefit from imatinib as part of best supportive care because there may be newly formed tumour cells or metastases that could respond to further imatinib therapy. However, the Committee was aware that in the RCT, from which the effectiveness data were derived, no further imatinib therapy was given. The Committee therefore concluded that it was appropriate not to include imatinib as part of best supportive care and that the best supportive care costs in the base case were appropriate. The Committee next discussed the source of the sunitinib effectiveness data and costs. The Committee noted that the median progression-free survival in the sunitinib arm of the RCT was shorter than that of the EAP. The Committee acknowledged the manufacturer's response that the EAP results should be viewed principally as confirmation of the safety and efficacy of sunitinib. The Committee agreed that the source of the sunitinib effectiveness data and costs should, if possible, be consistent with the effectiveness data and concluded that the sunitinib effectiveness data and costs should come from the RCT. The Committee then considered the difference between sunitinib costs that were included in the economic model and those that could be inferred from the RCT. The Committee noted that 22% of people assigned to sunitinib continued to receive it after disease progression. The costs of this continued treatment were not included in the original economic model, which assumed sunitinib was given only until disease progression. The Committee acknowledged that the effectiveness data came from the RCT and that it was possible that people who received sunitinib after disease progression could have experienced additional benefits. It also heard from clinical specialists that, in practice, sunitinib could be given after disease progression because it was possible that some of the tumour might still respond to sunitinib. Also, many people might experience 'tumour flare' if sunitinib treatment was completely withdrawn. Therefore the Committee agreed that it was important to incorporate the costs of sunitinib given after disease progression, as in the RCT, into the cost-effectiveness estimate. It therefore concluded that the most plausible ICER for sunitinib compared with best supportive care was £31,800 per QALY gained. The Committee next discussed the uncertainty surrounding the cost-effectiveness estimates. The Committee acknowledged the revised probabilistic sensitivity analysis presented by the manufacturer after the first Committee meeting. The Committee noted that at a willingness-to-pay threshold of £30,000 per QALY gained, then the most plausible ICER (£31,800) had around 42% probability of being cost effective. The Committee considered supplementary advice from NICE that should be taken into account when appraising treatments that may extend the life of patients with a short life expectancy and that are licensed for indications that affect small numbers of people with incurable illnesses. For this advice to be applied, all the following criteria must be met: The treatment is indicated for patients with a short life expectancy, normally less than 24 months. There is sufficient evidence to indicate that the treatment offers an extension to life, normally of at least an additional 3 months, compared with current NHS treatment. No alternative treatment with comparable benefits is available through the NHS. The treatment is licensed or otherwise indicated for small patient populations.In addition, when taking these criteria into account, the Committee must be persuaded that the estimates of the extension to life are robust and that the assumptions used in the reference case economic modelling are plausible, objective and robust. The Committee then discussed whether sunitinib for unresectable and/or metastatic malignant GIST, given after intolerance or resistance to imatinib, fulfilled the criteria for consideration as a life-extending, end-of-life treatment. It was aware that in England and Wales the total number of people concerned was between 90 and 150, which clearly did not materially influence the numbers of people who might be eligible for sunitinib treatment across all indications. The Committee noted from the clinical trial that the life expectancy for unresectable and/or metastatic malignant GIST, following intolerance or resistance to imatinib, with best supportive care alone was unlikely to be greater than 24 months and was potentially as low as 9 months. The Committee also noted that the evidence from the RPSFT analysis of the trial suggested that sunitinib increased survival by more than 3 months compared with best supportive care. It was further persuaded that sunitinib provided a marked change in the treatment of unresectable and/or metastatic malignant GIST that is intolerant or resistant to imatinib. In addition, the Committee noted the comments from patient experts and clinical specialists highlighting the important benefits of sunitinib. In summary, the Committee was satisfied that sunitinib met the criteria for being a life-extending, end-of-life treatment, and that the evidence presented for this consideration was sufficiently robust. The Committee then considered the most plausible cost-effectiveness estimate of £31,800 per QALY gained in light of the appraisal of a life-extending, end-of-life treatment, although this would probably be somewhat higher if the treatment entry criteria widened beyond ECOG performance status 0–1. It considered the impact of giving a greater weight to QALYs achieved in the later stages of terminal diseases, using the assumption that the extended survival period is experienced at the full quality of life anticipated for a healthy person of the same age. The Committee also considered the magnitude of additional weight that would need to be assigned to the original QALY benefits in this patient group for the cost effectiveness of the drug to fall within the current threshold range. The Committee concluded that the QALY weighting needed would be acceptable even accommodating the small minority of patients with poorer performance status than were entered (before crossover) into the pivotal trial. The Committee concluded that sunitinib as a treatment for unresectable and/or metastatic GIST that is resistant or intolerant to imatinib could be recommended as a cost-effective use of NHS resources. In summary, the Committee concluded that sunitinib could be recommended, within its licensed indication, as a treatment option for people with unresectable and/or metastatic malignant GIST after failure of imatinib treatment because of resistance or intolerance. Additionally, the Committee concluded that the use of sunitinib should be supervised by cancer specialists with experience in treating people with unresectable and/or metastatic malignant gastrointestinal stromal tumours after failure of imatinib treatment because of resistance or intolerance.# Recommendations for further research A trial comparing 37.5 mg sunitinib with 800 mg imatinib is currently recruiting participants. The Committee considered that rigorous data collection is needed on the life-extending benefits of sunitinib.# Related NICE guidance Imatinib for the treatment of unresectable and/or metastatic gastro-intestinal stromal tumours. NICE technology appraisal guidance 86 (2004).# Review of guidance The review date for a technology appraisal refers to the month and year in which the Guidance Executive will consider whether the technology should be reviewed. This decision will be taken in the light of information gathered by the Institute, and in consultation with consultees and commentators. The guidance on this technology was considered for review in January 2012. For details see the NICE website. Andrew DillonChief ExecutiveSeptember 2009# Changes after publication February 2014: implementation section updated to clarify that sunitinib is recommended as an option for treating gastrointestinal stromal tumours. Additional minor maintenance update also carried out. March 2012: minor maintenance# About this guidance NICE technology appraisal guidance is about the use of new and existing medicines and treatments in the NHS in England and Wales. This guidance was developed using the NICE single technology appraisal process. We have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available. Your responsibility This guidance represents the views of NICE and was arrived at after careful consideration of the evidence available. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. However, the guidance does not override the individual responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or guardian or carer. Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties. Copyright © National Institute for Health and Clinical Excellence 2009. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.	{'Guidance': 'Sunitinib is recommended, within its licensed indication, as a treatment option for people with unresectable and/or metastatic malignant gastrointestinal stromal tumours if:\n\nimatinib treatment has failed because of resistance or intolerance, and\n\nthe drug cost of sunitinib (excluding any related costs) for the first treatment cycle will be met by the manufacturer.\n\nThe use of sunitinib should be supervised by cancer specialists with experience in treating people with unresectable and/or metastatic malignant gastrointestinal stromal tumours after failure of imatinib treatment because of resistance or intolerance.', 'The technology ': "Sunitinib (Sutent, Pfizer) is one of a group of closely related tyrosine kinase inhibitors. It inhibits vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF) receptors on cancer cells, vascular endothelial cells and pericytes. This reduces tumour cell proliferation and tumour blood vessel development. Sunitinib has a UK marketing authorisation for the treatment of people with unresectable and/or metastatic malignant gastrointestinal stromal tumour (GIST) after failure of imatinib mesilate treatment due to resistance or intolerance.\n\nSunitinib is contraindicated in people who have hypersensitivity to sunitinib malate or to any of the excipients. The summary of product characteristics (SPC) lists the following conditions that may be associated with sunitinib treatment: cardiovascular events, skin and tissue problems, gastrointestinal events, haemorrhage, hypertension, haematological problems, venous thromboembolic events, pulmonary embolism and hypothyroidism. For full details of side effects and contraindications, see the SPC.\n\nSunitinib is administered orally. The recommended dosage is 50\xa0mg once daily, for 4 consecutive weeks, followed by a 2-week rest period (that is, a complete treatment cycle of 6\xa0weeks). The dose may be adjusted in steps of 12.5\xa0mg according to tolerability (within the dose range 25–75\xa0mg). The price for a pack of 50-mg capsules (28 per pack) is £3138.80 (excluding VAT; 'British national formulary' [BNF] edition 56). The manufacturer of sunitinib has agreed a patient access scheme with the Department of Health for GIST, in which the first treatment cycle of sunitinib is free to the NHS. The Department of Health considered that this patient access scheme does not constitute an excessive administrative burden on the NHS. Costs of subsequent treatment cycles may vary in different settings because of negotiated procurement discounts.", "The manufacturer's submission": "The Appraisal Committee (appendix A) considered evidence submitted by the manufacturer of sunitinib and a review of this submission by the Evidence Review Group (ERG; appendix B).\n\nIn the submission, the manufacturer presented evidence on the clinical effectiveness of sunitinib for the treatment of unresectable and/or metastatic malignant GIST that was within the marketing authorisation for sunitinib and in line with the appraisal scope. The main clinical-effectiveness evidence came from one randomised controlled trial (RCT). The RCT, A6181004, compared the effect of sunitinib plus best supportive care (n\xa0=\xa0207) with placebo plus best supportive care (n\xa0=\xa0105). Best supportive care was defined as symptom control, palliative care without active treatment and monitoring of progression. The trial was conducted in people with a good performance status (Eastern Cooperative Oncology Group [ECOG] status 0 or 1). Approximately 4% of people in the trial had initial imatinib intolerance and approximately 80% had received more than 400\xa0mg of imatinib daily before trial entry. People in the trial were stratified according to:\n\nbest outcome of prior imatinib treatment (progressive disease within 6\xa0months of starting imatinib treatment [primary resistance] or progressive disease after 6\xa0months of starting imatinib treatment [secondary resistance] or imatinib intolerance) and\n\nbaseline McGill pain questionnaire score (0 versus 1 or more).\n\nThe primary outcome in the study was time to tumour progression, which was defined as the time from the first dose of study drug to first documentation of progressive disease. The blinded phase of the RCT was stopped early when the first planned interim analysis demonstrated that the time to tumour progression in people randomised to receive sunitinib was statistically significantly longer than in people randomised to receive placebo. A total of 84% of people randomised to receive placebo plus best supportive care crossed over and received sunitinib plus best supportive care. Median time to tumour progression in the intention-to-treat (ITT) population was 27.3\xa0weeks in the sunitinib arm and 6.4\xa0weeks in the placebo arm (hazard ratio [HR] 0.33; 95% confidence interval [CI] 0.23 to 0.47, p\xa0<\xa00.0001). The median time to tumour progression for the group that crossed over from placebo to sunitinib was similar to that for the group originally randomised to receive sunitinib.\n\nDuring the blinded phase of the study, more than half of the people in both study arms of the trial were alive. However, the interim ITT analysis showed that overall survival was significantly longer for those who received sunitinib compared with those who received placebo (HR\xa00.491; 95% CI 0.290 to 0.831, p\xa0=\xa00.007). The ITT analysis of the entire study (that is, blinded plus open-label phase) showed that there was no statistically significant difference in overall survival for people who received sunitinib plus best supportive care (overall survival 73\xa0weeks) compared with people who received placebo plus best supportive care (overall survival 65\xa0weeks) (HR\xa00.876; 95% CI 0.679 to 1.129, p\xa0=\xa00.306).\n\nThe manufacturer also presented analyses of overall survival using a rank preserved structural failure time (RPSFT) model. This model was a 'post-hoc' approach taken by the manufacturer to control for the crossover from the placebo arm to the sunitinib arm. The RPSFT method estimated the overall survival of people randomised to receive placebo assuming that they had not crossed over; that is, as if they had remained on placebo for the duration of the trial. This method was therefore based on a comparison of the groups according to the way they were randomised. The RPSFT method proportionally 'shrinks' the estimated amount of additional survival conferred to people who crossed over to receive sunitinib, thereby changing the estimate of the hazard ratio in the ITT analysis used later in the economic analyses.\n\nThe initial RPSFT analysis suggested a statistically significantly longer overall survival for people who received sunitinib plus best supportive care (overall survival 73\xa0weeks) compared with those who received placebo plus best supportive care (overall survival 39\xa0weeks) (HR 0.505; 95%\xa0CI 0.388 to 0.658, p\xa0<\xa00.0001) for the entire study. However, following a recommendation from an independent statistician, the manufacturer revised the 95% confidence interval associated with the hazard ratio derived from the RPSFT approach. The revised RPSFT method did not change the significance, which remained that of the unadjusted ITT analysis (p = 0.306). It did, however, provide a lower estimate of the hazard ratio adjusted for crossover and a revised 95% confidence interval for the hazard ratio which, naturally, included one (that is, unity). The revised 95% confidence interval was 0.262 to 1.134.\n\nQuality of life was measured in the RCT using the European quality of life (EuroQoL) health state questionnaire (EQ-5D). More than 75% of people completed the EQ-5D questionnaire at each time point and there were no statistically significant differences reported between the treatment groups. Treatment-related adverse events and serious adverse events were more common in the sunitinib arm than in the placebo arm. A total of 83% of people in the sunitinib arm and 59% of people in the placebo arm experienced treatment-related adverse events of any severity. The manufacturer stated that the adverse events reported were generally of mild to moderate intensity and were easily managed by dose reduction, dose interruption or standard supportive medical treatments. A total of 9% of people randomised to sunitinib and 8% of people randomised to receive placebo discontinued treatment because of adverse events.\n\nThe manufacturer also provided details of an ongoing, open-label expanded access programme (EAP). This cohort study (A6181036) was set up to allow people with GIST, who might not have access to the drug because of study inclusion criteria or lack of regulatory approval where they live, to receive sunitinib. As of December 2007, 1126 people were enrolled in the EAP and the ITT population comprised 1117 people. People in the EAP were of ECOG performance status 0–4 and 68% of people had received dosages of more than 400\xa0mg of imatinib daily before joining the study. In the EAP, sunitinib treatment was given for as long as there was evidence of disease control according to the investigator. The EAP is scheduled to end in December 2009. At the time of data analysis, 50% of the ITT population were alive. The median time to tumour progression was 41\xa0weeks (95% CI 36 to 47) and the median overall survival was 75\xa0weeks (95% CI 68 to 84).\n\nThe manufacturer developed a Markov model to assess the cost effectiveness of sunitinib compared with best supportive care in people with unresectable and/or metastatic malignant GIST after failure of imatinib therapy because of resistance or intolerance. The model had three distinct health states: progression free, progressive disease (no active therapy) and death. All people entered the progression-free state of the model, assuming that imatinib therapy had failed. The model had a cycle length of 6\xa0weeks and the time horizon was 6\xa0years; the manufacturer stated that this reflected the maximum life expectancy of the population in the model. No subgroup analyses were conducted by the manufacturer.\n\nThe model used effectiveness data from the RCT (A6181004) described in paragraph 3.1. For progression-free survival, Weibull curves were fitted to the ITT data from the placebo plus best supportive care and sunitinib plus best supportive care arms independently. For overall survival, Weibull curves were fitted to the ITT data from the sunitinib plus best supportive care arm and to the RPSFT-adjusted data from the placebo plus best supportive care arm independently. In a sensitivity analysis, the manufacturer fitted a Weibull curve to the unadjusted ITT data for overall survival with placebo plus best supportive care.\n\nThe utility values used in the model were taken from the EQ-5D questionnaire used in the RCT. In the progression-free health state, a utility value of 0.731 was assigned to people receiving sunitinib plus best supportive care and a utility value of 0.781 was assigned to people receiving placebo plus best supportive care. In the progressive disease health state, a utility value of 0.577 was assigned to both arms. The manufacturer did not model the effect of adverse events on utility, and stated that the reduced utility values assigned to the sunitinib plus best supportive care arm would account for disutility from adverse events.\n\nResource use was not measured directly in the RCT, although the drug use and relative dose intensity estimates were derived from the RCT. In the model, the manufacturer assumed a relative dose intensity of 88.6% for sunitinib and cost data were taken from the BNF\xa056. The manufacturer had agreed a patient access scheme with the Department of Health, in which the first cycle of sunitinib is free to the NHS.\n\nWith discounting at 3.5% per year, sunitinib compared with best supportive care produced a base-case incremental cost-effectiveness ratio (ICER) of £27,365 per QALY gained. One-way sensitivity analyses demonstrated that the ICER was most sensitive to the source of overall survival data for the best supportive care arm. When the ITT data were used to model the placebo plus best supportive care overall survival curve, the ICER increased to £77,107 per QALY gained. Probabilistic sensitivity analyses suggested that sunitinib had a 50% probability of being cost effective compared with best supportive care at a willingness-to-pay threshold of £30,000 per QALY gained.\n\nThe ERG stated that the manufacturer's submission was generally of good quality and appropriate to the decision problem. Although the clinical-effectiveness evidence was derived from only one RCT, this RCT was of good quality and demonstrated that sunitinib plus best supportive care significantly improved time to tumour progression compared with placebo plus best supportive care. The ERG stated that the economic model developed by the manufacturer was appropriate for the decision problem and appeared to contain no logical errors or internal inconsistencies.\n\nThe ERG highlighted the following key areas of concern with the manufacturer's submission:\n\nthe use of the RPSFT method\n\nthe uncertainty surrounding the cost-effectiveness estimate provided by the manufacturer\n\nthe cost of sunitinib for people who continued to receive it after disease progression.\n\nThe ERG stated that the RPSFT method used by the manufacturer to control for the effects of crossover was uncommon and could not determine whether the method had been applied correctly. The ERG also highlighted a number of errors and omissions in the probabilistic sensitivity analyses. In particular, the ERG stated that the uncertainties in the progression-free and overall survival states were not modelled fully, as only the certainty of fit of the Weibull curves was assessed in sensitivity analyses for these parameters. The ERG also noted that the manufacturer had used standard deviations rather than standard errors for the utility values in the sensitivity analyses. The ERG was concerned, given the wide confidence interval around the estimate for the overall survival hazard ratio using the RPSFT method, that the uncertainty in the base-case ICER was substantial and likely to be higher than that presented by the manufacturer in the probabilistic sensitivity analyses. The ERG also highlighted a number of other, more minor, errors and omissions in the manufacturer's probabilistic sensitivity analyses.\n\nThe ERG noted that the economic model developed by the manufacturer assumed that sunitinib was only given until disease progression. In the RCT, from which the effectiveness of sunitinib was derived, 54 people (22%) received sunitinib after disease progression. The additional cost of sunitinib for these people, as estimated by the ERG, was £2237. This increased the base-case ICER from £27,400 to £31,800 per QALY gained. When the additional costs of sunitinib were incorporated into the sensitivity analyses that used the ITT data, the ICER increased from £77,100 to £90,500 per QALY gained. The ERG also noted that median progression-free survival in the RCT (and thus the progression-free survival used in the manufacturer's economic model) and the EAP differed markedly. When the ERG increased the median progression-free survival to equal that of the EAP (41\xa0weeks), the ICER increased the base-case from £27,400 to £46,300 per QALY gained. The ERG noted that the ICER increased substantially when the progression-free survival was taken from the EAP. It stated that this was because people who experienced longer progression-free survival received more sunitinib, which increased the acquisition costs.\n\nAfter the first Appraisal Committee meeting, the manufacturer presented updated cost-effectiveness analyses incorporating the sunitinib costs after disease progression, as requested by the Committee. The manufacturer confirmed that in the base-case cost-effectiveness estimate, only sunitinib costs incurred in the progression-free health state were taken into account, but that in the RCT a total of 22% of participants randomised to the sunitinib arm did receive sunitinib after disease progression. The manufacturer highlighted that there was insufficient evidence to know whether people with unresectable and/or metastatic malignant GIST would continue to receive sunitinib after disease progression in clinical practice. The manufacturer accepted the ERG's estimate of the additional sunitinib costs incurred after disease progression, and agreed that including these costs increased the base-case ICER from £27,365 to £31,817 per QALY gained.\n\nThe manufacturer also presented an updated cost-effectiveness analysis incorporating the sunitinib costs based on the sunitinib treatment duration in the EAP, as requested by the Committee. The manufacturer stated that the main value of the EAP was that it confirmed the safety and efficacy of sunitinib as demonstrated in the RCT. The manufacturer highlighted that the rationale for the difference in treatment duration between the EAP and RCT was unclear, pointing to the following factors:\n\nThe people in the EAP had not been followed up for as long as the people in the RCT.\n\nTumour measurements in the EAP were performed according to local standards of care, and treatment was continued for as long as there was evidence of disease control, unlike the study protocol for the RCT.\n\nThe EAP included participants who were ineligible for the RCT.The manufacturer's updated cost-effectiveness estimates incorporating the sunitinib treatment duration and costs from the EAP differed slightly from the ERG and increased the base-case ICER from £27,365 to £47,628 per QALY gained.\n\nThe manufacturer clarified the RPSFT method used to control for crossover and presented updated cost-effectiveness estimates using censoring to control for crossover, as requested by the Committee. The manufacturer restated that the RPSFT method was appropriate as it preserved the randomisation of the trial. However, as the RPSFT method was based on randomisation, it did not change the level of evidence against the null hypothesis and so the 95% confidence interval around the revised RPSFT hazard ratio was wide. The manufacturer also stated that the methods used had been corroborated by an independent statistical expert. The manufacturer highlighted that because of the high level of crossover, which occurred very early in the trial, and the fact that crossover was informative (that is, participants who did not crossover were likely to be different from those who did crossover), traditional approaches to account for crossover were inappropriate. The manufacturer highlighted that censoring the participants at the point at which they crossed over was unreliable because there were only 15 participants who did not crossover to receive sunitinib. Censoring the participants who crossed over to receive sunitinib resulted in an ICER in which best supportive care dominated sunitinib. An additional analysis incorporating data from the 15\xa0participants who did not crossover to sunitinib resulted in an ICER of £20,618 per QALY gained.\n\nThe manufacturer also presented updated probabilistic sensitivity analyses on all scenarios; these corrected for the errors and omissions that were identified by the ERG. At willingness-to-pay thresholds of £20,000 and £30,000 per QALY gained, the manufacturer's base-case ICER of £27,365 had a 17% and 57% probability of being cost effective, respectively. Incorporating the costs of sunitinib incurred after disease progression from the RCT resulted in a 7% and 42% probability of it being cost effective at willingness-to-pay thresholds of £20,000 and £30,000 per QALY gained, respectively. All the other updated cost-effectiveness analyses (except the £20,618) had a 0% probability of being cost effective at willingness-to-pay thresholds of £20,000 and £30,000 per QALY gained.\n\nThe ERG considered the updated analyses and clarification provided by the manufacturer. It agreed that the RPSFT method appeared appropriate. The ERG confirmed that the RPSFT method applied a multiplicative factor to the time spent after crossover rather than to the whole of overall survival. The ERG highlighted that the hazard ratio for overall survival produced using the RPSFT method (0.505) was similar to the hazard ratio for overall survival produced at the interim ITT analyses before crossover had occurred (0.49). It stated that this strengthened the confidence it had in the results derived using the RPSFT method. Additionally, the ERG agreed with the manufacturer that censoring the participants at crossover in this instance was an unreliable method for controlling for crossover. The ERG also noted that the first 4\xa0months of the overall survival curve for people who received best supportive care, who were then censored at the point at which they crossed over, was similar to the RPSFT overall survival curve. The ERG stated that this gave further credibility to the results derived using the RPSFT method because there would have been minimal censoring during the first 4 months.\n\nFull details of all the evidence are in the manufacturer's submission and the ERG report.", 'Consideration of the evidence': "The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of sunitinib for the treatment of GIST, having considered evidence on the nature of the condition and the value placed on the benefits of sunitinib by people with unresectable and/or metastatic malignant GIST, those who represent them, and clinical specialists. It was also mindful of the need to take account of the effective use of NHS resources.\n\nThe Committee first considered the clinical-effectiveness data presented by the manufacturer. It noted that there were statistically significant improvements in time to tumour progression and progression-free survival for people taking sunitinib plus best supportive care compared with people taking placebo plus best supportive care. The Committee noted that the estimates of time to tumour progression and progression-free survival were obtained at the first interim analysis and so were not confounded by any crossover. The Committee heard from clinical specialists and patient experts that the observed benefits in time to tumour progression and progression-free survival were clinically meaningful. The Committee was aware that, after the interim analysis, people were offered open-label sunitinib and that the ITT analysis was confounded by the crossover. The Committee accepted that the benefits seen in time to tumour progression and progression-free survival were such that a substantial improvement in overall survival with sunitinib treatment was probable. The Committee therefore concluded that sunitinib was a clinically effective treatment for unresectable and/or metastatic malignant GIST which is resistant or intolerant to imatinib. Additionally, the Committee understood that the use of sunitinib should be supervised by cancer specialists with experience in treating people with unresectable and/or metastatic malignant gastrointestinal stromal tumours after failure of imatinib treatment because of resistance or intolerance.\n\nThe Committee then discussed the cost-effectiveness estimate of sunitinib compared with best supportive care submitted by the manufacturer. The Committee considered the ERG comments that the model structure was appropriate for the decision problem. It also noted the concern raised by the ERG that the utility data supplied by the manufacturer in clarification could not be reconciled with data originally submitted. However, the Committee agreed that the cost-effectiveness estimate was relatively insensitive to variations in the utility values and therefore the utility values used in the base case were appropriate.\n\nThe Committee discussed the best supportive care effectiveness data that were used in the economic model. It agreed that the high level of crossover in the RCT confounded the ITT data for the best supportive care arm. The Committee therefore agreed that it was appropriate to adjust the best supportive care effectiveness data for the crossover that had occurred. The Committee considered that as censoring of the participants at the point at which they crossed over was based on very early data, the results would be unreliable. The Committee discussed the RPSFT method used by the manufacturer and the clarification provided after the first Appraisal Committee meeting and agreed that it was an acceptable approach. The Committee then discussed the best supportive care costs that were included in the economic model. The Committee noted that the base-case estimate did not include imatinib as part of best supportive care. The Committee heard from clinical specialists that in practice it may be possible that a person would benefit from imatinib as part of best supportive care because there may be newly formed tumour cells or metastases that could respond to further imatinib therapy. However, the Committee was aware that in the RCT, from which the effectiveness data were derived, no further imatinib therapy was given. The Committee therefore concluded that it was appropriate not to include imatinib as part of best supportive care and that the best supportive care costs in the base case were appropriate.\n\nThe Committee next discussed the source of the sunitinib effectiveness data and costs. The Committee noted that the median progression-free survival in the sunitinib arm of the RCT was shorter than that of the EAP. The Committee acknowledged the manufacturer's response that the EAP results should be viewed principally as confirmation of the safety and efficacy of sunitinib. The Committee agreed that the source of the sunitinib effectiveness data and costs should, if possible, be consistent with the effectiveness data and concluded that the sunitinib effectiveness data and costs should come from the RCT.\n\nThe Committee then considered the difference between sunitinib costs that were included in the economic model and those that could be inferred from the RCT. The Committee noted that 22% of people assigned to sunitinib continued to receive it after disease progression. The costs of this continued treatment were not included in the original economic model, which assumed sunitinib was given only until disease progression. The Committee acknowledged that the effectiveness data came from the RCT and that it was possible that people who received sunitinib after disease progression could have experienced additional benefits. It also heard from clinical specialists that, in practice, sunitinib could be given after disease progression because it was possible that some of the tumour might still respond to sunitinib. Also, many people might experience 'tumour flare' if sunitinib treatment was completely withdrawn. Therefore the Committee agreed that it was important to incorporate the costs of sunitinib given after disease progression, as in the RCT, into the cost-effectiveness estimate. It therefore concluded that the most plausible ICER for sunitinib compared with best supportive care was £31,800 per QALY gained.\n\nThe Committee next discussed the uncertainty surrounding the cost-effectiveness estimates. The Committee acknowledged the revised probabilistic sensitivity analysis presented by the manufacturer after the first Committee meeting. The Committee noted that at a willingness-to-pay threshold of £30,000 per QALY gained, then the most plausible ICER (£31,800) had around 42% probability of being cost effective.\n\nThe Committee considered supplementary advice from NICE that should be taken into account when appraising treatments that may extend the life of patients with a short life expectancy and that are licensed for indications that affect small numbers of people with incurable illnesses. For this advice to be applied, all the following criteria must be met:\n\nThe treatment is indicated for patients with a short life expectancy, normally less than 24 months.\n\nThere is sufficient evidence to indicate that the treatment offers an extension to life, normally of at least an additional 3\xa0months, compared with current NHS treatment.\n\nNo alternative treatment with comparable benefits is available through the NHS.\n\nThe treatment is licensed or otherwise indicated for small patient populations.In addition, when taking these criteria into account, the Committee must be persuaded that the estimates of the extension to life are robust and that the assumptions used in the reference case economic modelling are plausible, objective and robust.\n\nThe Committee then discussed whether sunitinib for unresectable and/or metastatic malignant GIST, given after intolerance or resistance to imatinib, fulfilled the criteria for consideration as a life-extending, end-of-life treatment. It was aware that in England and Wales the total number of people concerned was between 90 and 150, which clearly did not materially influence the numbers of people who might be eligible for sunitinib treatment across all indications. The Committee noted from the clinical trial that the life expectancy for unresectable and/or metastatic malignant GIST, following intolerance or resistance to imatinib, with best supportive care alone was unlikely to be greater than 24\xa0months and was potentially as low as 9\xa0months. The Committee also noted that the evidence from the RPSFT analysis of the trial suggested that sunitinib increased survival by more than 3\xa0months compared with best supportive care. It was further persuaded that sunitinib provided a marked change in the treatment of unresectable and/or metastatic malignant GIST that is intolerant or resistant to imatinib. In addition, the Committee noted the comments from patient experts and clinical specialists highlighting the important benefits of sunitinib. In summary, the Committee was satisfied that sunitinib met the criteria for being a life-extending, end-of-life treatment, and that the evidence presented for this consideration was sufficiently robust.\n\nThe Committee then considered the most plausible cost-effectiveness estimate of £31,800 per QALY gained in light of the appraisal of a life-extending, end-of-life treatment, although this would probably be somewhat higher if the treatment entry criteria widened beyond ECOG performance status 0–1. It considered the impact of giving a greater weight to QALYs achieved in the later stages of terminal diseases, using the assumption that the extended survival period is experienced at the full quality of life anticipated for a healthy person of the same age. The Committee also considered the magnitude of additional weight that would need to be assigned to the original QALY benefits in this patient group for the cost effectiveness of the drug to fall within the current threshold range. The Committee concluded that the QALY weighting needed would be acceptable even accommodating the small minority of patients with poorer performance status than were entered (before crossover) into the pivotal trial. The Committee concluded that sunitinib as a treatment for unresectable and/or metastatic GIST that is resistant or intolerant to imatinib could be recommended as a cost-effective use of NHS resources.\n\nIn summary, the Committee concluded that sunitinib could be recommended, within its licensed indication, as a treatment option for people with unresectable and/or metastatic malignant GIST after failure of imatinib treatment because of resistance or intolerance. Additionally, the Committee concluded that the use of sunitinib should be supervised by cancer specialists with experience in treating people with unresectable and/or metastatic malignant gastrointestinal stromal tumours after failure of imatinib treatment because of resistance or intolerance.", 'Recommendations for further research': 'A trial comparing 37.5 mg sunitinib with 800\xa0mg imatinib is currently recruiting participants.\n\nThe Committee considered that rigorous data collection is needed on the life-extending benefits of sunitinib.', 'Related NICE guidance': 'Imatinib for the treatment of unresectable and/or metastatic gastro-intestinal stromal tumours. NICE technology appraisal guidance 86 (2004).', 'Review of guidance': 'The review date for a technology appraisal refers to the month and year in which the Guidance Executive will consider whether the technology should be reviewed. This decision will be taken in the light of information gathered by the Institute, and in consultation with consultees and commentators.\n\nThe guidance on this technology was considered for review in January 2012. For details see the NICE website.\n\nAndrew DillonChief ExecutiveSeptember 2009', 'Changes after publication': 'February 2014: implementation section updated to clarify that sunitinib is recommended as an option for treating gastrointestinal stromal tumours. Additional minor maintenance update also carried out.\n\nMarch 2012: minor maintenance', 'About this guidance': 'NICE technology appraisal guidance is about the use of new and existing medicines and treatments in the NHS in England and Wales.\n\nThis guidance was developed using the NICE single technology appraisal process.\n\nWe have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available.\n\nYour responsibility\n\nThis guidance represents the views of NICE and was arrived at after careful consideration of the evidence available. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. However, the guidance does not override the individual responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.\n\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.\n\nCopyright\n\n© National Institute for Health and Clinical Excellence 2009. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.'}	https://www.nice.org.uk/guidance/ta179	Evidence-based recommendations on sunitinib (Sutent) for treating gastrointestinal stromal tumours in adults.
41a13c1982f3d30d0bc721d4cda2174834db3d93	nice	Extracorporeal albumin dialysis for acute liver failure	Extracorporeal albumin dialysis for acute liver failure # Guidance This guidance replaces previous guidance on extracorporeal albumin dialysis for acute-on-chronic liver failure (interventional procedure guidance 45) The evidence on extracorporeal albumin dialysis for acute liver failure raises no major safety concerns. However, current evidence on its efficacy is inadequate in quality and quantity. Therefore, this procedure should only be used with special arrangements for clinical governance, consent and audit or research. Clinicians wishing to undertake extracorporeal albumin dialysis for acute liver failure should take the following actions. Inform the clinical governance leads in their Trusts. Ensure that patients and their carers understand the uncertainty about the procedure's efficacy and provide them with clear written information (subject to the requirement for an emergency procedure). In addition, the use of NICE's information for patients ('Understanding NICE guidance') is recommended. Audit and review clinical outcomes of all patients having extracorporeal albumin dialysis for acute liver failure (see section 3.1). NICE encourages further research into extracorporeal albumin dialysis for acute liver failure. This should describe clearly the indications for treatment. Short- and longer-term survival and the numbers of patients 'bridged to transplant' should be documented and compared with standard treatments. Further information about the utility of biochemical markers to guide the frequency of treatment would be helpful. NICE may review the procedure on publication of further evidence.# The procedure # Indications and current treatments In acute liver failure there is rapid deterioration of liver function. It has a high mortality rate. Causes include poisoning due to alcohol, pharmaceutical or recreational drugs and viral infection. Less common causes are metabolic disease and acute fatty liver of pregnancy. There are few treatment options for patients with diminishing liver function. Some patients recover liver function with supportive medical therapy including haemodialysis/filtration. Other patients need transplantation. However, there is a shortage of donor livers. # Outline of the procedure This procedure aims to support the patient until either their own liver function recovers or a transplant becomes available. The procedure removes toxins bound to albumin in the blood in addition to the water-soluble toxins that can be removed by haemodialysis. The blood is dialysed through a membrane against an albumin-rich dialysate. Toxic molecules bound to albumin in the blood pass through the membrane and bind onto the albumin molecules of the dialysate. The dialysate is then passed through an activated charcoal and an anion-exchange resin column (to remove toxins bound to albumin) and through a conventional filter (to remove water-soluble toxins). The dialysate is thus regenerated, and can be recirculated against the patient's blood. A number of different systems are available for this procedure. Sections 2.3 and 2.4 describe efficacy and safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview. # Efficacy A meta-analysis of 4 randomised controlled trials (RCTs) and 2 non-randomised controlled studies, which included 128 patients in total, reported no significant difference in 30-day all-cause mortality between patients who had extracorporeal albumin dialysis and those who had standard medical treatment (relative risk 0.56; 95% confidence interval 0.28 to 1.14; p = 0.11). No significant differences in mortality were reported between treatment groups in the subgroups of patients with acute-on-chronic liver failure (RR 0.49; 95% CI 0.12 to 2.17; p = 0.35) or those with acute liver failure (RR 0.49; 95% CI 0.15 to 1.58; p = 0.23). An RCT of 24 patients with cirrhosis of the liver treated by albumin dialysis or standard haemodialysis reported no significant difference in 6-month survival between 3 treatment groups (6/8 and 5/8 patients who had albumin dialysis by 2 different systems, and 3/6 patients who had standard haemodialysis, survived) (p = 0.40). A non-randomised controlled trial of 79 patients with acute alcoholic liver disease reported that survival at 3-year follow-up was significantly greater after extracorporeal albumin dialysis (52% ) than after standard medical therapy (17% ) (p = 0.0035). A non-randomised controlled trial of 159 patients reported no significant difference in overall survival at 6-month follow-up between patients treated by extracorporeal albumin dialysis (75% ) and patients treated with standard medical therapy (61% ) (p = 0.07). The Specialist Advisers listed key efficacy outcomes as survival or successful bridge to transplant, reduced intracranial pressure/encephalopathy and improved haemodynamic stability. # Safety A case series of 30 patients reported that 30% (9/30) of patients developed positive blood cultures 2–17 days after extracorporeal albumin dialysis treatment. All 9 patients died. A case report of 2 patients treated by albumin dialysis described severe pulmonary oedema in both patients. (Therapy was suspended in 1 patient.) In both patients the oedema resolved within 24 hours of aggressive medical treatment. One patient died at 9 days and the other at 201 days of follow-up. A case series of 191 patients treated by 2027 extracorporeal albumin dialysis sessions reported transitory hypotension in 14% (292/2027) of treatments. Transitory hypoglycaemia requiring medical management occurred in 17% (335/2027) of treatments, all in patients with Model for End-stage Liver Disease (MELD) scores of 30–40 (MELD scores range from 1 to 40 ). The Specialist Advisers listed adverse events as increased variceal bleeding and infection. They considered theoretical adverse events to include coagulopathy, shock, electrolyte abnormalities and thrombosis in the dialysis circuit.# Further information This guidance requires that clinicians undertaking the procedure make special arrangements for audit. NICE has identified relevant audit criteria and has developed an audit tool (which is for use at local discretion). For related NICE guidance see our website. # Information for patients NICE has produced information on this procedure for patients and carers ('Understanding NICE guidance'). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.# About this guidance NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland. This guidance was developed using the NICE interventional procedure guidance process. It updates and replaces NICE interventional procedure guidance 45. This guidance has been incorporated into the NICE pathway on alcohol use disorders, along with other related guidance and products. We have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available. Changes since publication January 2012: minor maintenance. Your responsibility This guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer. Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties. Copyright © National Institute for Health and Clinical Excellence 2009. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE. Contact NICE National Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT www.nice.org.uk nice@nice.org.uk	{'Guidance': "This guidance replaces previous guidance on extracorporeal albumin dialysis for acute-on-chronic liver failure (interventional procedure guidance 45)\n\nThe evidence on extracorporeal albumin dialysis for acute liver failure raises no major safety concerns. However, current evidence on its efficacy is inadequate in quality and quantity. Therefore, this procedure should only be used with special arrangements for clinical governance, consent and audit or research.\n\nClinicians wishing to undertake extracorporeal albumin dialysis for acute liver failure should take the following actions.\n\nInform the clinical governance leads in their Trusts.\n\nEnsure that patients and their carers understand the uncertainty about the procedure's efficacy and provide them with clear written information (subject to the requirement for an emergency procedure). In addition, the use of NICE's information for patients ('Understanding NICE guidance') is recommended.\n\nAudit and review clinical outcomes of all patients having extracorporeal albumin dialysis for acute liver failure (see section 3.1).\n\nNICE encourages further research into extracorporeal albumin dialysis for acute liver failure. This should describe clearly the indications for treatment. Short- and longer-term survival and the numbers of patients 'bridged to transplant' should be documented and compared with standard treatments. Further information about the utility of biochemical markers to guide the frequency of treatment would be helpful. NICE may review the procedure on publication of further evidence.", 'The procedure': "# Indications and current treatments\n\nIn acute liver failure there is rapid deterioration of liver function. It has a high mortality rate. Causes include poisoning due to alcohol, pharmaceutical or recreational drugs and viral infection. Less common causes are metabolic disease and acute fatty liver of pregnancy.\n\nThere are few treatment options for patients with diminishing liver function. Some patients recover liver function with supportive medical therapy including haemodialysis/filtration. Other patients need transplantation. However, there is a shortage of donor livers.\n\n# Outline of the procedure\n\nThis procedure aims to support the patient until either their own liver function recovers or a transplant becomes available. The procedure removes toxins bound to albumin in the blood in addition to the water-soluble toxins that can be removed by haemodialysis.\n\nThe blood is dialysed through a membrane against an albumin-rich dialysate. Toxic molecules bound to albumin in the blood pass through the membrane and bind onto the albumin molecules of the dialysate. The dialysate is then passed through an activated charcoal and an anion-exchange resin column (to remove toxins bound to albumin) and through a conventional filter (to remove water-soluble toxins). The dialysate is thus regenerated, and can be recirculated against the patient's blood.\n\nA number of different systems are available for this procedure.\n\nSections 2.3 and 2.4 describe efficacy and safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview.\n\n# Efficacy\n\nA meta-analysis of 4 randomised controlled trials (RCTs) and 2 non-randomised controlled studies, which included 128 patients in total, reported no significant difference in 30-day all-cause mortality between patients who had extracorporeal albumin dialysis and those who had standard medical treatment (relative risk [RR] 0.56; 95% confidence interval [CI] 0.28 to 1.14; p = 0.11). No significant differences in mortality were reported between treatment groups in the subgroups of patients with acute-on-chronic liver failure (RR 0.49; 95% CI 0.12 to 2.17; p = 0.35) or those with acute liver failure (RR 0.49; 95% CI 0.15 to 1.58; p = 0.23).\n\nAn RCT of 24 patients with cirrhosis of the liver treated by albumin dialysis or standard haemodialysis reported no significant difference in 6-month survival between 3 treatment groups (6/8 and 5/8 patients who had albumin dialysis by 2 different systems, and 3/6 patients who had standard haemodialysis, survived) (p = 0.40).\n\nA non-randomised controlled trial of 79 patients with acute alcoholic liver disease reported that survival at 3-year follow-up was significantly greater after extracorporeal albumin dialysis (52% [17/33]) than after standard medical therapy (17% [8/46]) (p = 0.0035). A non-randomised controlled trial of 159 patients reported no significant difference in overall survival at 6-month follow-up between patients treated by extracorporeal albumin dialysis (75% [85/113]) and patients treated with standard medical therapy (61% [28/46]) (p = 0.07).\n\nThe Specialist Advisers listed key efficacy outcomes as survival or successful bridge to transplant, reduced intracranial pressure/encephalopathy and improved haemodynamic stability.\n\n# Safety\n\nA case series of 30 patients reported that 30% (9/30) of patients developed positive blood cultures 2–17 days after extracorporeal albumin dialysis treatment. All 9 patients died.\n\nA case report of 2 patients treated by albumin dialysis described severe pulmonary oedema in both patients. (Therapy was suspended in 1 patient.) In both patients the oedema resolved within 24 hours of aggressive medical treatment. One patient died at 9 days and the other at 201 days of follow-up.\n\nA case series of 191 patients treated by 2027 extracorporeal albumin dialysis sessions reported transitory hypotension in 14% (292/2027) of treatments. Transitory hypoglycaemia requiring medical management occurred in 17% (335/2027) of treatments, all in patients with Model for End-stage Liver Disease (MELD) scores of 30–40 (MELD scores range from 1 [least severe] to 40 [most severe]).\n\nThe Specialist Advisers listed adverse events as increased variceal bleeding and infection. They considered theoretical adverse events to include coagulopathy, shock, electrolyte abnormalities and thrombosis in the dialysis circuit.", 'Further information': "This guidance requires that clinicians undertaking the procedure make special arrangements for audit. NICE has identified relevant audit criteria and has developed an audit tool (which is for use at local discretion).\n\nFor related NICE guidance see our website.\n\n# Information for patients\n\nNICE has produced information on this procedure for patients and carers ('Understanding NICE guidance'). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.", 'About this guidance': 'NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland.\n\nThis guidance was developed using the NICE interventional procedure guidance process.\n\nIt updates and replaces NICE interventional procedure guidance 45.\n\nThis guidance has been incorporated into the NICE pathway on alcohol use disorders, along with other related guidance and products.\n\nWe have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available.\n\nChanges since publication\n\nJanuary 2012: minor maintenance.\n\nYour responsibility\n\nThis guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.\n\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.\n\nCopyright\n\n© National Institute for Health and Clinical Excellence 2009. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.\n\nContact NICE\n\nNational Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT\n\nwww.nice.org.uk\n \n nice@nice.org.uk\n 0845 033 7780'}	https://www.nice.org.uk/guidance/ipg316
9b78666b926b27466c582fb72aa69b092be82881	nice	Individually magnetic resonance imaging-designed unicompartmental interpositional implant insertion for osteoarthritis of the knee	Individually magnetic resonance imaging-designed unicompartmental interpositional implant insertion for osteoarthritis of the knee # Guidance Current evidence on the safety and efficacy of individually magnetic resonance imaging (MRI)-designed unicompartmental interpositional implant insertion for osteoarthritis of the knee is inadequate in quantity and quality. Therefore, this procedure should only be used in the context of research studies. These should include clear descriptions of patient selection; and should report both objective and patient-reported outcomes and the length of time before joint replacement is required. NICE may review the procedure on publication of further evidence.# The procedure # Indications and current treatments Osteoarthritis of the knee is the result of progressive degeneration of the menisci and articular cartilage of the joint, leading to exposure of the bone surface. It causes pain, stiffness, swelling and difficulty in walking. Treatment options depend on the severity of the osteoarthritis. Conservative treatments include medication to relieve pain and inflammation, physiotherapy and/or prescribed exercise and corticosteroid injection. Surgical options include upper tibial osteotomy to realign the leg and unicompartmental knee replacement. Patients with severe osteoarthritis may need total knee replacement. # Outline of the procedure The aim of this procedure is to relieve pain, increase function and prevent damaging eccentric loading of the knee, thereby delaying progression of osteoarthritis and the need for total knee replacement. This procedure aims to correct the leg axis so that the line that passes through the centre of the hip to the centre of the ankle joint also passes through the centre of the knee joint (as in people without eccentric knee loading). This is achieved by insertion of an individually MRI-designed metallic implant into either the medial or lateral compartment of the knee joint (whichever is required). An MRI scan of the knee is performed to enable bespoke design of a metallic implant. The operation is usually carried out with the patient under general anaesthesia, and may be done as day surgery. Before implantation, the patient may have an arthroscopic procedure to remove osteophytes. The individually designed metallic implant is inserted into either the medial or lateral compartment of the knee joint, depending on the change in leg axis required. Fluoroscopy may be used to confirm the position of the implant. Sections 2.3 and 2.4 describe efficacy and safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview. # Efficacy In a case series of 27 patients with early- to mid-stage unicompartmental osteoarthritis of the knee treated by arthroscopic removal of osteophytes followed by insertion of an MRI-designed implant, the average correction in leg axis was –4.4° preoperatively to –0.9° postoperatively. Successful leg axis correction to 0° and/or slight undercorrection of up to 2° was reported in 85% (23/27) of patients (preoperative leg axis measurements not given). The remaining 4 patients were reported to have had overcorrections of leg axis of 0.2°, 0.5° and 0.9° (2 patients). The follow-up MRI showed a low average loss of correction of 0.5° (range 0–1°) at 12–22 months. For all 27 patients, the correlation coefficient between implant offset (minimal thickness of the implant) and extent of axis correction was reported to be 0.84 (a value of 0.80 was considered 'good'). The Specialist Advisers listed key efficacy outcomes as reduced pain, ability to return to work and ability to perform activities of daily living and sports. They considered uncertainties about the efficacy of the procedure to be similar to the uncertainties relating to the non-customised implants that preceded the MRI-designed implant. These include failure to provide good pain relief, dislocation or subluxation of the device and a high revision rate compared with standard types of knee replacement. # Safety The case series reported that there were no dislocations during or after the procedure but did not report any other safety data. Implant dislocation was reported in 7% (4/60) of patients after insertion of an MRI-designed implant in an unpublished case series. A revision rate of approximately 5% after insertion of an MRI-designed implant was reported in an unpublished trial of 84 patients (absolute number and time of occurrence not stated). The Specialist Advisers considered theoretical adverse events to include implant dislocation, infection, persistence of pain and venous thromboembolism. One Specialist Adviser expressed concern that loosening of the implant may cause further wear to the joint, which may make knee replacement more difficult.# Further information NICE has published interventional procedures guidance on arthroscopic knee washout, with or without debridement, for the treatment of osteoarthritis and artificial trapeziometacarpal joint replacement for end-stage osteoarthritis. NICE has also published a clinical guideline on the care and management of osteoarthritis in adults. # Information for patients NICE has produced information on this procedure for patients and carers ('Understanding NICE guidance'). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.# About this guidance NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland. This guidance was developed using the NICE interventional procedure guidance process. We have produced a summary of this guidance for patients and carers. Information about the evidence it is based on is also available. Changes since publication January 2012: minor maintenance. Your responsibility This guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer. Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties. Copyright © National Institute for Health and Clinical Excellence 2009. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE. Contact NICE National Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT www.nice.org.uk nice@nice.org.uk	{'Guidance': 'Current evidence on the safety and efficacy of individually magnetic resonance imaging (MRI)-designed unicompartmental interpositional implant insertion for osteoarthritis of the knee is inadequate in quantity and quality. Therefore, this procedure should only be used in the context of research studies. These should include clear descriptions of patient selection; and should report both objective and patient-reported outcomes and the length of time before joint replacement is required.\n\nNICE may review the procedure on publication of further evidence.', 'The procedure': "# Indications and current treatments\n\nOsteoarthritis of the knee is the result of progressive degeneration of the menisci and articular cartilage of the joint, leading to exposure of the bone surface. It causes pain, stiffness, swelling and difficulty in walking.\n\nTreatment options depend on the severity of the osteoarthritis. Conservative treatments include medication to relieve pain and inflammation, physiotherapy and/or prescribed exercise and corticosteroid injection. Surgical options include upper tibial osteotomy to realign the leg and unicompartmental knee replacement. Patients with severe osteoarthritis may need total knee replacement.\n\n# Outline of the procedure\n\nThe aim of this procedure is to relieve pain, increase function and prevent damaging eccentric loading of the knee, thereby delaying progression of osteoarthritis and the need for total knee replacement. This procedure aims to correct the leg axis so that the line that passes through the centre of the hip to the centre of the ankle joint also passes through the centre of the knee joint (as in people without eccentric knee loading). This is achieved by insertion of an individually MRI-designed metallic implant into either the medial or lateral compartment of the knee joint (whichever is required).\n\nAn MRI scan of the knee is performed to enable bespoke design of a metallic implant. The operation is usually carried out with the patient under general anaesthesia, and may be done as day surgery. Before implantation, the patient may have an arthroscopic procedure to remove osteophytes. The individually designed metallic implant is inserted into either the medial or lateral compartment of the knee joint, depending on the change in leg axis required. Fluoroscopy may be used to confirm the position of the implant.\n\nSections 2.3 and 2.4 describe efficacy and safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview.\n\n# Efficacy\n\nIn a case series of 27 patients with early- to mid-stage unicompartmental osteoarthritis of the knee treated by arthroscopic removal of osteophytes followed by insertion of an MRI-designed implant, the average correction in leg axis was –4.4° preoperatively to –0.9° postoperatively. Successful leg axis correction to 0° and/or slight undercorrection of up to 2° was reported in 85% (23/27) of patients (preoperative leg axis measurements not given). The remaining 4 patients were reported to have had overcorrections of leg axis of 0.2°, 0.5° and 0.9° (2 patients). The follow-up MRI showed a low average loss of correction of 0.5° (range 0–1°) at 12–22 months. For all 27 patients, the correlation coefficient between implant offset (minimal thickness of the implant) and extent of axis correction was reported to be 0.84 (a value of 0.80 was considered 'good').\n\nThe Specialist Advisers listed key efficacy outcomes as reduced pain, ability to return to work and ability to perform activities of daily living and sports. They considered uncertainties about the efficacy of the procedure to be similar to the uncertainties relating to the non-customised implants that preceded the MRI-designed implant. These include failure to provide good pain relief, dislocation or subluxation of the device and a high revision rate compared with standard types of knee replacement.\n\n# Safety\n\nThe case series reported that there were no dislocations during or after the procedure but did not report any other safety data. Implant dislocation was reported in 7% (4/60) of patients after insertion of an MRI-designed implant in an unpublished case series.\n\nA revision rate of approximately 5% after insertion of an MRI-designed implant was reported in an unpublished trial of 84 patients (absolute number and time of occurrence not stated).\n\nThe Specialist Advisers considered theoretical adverse events to include implant dislocation, infection, persistence of pain and venous thromboembolism. One Specialist Adviser expressed concern that loosening of the implant may cause further wear to the joint, which may make knee replacement more difficult.", 'Further information': "NICE has published interventional procedures guidance on arthroscopic knee washout, with or without debridement, for the treatment of osteoarthritis and artificial trapeziometacarpal joint replacement for end-stage osteoarthritis. NICE has also published a clinical guideline on the care and management of osteoarthritis in adults.\n\n# Information for patients\n\nNICE has produced information on this procedure for patients and carers ('Understanding NICE guidance'). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.", 'About this guidance': 'NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland.\n\nThis guidance was developed using the NICE interventional procedure guidance process.\n\nWe have produced a summary of this guidance for patients and carers. Information about the evidence it is based on is also available.\n\nChanges since publication\n\nJanuary 2012: minor maintenance.\n\nYour responsibility\n\nThis guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.\n\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.\n\nCopyright\n\n© National Institute for Health and Clinical Excellence 2009. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.\n\nContact NICE\n\nNational Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT\n\nwww.nice.org.uk\n \n nice@nice.org.uk\n 0845 033 7780'}	https://www.nice.org.uk/guidance/ipg317
4c058c171c719ad16161b2706d63e1f7f33e5c20	nice	Alitretinoin for the treatment of severe chronic hand eczema	Alitretinoin for the treatment of severe chronic hand eczema Evidence-based recommendations on alitretinoin (Toctino) for treating severe chronic hand eczema in adults. # Guidance Alitretinoin is recommended, within its licensed indication, as a treatment option for adults with severe chronic hand eczema that has not responded to potent topical corticosteroids if the person has: severe disease, as defined by the physician's global assessment (PGA) and a dermatology life quality index (DLQI) score of 15 or more. Alitretinoin treatment should be stopped: as soon as an adequate response (hands clear or almost clear) has been achieved or if the eczema remains severe (as defined by the PGA) at 12 weeks or if an adequate response (hands clear or almost clear) has not been achieved by 24 weeks. Only dermatologists, or physicians with experience in both managing severe chronic hand eczema and the use of systemic retinoids, should start and monitor treatment with alitretinoin. When using the DLQI, healthcare professionals should take into account any physical, sensory or learning disabilities, or other communication difficulties that could affect the responses to the DLQI. In such cases, healthcare professionals should ensure that the DLQI continues to be a sufficiently accurate measure.# The technology Oral alitretinoin (Toctino, Basilea Pharmaceuticals) is indicated for use in adults who have severe chronic hand eczema that is unresponsive to treatment with potent topical corticosteroids. 'Severe' chronic hand eczema (that is, marked signs of eczema, or oedema, fissures or functional impairment) is defined using the physician's global assessment (PGA; see section 3.2). The recommended dosage is 30 mg once daily for 12–24 weeks. The dosage can be reduced to 10 mg once daily if there are unacceptable adverse effects. The summary of product characteristics (SPC) specifies that if a person still has severe disease after the first 12 weeks, stopping treatment should be considered. In the event of relapse, further treatment courses may be of benefit. Alitretinoin is a derivative of retinoic acid (9-cis-retinoic acid) that binds to and activates intracellular retinoid receptors. These receptors regulate cellular differentiation and proliferation. The most frequent adverse effects seen with alitretinoin include headache, dry mouth, anaemia, flushing and erythema. Increases in cholesterol and triglyceride levels (hyperlipidaemia) have also been observed. Adverse effects are generally dose related and reversible. Alitretinoin is teratogenic and therefore contraindicated in women of childbearing potential unless all of the conditions of the Pregnancy Prevention Programme (as outlined in the SPC) are met. Alitretinoin should not be prescribed if the person's eczema can be adequately controlled by standard measures, including skin protection, avoiding allergens and irritants, and treatment with potent topical corticosteroids. For full details of side effects and contraindications, see the SPC. Alitretinoin costs £411.43 for a pack of 30 × 30-mg capsules (excluding VAT; 'British national formulary' edition 57). Costs may vary in different settings because of negotiated procurement discounts.# The manufacturer's submission The Appraisal Committee (appendix A) considered evidence submitted by the manufacturer of alitretinoin and a review of this submission by the Evidence Review Group (ERG; appendix B). The manufacturer approached the decision problem by comparing alitretinoin with ciclosporin, oral and topical PUVA (psoralen and long-wave ultraviolet radiation), and azathioprine. The population considered was adults with severe chronic hand eczema that is unresponsive to potent topical corticosteroids. The primary outcome measures outlined in the decision problem were overall severity of chronic hand eczema (as defined by the PGA), modified total lesion symptom score (mTLSS), patient's global assessment of improvement, time to response, time to relapse and a disease-specific quality of life measure, namely the dermatology life quality index (DLQI). The primary outcome measure used in the clinical trials was severity of chronic hand eczema as defined by the PGA. This combined the grading of disease severity against a photographic guide with an indication of symptoms (pruritus and/or pain) and degree of functional impairment. The PGA describes five severity states for chronic hand eczema (clear, almost clear, mild, moderate and severe), and a combined 'clear or almost clear' category was used to define response to treatment in the trials. The manufacturer's submission presented evidence on the clinical effectiveness of alitretinoin from two multinational randomised controlled trials (RCTs): BAP0003, a 12-week phase II trial (n = 319) comparing three doses of alitretinoin (10 mg, 20 mg and 40 mg daily) with placebo; and BAP00089, a 24-week phase III trial (n = 1032) evaluating daily 10 mg and 30 mg doses of alitretinoin versus placebo. It also presented evidence from BAP00091, an extension of the BAP00089 RCT in which non-responding and responding–relapsing people were followed up for 24 weeks. In BAP00091, all people (n = 360) in BAP00089 whose eczema had not responded or who had disease relapse within 24 weeks of treatment received a further 12-week or 24-week course of either 10 mg or 30 mg of alitretinoin or placebo (people from BAP00089 who had received placebo were assigned to receive placebo again; people who had received alitretinoin were given a further course of treatment with the same dose of alitretinoin or assigned to receive placebo). All trials included people whose eczema had not responded to potent topical corticosteroids. The BAP00089 RCT included people with 'severe' eczema as defined by PGA score. The BAP0003 trial included people with either 'moderate' or 'severe' eczema as defined by PGA score. Both RCTs found that alitretinoin treatment resulted in a greater proportion of people with hands clear or almost clear at 12 and 24 weeks compared with placebo, as assessed by PGA score and patient's global assessment of improvement. The differences were statistically significant (although in the BAP0003 trial, only the 40 mg dose of alitretinoin gave statistically significant results compared with placebo). In the BAP00089 trial, 47.7% of people were reported as having clear or almost clear skin by week 24 of treatment with 30 mg of alitretinoin, compared with 16.6% for placebo (p < 0.001). The BAP00089 trial also measured rates of remission and found that among people whose eczema had responded to alitretinoin treatment, 30% treated with 30 mg and 37% treated with 10 mg relapsed during the 24-week follow-up period. The manufacturer reported that in the BAP0003 study, 26% of people whose eczema had responded to treatment with alitretinoin relapsed (mTLSS score of 75% of the baseline value) within 12 weeks of the end of the treatment. In the extension study (BAP00091), participants were divided into two cohorts. Cohort A consisted of 117 people whose eczema had relapsed within 24 weeks of treatment, and a double-blind design was used. People were assigned to receive the same dose of alitretinoin as in BAP00089 or placebo; those who had received placebo in BAP00089 were again assigned to the placebo group. In this trial, 21 people were given 10 mg of alitretinoin, 49 people were given 30 mg of alitretinoin and 47 people were given placebo, for a period of 12 or 24 weeks. A statistically significantly greater proportion of people treated again with 30 mg of alitretinoin had a PGA state of hands clear or almost clear than those treated with placebo (79.6% and 8.3% respectively, p < 0.001). Cohort B consisted of 243 people whose eczema had not responded to treatment in the original RCT. All were given 30 mg of alitretinoin and an open-label design was used. Nearly 50% of people whose eczema had not initially responded to treatment after 24 weeks responded to a further 12-week or 24-week course of 30 mg of alitretinoin once daily. The manufacturer also provided details of subgroup analyses from the BAP00089 trial. The 30 mg dose of alitretinoin resulted in a higher proportion of people with hands clear or almost clear than placebo in people with hyperkeratotic disease (54% versus 12%), pompholyx disease (33% versus 30%), and hyperkeratotic and pompholyx disease together (33% versus 12%). It was not stated whether these differences were statistically significant. The manufacturer reported that information on health-related quality of life (HRQoL) was collected only during the phase II BAP0003 study and that 51.4% of people in both treatment groups (alitretinoin and placebo) completed DLQI questionnaires. The median change in HRQoL from baseline was greater with alitretinoin than with placebo (–3 and –2 respectively). The findings were not statistically significant, but the manufacturer pointed out that this may have been because of the lack of statistical power of the study. The manufacturer did not include the DLQI or any other measure of HRQoL in any subsequent trials or analyses. The primary source of data on adverse events in the manufacturer's submission was the phase III RCT (BAP00089). Treatment-related serious adverse events with alitretinoin were rare (an incidence of 1% at a dose of 30 mg). The most common adverse event was headache (20% at 30 mg; 11% at 10 mg), and a small proportion of people had elevated blood triglycerides (3% at 30 mg; 1% at 10 mg) and high total cholesterol (14% at 30 mg; 3% at 10 mg). The number of people who withdrew from the trial because of adverse events was 39 (9.5%) for 30 mg of alitretinoin and 24 (5.7%) for 10 mg of alitretinoin. The number of people who refused to continue treatment for other reasons was 16 (3.9%) for 30 mg of alitretinoin and 24 (5.7%) for 10 mg of alitretinoin. The manufacturer pointed out that there were no trials that compared alitretinoin directly with any of the comparators specified in the scope for the appraisal. It explained that subsequent searches were carried out to identify trials that assessed the efficacy of PUVA, ciclosporin and azathioprine for the treatment of chronic hand eczema. This search identified 13 trials of PUVA for the treatment of chronic hand eczema, of which eight met the criteria for inclusion in the review. One trial of ciclosporin and no trials of azathioprine were identified. The manufacturer explained that a mixed-treatment comparison could not be carried out because none of the RCTs using PUVA or ciclosporin had a placebo control arm, and therefore no common link could be established between the trials of alitretinoin, PUVA and ciclosporin. The manufacturer submitted a cost-effectiveness analysis from a de novo Markov-based patient-level model using a hypothetical cohort of people with severe chronic hand eczema. The demographic characteristics of the model population reflected those of the participants in the BAP00089 trial, and 15% of the women were assumed to be of childbearing potential. The model had five health states that were defined according to PGA score: severe, moderate and mild chronic hand eczema, remission (people whose chronic hand eczema was rated as 'clear' or 'almost clear' by 24 weeks), and refractory disease (people whose chronic hand eczema was rated 'moderate', 'mild' or had returned to a PGA state of 'severe' at 24 weeks). The model was designed to compare oral alitretinoin with PUVA, ciclosporin, azathioprine and best supportive care. The model had a 3-year time horizon, and a treatment course of alitretinoin was assumed to be given for between 12 and 24 weeks at an initial dosage of 30 mg once daily. The efficacy estimates for alitretinoin in the model were taken from the phase III clinical trial (BAP00089) for the first treatment cycle, and from cohort A of the phase III extension trial (BAP00091) for subsequent treatment cycles. Estimates of the efficacy of the comparators were obtained from a panel of seven dermatologists. Data on the number of adverse events and the probabilities of dose reduction or withdrawal from treatment were informed by BAP00089 or by the manufacturer's assumptions. Time to relapse following remission was informed by the BAP00089 trial for alitretinoin and by expert clinical opinion for the comparators. For alitretinoin, the estimates of the proportion of people who move to each PGA state after initial treatment were obtained from the BAP00089 trial, and retreatment estimates were obtained from the BAP00091 trial. The corresponding estimates for the comparator interventions were obtained from expert opinion. The utility values for all health states were derived using data collected from the BAP0003 trial to predict DLQI scores that correspond to each PGA state. A published algorithm of the relationship between DLQI scores and EQ-5D scores in people with psoriasis was then used to predict EQ5D-based utility values from DLQI scores. The model applied the utility scores associated with the 'severe' PGA state to people whose disease was rated as severe and who were still receiving treatment, and to people whose disease was deemed to be refractory. The 'moderate' and 'mild' utility scores were applied to people receiving treatment whose disease was rated moderate and mild, respectively, on the PGA scale. The utility scores for the states of 'clear' and 'almost clear' were averaged to provide a single utility score that was applied to people whose disease was in remission. The manufacturer also provided a set of alternative utility estimates from an unpublished study by Augustin (Augustin M: unpublished data 2008). These EQ-5D scores were predicted from the observed average DLQI scores of the people within each PGA state. Adverse events were assumed to have no impact on HRQoL. It was assumed that if an adverse event occurred (either headache or hyperlipidaemia), 20% of people with headache and 40% of people with hyperlipidaemia would switch to a lower dose (10 mg of alitretinoin, once daily); treatment would continue unchanged at 30 mg of alitretinoin for the remainder of people with headache or hyperlipidaemia. It was then assumed that those people who switched to the lower dose and who experienced a subsequent adverse event had a 20% probability of withdrawal owing to headache and a 40% probability of withdrawal owing to hyperlipidaemia. The people who withdrew would enter the refractory state, and the remaining people in this group would continue treatment with 10 mg of alitretinoin. The costs associated with treatment, monitoring and adverse events were included in the model. The manufacturer's original base case resulted in an incremental cost-effectiveness ratio (ICER) of £8614 per quality-adjusted life year (QALY) gained for alitretinoin compared with ciclosporin. Alitretinoin dominated PUVA. A comparison of alitretinoin with azathioprine resulted in an ICER of £10,612 per QALY gained. The manufacturer carried out two subgroup analyses. The first subgroup was people with hyperkeratotic disease. For this subgroup, the manufacturer adjusted the efficacy data for alitretinoin to reflect the improved efficacy that had been observed in the BAP00089 trial predominantly in people with hyperkeratotic disease. The second subgroup analysis was in women of childbearing potential. The efficacy was assumed to be the same in these women as in the base case, but the care of these women was assumed to incur additional costs associated with conception counselling and pregnancy testing. The consequences of the Pregnancy Prevention Programme not working were not considered. The manufacturer's subgroup analyses for people with hyperkeratotic disease resulted in an ICER of £11,177 per QALY gained for alitretinoin compared with ciclosporin. Alitretinoin dominated PUVA. The comparison of alitretinoin with azathioprine resulted in an ICER of £13,174 per QALY gained. The manufacturer's subgroup analyses for women of childbearing age resulted in ICERs for alitretinoin of £9109, £11,038 and £54 per QALY gained, compared with ciclosporin, azathioprine and PUVA respectively. In response to a request for clarification from the ERG, the manufacturer submitted a revised model comparing alitretinoin with best supportive care. The manufacturer's revised base case resulted in an ICER of £12,931 per QALY gained. The ICER was £15,018 per QALY gained for people with hyperkeratotic disease and £26,013 per QALY gained for people with hyperkeratotic and pompholyx disease. The manufacturer undertook a one-way sensitivity analysis of the time horizon of the revised model. Using just a 1-year (rather than a 3-year) time horizon resulted in an ICER of £21,562 per QALY gained. The ERG highlighted a number of concerns with the clinical and cost effectiveness information in the manufacturer's submission, including: the validity of the efficacy estimates for the comparators the possibility that the population and some assumptions in the model may not reflect clinical practice in England and Wales the high degree of uncertainty because derived utility values were used rather than directly observed HRQoL values errors in the model's visual basic for applications (VBA) code. The ERG regarded the comparisons of alitretinoin with azathioprine, ciclosporin and PUVA in the original manufacturer's submission to be of limited value. This was because the efficacy data for the comparators were based on expert clinical opinion only. Although the ERG accepted that there was no appropriate clinical trial evidence, it did not think the elicitation process used was sufficiently rigorous. It therefore questioned the validity of the efficacy estimates for the comparators used in the model, and noted the absence of any quantification of the uncertainty around these estimates. The ERG therefore viewed the comparison of alitretinoin with placebo in the revised model to be of greater relevance, and focused its evaluation on this aspect of the model. The ERG questioned whether the model population (people with severe chronic hand eczema as defined by PGA score) reflected the population of people with corticosteroid-refractory chronic hand eczema for whom clinicians would aim to provide treatment. The ERG was unsure of the validity of some of the model assumptions. These included the assumptions that people would stop treatment as soon as their disease responded, even if this was after only 4 or 8 weeks of treatment; that all people who relapse return to the PGA severe state, even though the time to relapse was informed by trial data that used a definition of relapse based on return to 75% baseline mTLSS; and that people receiving alitretinoin would visit a dermatologist every 4 weeks. The ERG viewed the derived utility values used in the model as a major source of uncertainty for the cost-effectiveness analysis. It also considered that the utility estimates obtained using the directly observed relationship between PGA state and DLQI score from the Augustin study may be a more appropriate basis for modelling than the analysis of change in DLQI score calculated based on PGA state from the BAP0003 trial. The ERG stated that there were errors in the model's VBA code. This meant that the first 4 weeks of every treatment cycle except the first cycle were omitted from the model. It also pointed out that adverse events associated with alitretinoin had been removed from the revised model that compared alitretinoin with best supportive care. The ERG carried out an additional exploratory cost-effectiveness analysis using the manufacturer's original model. It explained that the results given by the manufacturer were not fully incremental, consisting of pairwise comparisons between alitretinoin and the comparators. The ERG explained that integrating the supportive care arm from the revised model into a fully incremental analysis was possible because the manufacturer removed adverse events from the revised model and did not report on the adverse-event profile associated with supportive care. The ERG's incremental analysis found that alitretinoin extendedly dominated ciclosporin, alitretinoin dominated PUVA, best supportive care dominated azathioprine, and the comparison of alitretinoin with best supportive care resulted in an ICER of £12,931 per QALY gained. The ERG also conducted exploratory sensitivity analyses using the manufacturer's revised model (which compared alitretinoin with best supportive care). Using the utility estimates from the Augustin study and the assumption that people (except women of childbearing potential) see a dermatologist once every 6 weeks if they are taking alitretinoin and once every 12 weeks if they are receiving best supportive care (rather than once every 4 weeks) resulted in an ICER of £27,997 per QALY gained for alitretinoin compared with best supportive care. Using the ERG-modified VBA code so that people with relapsing disease moved to the appropriate PGA state (30.6% of people whose disease relapsed moved to the moderate state and the remainder to the severe state) resulted in an ICER of £29,864 per QALY gained for alitretinoin compared with best supportive care. Reinstating adverse events for alitretinoin resulted in an ICER of £29,200 per QALY gained for alitretinoin compared with best supportive care. Using all modifications described in sections 3.26 and 3.27, but keeping the utility data from the original model (taken from BAP0003), resulted in an ICER of £15,084 per QALY gained for alitretinoin compared with best supportive care. Using all modifications described in 3.26 and 3.27, including the alternative utility data from the Augustin study, resulted in an ICER of £30,918 per QALY gained for alitretinoin compared with best supportive care. Full details of all the evidence are in the manufacturer's submission and the ERG report.# Consideration of the evidence The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of alitretinoin, having considered evidence on the nature of severe chronic hand eczema and the value placed on the benefits of alitretinoin by people with the condition, those who represent them, and clinical specialists. It also took into account the effective use of NHS resources. # Clinical effectiveness The Committee heard from the clinical specialists and patient expert that there is a need for new treatments for people with severe chronic hand eczema that is refractory to topical corticosteroids. This is because treatment options are limited and there are no licensed treatments available. The Committee also heard that severe chronic hand eczema is a very debilitating condition. This is because it can be disfiguring, can result in severe functional limitation and may be associated with depression, anxiety and social stigma. The Committee discussed the treatment options currently available in the UK for people with severe chronic hand eczema that is refractory to topical corticosteroids. These are the immunosuppressants ciclosporin and azathioprine, and PUVA. It heard the clinical specialists' concerns about using treatments that work by suppressing the immune system because of potential adverse effects over the longer term, such as re-activation of tuberculosis. For this reason, the clinical specialists stated that they would be cautious in their use of immunosuppressants and that such treatments would be reserved for people with the most severe symptoms. The Committee also heard from the clinical specialists about concerns over the adverse effects of comparator treatments: for example, ciclosporin is associated with an increased risk of lymphoma and skin cancer, and PUVA is known to be carcinogenic. The Committee heard from the patient expert that alitretinoin would be well tolerated by most people, with limited short-term or long-term adverse effects that would be no worse than those of the current treatments. The clinical specialists confirmed that there was an increase in blood levels of triglycerides and cholesterol in some people using alitretinoin, but that these effects would be carefully monitored and medically managed in practice. The Committee noted the subgroup analyses provided by the manufacturer for people with hyperkeratotic and/or pompholyx disease. However, it heard from the clinical specialists that it would be impractical to differentiate these subgroups in practice. The clinical specialists also stated that they would expect treatment with alitretinoin for severe chronic hand eczema to be started and monitored by specialist dermatologists with appropriate expertise in managing hand eczema. The Committee discussed the clinical effectiveness of alitretinoin in treating severe chronic hand eczema and considered all of the available evidence. It agreed that an RCT comparing alitretinoin with the current treatments for severe chronic hand eczema would have been ideal. The Committee was aware that the alternative treatments for this disease generally lack a robust evidence base, and so the manufacturer was unable to conduct an indirect comparison of alitretinoin with the standard treatments. The Committee noted the trial comparing 10 mg and 30 mg doses of alitretinoin with best supportive care, which demonstrated that alitretinoin was more clinically effective than best supportive care. The Committee therefore concluded that alitretinoin is a clinically effective treatment for severe chronic hand eczema compared with best supportive care. # Cost effectiveness The Committee discussed the plausibility of the efficacy estimates for the comparators in the manufacturer's model. The Committee heard from the ERG that using a panel of dermatologists to determine the efficacy estimates for the comparators for the model was appropriate. However, the manufacturer did not provide details of the range of opinions obtained, whether the opinions had been weighted or whether the estimates had been adjusted to exclude the effect of placebo. The Committee therefore agreed that the estimates of efficacy for the comparators in the model should be considered with caution. The Committee also heard from the clinical specialists that the efficacy estimates for the comparators in the manufacturer's model did not reflect experience in clinical practice – in particular, azathioprine is considered to be more clinically effective than best supportive care. The specialists stated that in their experience some people's eczema would respond adequately to one of the available comparator treatments. The Committee noted comments from consultees on the side effects of treatment and the weak evidence base for azathioprine, ciclosporin and PUVA. Overall, the Committee concluded that the evidence base for the potential comparators azathioprine, ciclosporin and PUVA was weak and highly contentious. It agreed that an analysis of the cost effectiveness of alitretinoin compared with azathioprine, ciclosporin and PUVA could not be reliably considered further, given the present state of knowledge. It would therefore only consider the revised economic model comparing alitretinoin with best supportive care. The Committee noted that the manufacturer's base case for 30 mg of alitretinoin compared with best supportive care and the corresponding ERG analysis both gave ICER estimates of approximately £13,000 per QALY gained. The Committee noted that this analysis included discontinuing treatment as soon as an adequate response (defined as hands clear or almost clear) was achieved, or after 12 weeks if the symptoms were still classed as severe, or after 24 weeks if an adequate response (hands clear or almost clear) was not achieved. The Committee noted that the ERG had explored the following modifications to the manufacturer's model: People (except women of childbearing potential) would see a dermatologist once every 6 weeks with alitretinoin and once every 12 weeks with best supportive care. The VBA code was modified so that people with disease moved to an appropriate PGA state (30.6% of people with relapsing disease moved to the moderate state and the remainder to the severe state). Adverse events associated with alitretinoin treatment were reinstated from the original model. The Committee discussed the ERG's assumptions and modifications. Firstly, it considered the assumption in the manufacturer's model that people would stop treatment before 12 weeks if an adequate response was achieved. The Committee heard from the clinical specialists that this assumption did reflect clinical practice in the UK and that people receiving alitretinoin would be seen by a dermatologist every 6 weeks. The Committee therefore accepted this assumption. The Committee then discussed whether people would be treated again only when the condition had relapsed to a severe state. The Committee heard from the clinical specialists that they may find it difficult not to begin treatment again before a person's hands had returned to the severe state. The Committee therefore accepted the ERG's assumption of earlier retreatment in a proportion of people. Finally, the Committee accepted that the adverse events associated with alitretinoin treatment needed to be reinstated in the revised model. The Committee noted that the modelling of the adverse events did not capture all monitoring and treatment related to cardiovascular risk or outcomes related to long-term effects that may result from increased blood lipid levels. However, the Committee acknowledged that, because modelling was plausible only to compare alitretinoin with best supportive care, long-term adverse effects of currently used treatments (such as an increased risk of cancer) were also not included in the modelling. For the same reason, the high cost of PUVA was not included in the economic evaluation. The Committee discussed the relative merits and disadvantages of the methods used to estimate utility values in the BAP0003 trial and the Augustin study. The Committee acknowledged that both studies were subject to a high degree of uncertainty, as both estimated utilities indirectly. The Committee noted that the manufacturer did not use the DLQI scores from groups of people defined according to their PGA state directly, although this would have been possible. Instead, the manufacturer used a two-stage process to obtain utility estimates via DLQI scores for PGA states. In comparison, the Augustin study measured DLQI scores directly in groups of people defined according to their PGA state. However, the Augustin study identified a higher utility value for mild disease than for the state of hands clear or almost clear, which the Committee noted was counterintuitive. The Committee noted the sensitivity analyses provided by the ERG, and that using some of the ERG's plausible assumptions would lead to small increases in the ICERs. However, it also noted that the major driver of the model was the choice of the utility values, with a much bigger utility gain from moving from the severe PGA state to the hands clear or almost clear state in the BAP0003 study (0.33) than in the Augustin study (0.14). The Committee noted that including all modifications suggested by the ERG and using the original utility values (derived from the BAP0003 trial) increased the ICER for alitretinoin compared with best supportive care to £15,000 per QALY gained. Including all modifications suggested by the ERG and using the utility values from the Augustin study increased the ICER to £31,000 per QALY gained. The Committee then noted the concerns expressed by the patient expert and clinical specialists that the likely impact of chronic hand eczema on quality of life for people whose eczema is classified as severe may have been underestimated in the Augustin study (that is, the DLQI score estimated for the PGA severe state may not accurately reflect the impact of eczema in people who would be considered as candidates for alitretinoin in practice). In the absence of more robust data, the Committee agreed that the utility estimate for PGA-defined severe chronic hand eczema in the Augustin study may have underestimated the impact of the condition. The Committee also agreed that the benefits of moving from the state of severe chronic hand eczema to the state of hands clear or almost clear would be considerable. The Committee agreed that the uncertainty about the relationship between DLQI score and PGA state was too great to base recommendations on PGA state alone, and that it would be appropriate to include guidance on DLQI eligibility criteria for treatment. The Committee discussed what DLQI score was appropriate to define eligibility for treatment with alitretinoin. The Committee considered concerns raised by consultees that a DLQI score of 15 was too high, but thought that this score reflected the deterioration in quality of life produced by a condition affecting the hands that is severe as defined by the PGA. The Committee noted comments from consultees advocating a DLQI score of 10, in line with the current eligibility criteria for biological treatments for psoriasis. However, the Committee considered that psoriasis and severe chronic hand eczema could have different effects on HRQoL. It also agreed, on the basis of the testimony of the patient expert, that severe chronic hand eczema is likely to be associated with a particularly high DLQI score. The Committee discussed the implications for the cost effectiveness of alitretinoin of using different DLQI thresholds. It noted that the benefit of alitretinoin had been established in a population with severe disease for whom the manufacturer had calculated a DLQI score of 15. It concluded that the economic case had therefore been made for this population. The Committee therefore concluded that treatment with alitretinoin for people whose eczema is sufficiently severe to result in a DLQI score of 15 or more would represent a cost-effective use of NHS resources. The Committee discussed the place of alitretinoin in the pathway of care. It heard that the different comparator treatments could be effective in achieving an adequate response in some people with severe chronic hand eczema. However, the Committee agreed that it was not appropriate to make recommendations about the place of alitretinoin in the pathway of care because robust cost-effectiveness estimates were not available for alitretinoin compared with any active comparator treatments. It also noted that azothiaprine and ciclosporin, although licensed for related conditions, do not have a marketing authorisation for severe chronic hand eczema. In addition, the Committee noted the concerns of consultees about the adverse effects associated with comparator treatments and the lack of RCT evidence of their effectiveness in treating severe chronic hand eczema. The Committee discussed comments from consultees that treatment should not be stopped if the eczema remains severe (as defined by the PGA) at 12 weeks, because a longer time period would be needed to assess a response to treatment. However, it noted that the SPC for alitretinoin specifies that discontinuation of treatment should be considered if symptoms are still classed as severe at 12 weeks, and that such treatment discontinuation was included in the cost-effectiveness analysis. The Committee agreed with the suggestion from consultees to state in the guidance that treatment with alitretinoin should be stopped if an adequate response (hands clear or almost clear) has not been achieved by 24 weeks. The Committee also discussed the suggestion by consultees to provide specific advice about what treatments to give after 24 weeks. It agreed that this level of detail would be outside the remit for a technology appraisal. The Committee also discussed whether only dermatologists with specialist experience in managing severe hand eczema should start and monitor treatment with alitretinoin. The Committee noted consultee comments that other clinical staff should be included, as this would enable people to receive treatment more quickly. The Committee acknowledged that specialist nurses could have an important role in the management of severe chronic hand eczema, but agreed that guidance on who should start and monitor treatment with alitretinoin should reflect the marketing authorisation for the drug. Therefore it is recommended that only dermatologists, or physicians with experience in both managing severe hand eczema the use of systemic retinoids, should start and monitor treatment with alitretinoin. In considering the evidence and reaching its conclusions, the Committee was aware of NICE's duties under the equalities legislation, and considered whether those duties required it to alter or to add to its recommendations in any way. The Committee was aware that a number of the questions in the DLQI focus on aspects that depend on physical activity, such as shopping, working in the home or garden, or sport. The DLQI would therefore need to be used judiciously in people with a physical disability to take account of their lower baseline level of physical activity. Furthermore, sensory or learning disabilities, or other communication difficulties, could also affect the responses to the DLQI. The Committee agreed that in such cases, healthcare professionals should ensure that the DLQI continues to be a sufficiently accurate measure. The Committee additionally heard from the clinical specialists that there may be people who, for cultural reasons, will be unable to comply with some aspects of treatment of severe chronic hand eczema (for example, wearing gloves or not carrying out certain household tasks that expose them to known irritants). However, the Committee noted that the SPC for alitretinoin states that it should not be prescribed if the patient's eczema can be adequately controlled by standard measures, including skin protection and avoidance of allergens and irritants. Therefore it was not possible for the Committee to consider this group separately.# Recommendations for further research The Committee recommends that phase III trials should be conducted that compare alitretinoin with ciclosporin, azathioprine and PUVA in people who have severe chronic hand eczema that is unresponsive to treatment with potent topical corticosteroids. The Committee recommends that a study should be conducted that estimates utility values using directly observed health-related quality of life values (such as EQ-5D scores) in people with severe chronic hand eczema that is unresponsive to treatment with potent topical corticosteroids.# Related NICE guidance Tacrolimus and pimecrolimus for atopic eczema. NICE technology appraisal guidance 82 (2004). Frequency of application of topical corticosteroids for eczema. NICE technology appraisal guidance 81 (2004).# Review of guidance The guidance on this technology will be considered for review in August 2012. The Guidance Executive will decide whether the technology should be reviewed based on information gathered by NICE, and in consultation with consultees and commentators. Andrew DillonChief ExecutiveAugust 2009# Changes after publication February 2014: implementation section updated to clarify that alitretinoin is recommended as an option for treating severe chronic hand eczema. Additional minor maintenance update also carried out. March 2012: minor maintenance# About this guidance NICE technology appraisal guidance is about the use of new and existing medicines and treatments in the NHS in England and Wales. This guidance was developed using the NICE single technology appraisal process. We have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available. Your responsibility This guidance represents the views of NICE and was arrived at after careful consideration of the evidence available. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. However, the guidance does not override the individual responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or guardian or carer. Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties. Copyright © National Institute for Health and Clinical Excellence 2009. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.	{'Guidance ': "Alitretinoin is recommended, within its licensed indication, as a treatment option for adults with severe chronic hand eczema that has not responded to potent topical corticosteroids if the person has:\n\nsevere disease, as defined by the physician's global assessment (PGA) and\n\na dermatology life quality index (DLQI) score of 15 or more.\n\nAlitretinoin treatment should be stopped:\n\nas soon as an adequate response (hands clear or almost clear) has been achieved or\n\nif the eczema remains severe (as defined by the PGA) at 12\xa0weeks\xa0or\n\nif an adequate response (hands clear or almost clear) has not been achieved by 24\xa0weeks.\n\nOnly dermatologists, or physicians with experience in both managing severe chronic hand eczema and the use of systemic retinoids, should start and monitor treatment with alitretinoin.\n\nWhen using the DLQI, healthcare professionals should take into account any physical, sensory or learning disabilities, or other communication difficulties that could affect the responses to the DLQI. In such cases, healthcare professionals should ensure that the DLQI continues to be a sufficiently accurate measure.", 'The technology': "Oral alitretinoin (Toctino, Basilea Pharmaceuticals) is indicated for use in adults who have severe chronic hand eczema that is unresponsive to treatment with potent topical corticosteroids. 'Severe' chronic hand eczema (that is, marked signs of eczema, or oedema, fissures or functional impairment) is defined using the physician's global assessment (PGA; see section 3.2).\n\nThe recommended dosage is 30 mg once daily for 12–24 weeks. The dosage can be reduced to 10\xa0mg once daily if there are unacceptable adverse effects. The summary of product characteristics (SPC) specifies that if a person still has severe disease after the first 12\xa0weeks, stopping treatment should be considered. In the event of relapse, further treatment courses may be of benefit.\n\nAlitretinoin is a derivative of retinoic acid (9-cis-retinoic acid) that binds to and activates intracellular retinoid receptors. These receptors regulate cellular differentiation and proliferation.\n\nThe most frequent adverse effects seen with alitretinoin include headache, dry mouth, anaemia, flushing and erythema. Increases in cholesterol and triglyceride levels (hyperlipidaemia) have also been observed. Adverse effects are generally dose related and reversible. Alitretinoin is teratogenic and therefore contraindicated in women of childbearing potential unless all of the conditions of the Pregnancy Prevention Programme (as outlined in the SPC) are met. Alitretinoin should not be prescribed if the person's eczema can be adequately controlled by standard measures, including skin protection, avoiding allergens and irritants, and treatment with potent topical corticosteroids. For full details of side effects and contraindications, see the SPC.\n\nAlitretinoin costs £411.43 for a pack of 30\xa0×\xa030-mg capsules (excluding VAT; 'British national formulary' [BNF] edition 57). Costs may vary in different settings because of negotiated procurement discounts.", "The manufacturer's submission": "The Appraisal Committee (appendix A) considered evidence submitted by the manufacturer of alitretinoin and a review of this submission by the Evidence Review Group (ERG; appendix B).\n\nThe manufacturer approached the decision problem by comparing alitretinoin with ciclosporin, oral and topical PUVA (psoralen and long-wave ultraviolet radiation), and azathioprine. The population considered was adults with severe chronic hand eczema that is unresponsive to potent topical corticosteroids. The primary outcome measures outlined in the decision problem were overall severity of chronic hand eczema (as defined by the PGA), modified total lesion symptom score (mTLSS), patient's global assessment of improvement, time to response, time to relapse and a disease-specific quality of life measure, namely the dermatology life quality index (DLQI).\n\nThe primary outcome measure used in the clinical trials was severity of chronic hand eczema as defined by the PGA. This combined the grading of disease severity against a photographic guide with an indication of symptoms (pruritus and/or pain) and degree of functional impairment. The PGA describes five severity states for chronic hand eczema (clear, almost clear, mild, moderate and severe), and a combined 'clear or almost clear' category was used to define response to treatment in the trials.\n\nThe manufacturer's submission presented evidence on the clinical effectiveness of alitretinoin from two multinational randomised controlled trials (RCTs): BAP0003, a 12-week phase II trial (n\xa0=\xa0319) comparing three doses of alitretinoin (10 mg, 20\xa0mg and 40\xa0mg daily) with placebo; and BAP00089, a 24-week phase III trial (n\xa0=\xa01032) evaluating daily 10\xa0mg and 30\xa0mg doses of alitretinoin versus placebo. It also presented evidence from BAP00091, an extension of the BAP00089 RCT in which non-responding and responding–relapsing people were followed up for 24 weeks. In BAP00091, all people (n\xa0=\xa0360) in BAP00089 whose eczema had not responded or who had disease relapse within 24\xa0weeks of treatment received a further 12-week or 24-week course of either 10 mg or 30 mg of alitretinoin or placebo (people from BAP00089 who had received placebo were assigned to receive placebo again; people who had received alitretinoin were given a further course of treatment with the same dose of alitretinoin or assigned to receive placebo). All trials included people whose eczema had not responded to potent topical corticosteroids. The BAP00089 RCT included people with 'severe' eczema as defined by PGA score. The BAP0003 trial included people with either 'moderate' or 'severe' eczema as defined by PGA score.\n\nBoth RCTs found that alitretinoin treatment resulted in a greater proportion of people with hands clear or almost clear at 12 and 24\xa0weeks compared with placebo, as assessed by PGA score and patient's global assessment of improvement. The differences were statistically significant (although in the BAP0003 trial, only the 40\xa0mg dose of alitretinoin gave statistically significant results compared with placebo). In the BAP00089 trial, 47.7% of people were reported as having clear or almost clear skin by week 24 of treatment with 30 mg of alitretinoin, compared with 16.6% for placebo (p < 0.001). The BAP00089 trial also measured rates of remission and found that among people whose eczema had responded to alitretinoin treatment, 30% treated with 30 mg and 37% treated with 10 mg relapsed during the 24-week follow-up period. The manufacturer reported that in the BAP0003 study, 26% of people whose eczema had responded to treatment with alitretinoin relapsed (mTLSS score of 75% of the baseline value) within 12 weeks of the end of the treatment.\n\nIn the extension study (BAP00091), participants were divided into two cohorts. Cohort A consisted of 117 people whose eczema had relapsed within 24 weeks of treatment, and a double-blind design was used. People were assigned to receive the same dose of alitretinoin as in BAP00089 or placebo; those who had received placebo in BAP00089 were again assigned to the placebo group. In this trial, 21 people were given 10 mg of alitretinoin, 49\xa0people were given 30 mg of alitretinoin and 47 people were given placebo, for a period of 12 or 24 weeks. A statistically significantly greater proportion of people treated again with 30 mg of alitretinoin had a PGA state of hands clear or almost clear than those treated with placebo (79.6% and 8.3% respectively, p\xa0<\xa00.001). Cohort B consisted of 243 people whose eczema had not responded to treatment in the original RCT. All were given 30\xa0mg of alitretinoin and an open-label design was used. Nearly 50% of people whose eczema had not initially responded to treatment after 24 weeks responded to a further 12-week or 24-week course of 30 mg of alitretinoin once daily.\n\nThe manufacturer also provided details of subgroup analyses from the BAP00089 trial. The 30 mg dose of alitretinoin resulted in a higher proportion of people with hands clear or almost clear than placebo in people with hyperkeratotic disease (54% versus 12%), pompholyx disease (33% versus 30%), and hyperkeratotic and pompholyx disease together (33% versus 12%). It was not stated whether these differences were statistically significant.\n\nThe manufacturer reported that information on health-related quality of life (HRQoL) was collected only during the phase II BAP0003 study and that 51.4% of people in both treatment groups (alitretinoin and placebo) completed DLQI questionnaires. The median change in HRQoL from baseline was greater with alitretinoin than with placebo (–3 [for doses of 20 and 40\xa0mg of alitretinoin] and –2 respectively). The findings were not statistically significant, but the manufacturer pointed out that this may have been because of the lack of statistical power of the study. The manufacturer did not include the DLQI or any other measure of HRQoL in any subsequent trials or analyses.\n\nThe primary source of data on adverse events in the manufacturer's submission was the phase III RCT (BAP00089). Treatment-related serious adverse events with alitretinoin were rare (an incidence of 1% at a dose of 30 mg). The most common adverse event was headache (20% at 30 mg; 11% at 10 mg), and a small proportion of people had elevated blood triglycerides (3% at 30\xa0mg; 1% at 10 mg) and high total cholesterol (14% at 30 mg; 3% at 10\xa0mg). The number of people who withdrew from the trial because of adverse events was 39 (9.5%) for 30 mg of alitretinoin and 24 (5.7%) for 10 mg of alitretinoin. The number of people who refused to continue treatment for other reasons was 16 (3.9%) for 30 mg of alitretinoin and 24 (5.7%) for 10 mg of alitretinoin.\n\nThe manufacturer pointed out that there were no trials that compared alitretinoin directly with any of the comparators specified in the scope for the appraisal. It explained that subsequent searches were carried out to identify trials that assessed the efficacy of PUVA, ciclosporin and azathioprine for the treatment of chronic hand eczema. This search identified 13 trials of PUVA for the treatment of chronic hand eczema, of which eight met the criteria for inclusion in the review. One trial of ciclosporin and no trials of azathioprine were identified. The manufacturer explained that a mixed-treatment comparison could not be carried out because none of the RCTs using PUVA or ciclosporin had a placebo control arm, and therefore no common link could be established between the trials of alitretinoin, PUVA and ciclosporin.\n\nThe manufacturer submitted a cost-effectiveness analysis from a de novo Markov-based patient-level model using a hypothetical cohort of people with severe chronic hand eczema. The demographic characteristics of the model population reflected those of the participants in the BAP00089 trial, and 15% of the women were assumed to be of childbearing potential. The model had five health states that were defined according to PGA score: severe, moderate and mild chronic hand eczema, remission (people whose chronic hand eczema was rated as 'clear' or 'almost clear' by 24 weeks), and refractory disease (people whose chronic hand eczema was rated 'moderate', 'mild' or had returned to a PGA state of 'severe' at 24 weeks). The model was designed to compare oral alitretinoin with PUVA, ciclosporin, azathioprine and best supportive care. The model had a 3-year time horizon, and a treatment course of alitretinoin was assumed to be given for between 12 and 24\xa0weeks at an initial dosage of 30 mg once daily.\n\nThe efficacy estimates for alitretinoin in the model were taken from the phase III clinical trial (BAP00089) for the first treatment cycle, and from cohort A of the phase III extension trial (BAP00091) for subsequent treatment cycles. Estimates of the efficacy of the comparators were obtained from a panel of seven dermatologists. Data on the number of adverse events and the probabilities of dose reduction or withdrawal from treatment were informed by BAP00089 or by the manufacturer's assumptions. Time to relapse following remission was informed by the BAP00089 trial for alitretinoin and by expert clinical opinion for the comparators. For alitretinoin, the estimates of the proportion of people who move to each PGA state after initial treatment were obtained from the BAP00089 trial, and retreatment estimates were obtained from the BAP00091 trial. The corresponding estimates for the comparator interventions were obtained from expert opinion.\n\nThe utility values for all health states were derived using data collected from the BAP0003 trial to predict DLQI scores that correspond to each PGA state. A published algorithm of the relationship between DLQI scores and EQ-5D scores in people with psoriasis was then used to predict EQ5D-based utility values from DLQI scores. The model applied the utility scores associated with the 'severe' PGA state to people whose disease was rated as severe and who were still receiving treatment, and to people whose disease was deemed to be refractory. The 'moderate' and 'mild' utility scores were applied to people receiving treatment whose disease was rated moderate and mild, respectively, on the PGA scale. The utility scores for the states of 'clear' and 'almost clear' were averaged to provide a single utility score that was applied to people whose disease was in remission. The manufacturer also provided a set of alternative utility estimates from an unpublished study by Augustin (Augustin M: unpublished data 2008). These EQ-5D scores were predicted from the observed average DLQI scores of the people within each PGA state. Adverse events were assumed to have no impact on HRQoL.\n\nIt was assumed that if an adverse event occurred (either headache or hyperlipidaemia), 20% of people with headache and 40% of people with hyperlipidaemia would switch to a lower dose (10 mg of alitretinoin, once daily); treatment would continue unchanged at 30\xa0mg of alitretinoin for the remainder of people with headache or hyperlipidaemia. It was then assumed that those people who switched to the lower dose and who experienced a subsequent adverse event had a 20% probability of withdrawal owing to headache and a 40% probability of withdrawal owing to hyperlipidaemia. The people who withdrew would enter the refractory state, and the remaining people in this group would continue treatment with 10 mg of alitretinoin. The costs associated with treatment, monitoring and adverse events were included in the model.\n\nThe manufacturer's original base case resulted in an incremental cost-effectiveness ratio (ICER) of £8614 per quality-adjusted life year (QALY) gained for alitretinoin compared with ciclosporin. Alitretinoin dominated PUVA. A comparison of alitretinoin with azathioprine resulted in an ICER of £10,612 per QALY gained.\n\nThe manufacturer carried out two subgroup analyses. The first subgroup was people with hyperkeratotic disease. For this subgroup, the manufacturer adjusted the efficacy data for alitretinoin to reflect the improved efficacy that had been observed in the BAP00089 trial predominantly in people with hyperkeratotic disease. The second subgroup analysis was in women of childbearing potential. The efficacy was assumed to be the same in these women as in the base case, but the care of these women was assumed to incur additional costs associated with conception counselling and pregnancy testing. The consequences of the Pregnancy Prevention Programme not working were not considered.\n\nThe manufacturer's subgroup analyses for people with hyperkeratotic disease resulted in an ICER of £11,177 per QALY gained for alitretinoin compared with ciclosporin. Alitretinoin dominated PUVA. The comparison of alitretinoin with azathioprine resulted in an ICER of £13,174 per QALY gained. The manufacturer's subgroup analyses for women of childbearing age resulted in ICERs for alitretinoin of £9109, £11,038 and £54 per QALY gained, compared with ciclosporin, azathioprine and PUVA respectively.\n\nIn response to a request for clarification from the ERG, the manufacturer submitted a revised model comparing alitretinoin with best supportive care. The manufacturer's revised base case resulted in an ICER of £12,931 per QALY gained. The ICER was £15,018 per QALY gained for people with hyperkeratotic disease and £26,013 per QALY gained for people with hyperkeratotic and pompholyx disease.\n\nThe manufacturer undertook a one-way sensitivity analysis of the time horizon of the revised model. Using just a 1-year (rather than a 3-year) time horizon resulted in an ICER of £21,562 per QALY gained.\n\nThe ERG highlighted a number of concerns with the clinical and cost effectiveness information in the manufacturer's submission, including:\n\nthe validity of the efficacy estimates for the comparators\n\nthe possibility that the population and some assumptions in the model may not reflect clinical practice in England and Wales\n\nthe high degree of uncertainty because derived utility values were used rather than directly observed HRQoL values\n\nerrors in the model's visual basic for applications (VBA) code.\n\nThe ERG regarded the comparisons of alitretinoin with azathioprine, ciclosporin and PUVA in the original manufacturer's submission to be of limited value. This was because the efficacy data for the comparators were based on expert clinical opinion only. Although the ERG accepted that there was no appropriate clinical trial evidence, it did not think the elicitation process used was sufficiently rigorous. It therefore questioned the validity of the efficacy estimates for the comparators used in the model, and noted the absence of any quantification of the uncertainty around these estimates. The ERG therefore viewed the comparison of alitretinoin with placebo in the revised model to be of greater relevance, and focused its evaluation on this aspect of the model.\n\nThe ERG questioned whether the model population (people with severe chronic hand eczema as defined by PGA score) reflected the population of people with corticosteroid-refractory chronic hand eczema for whom clinicians would aim to provide treatment.\n\nThe ERG was unsure of the validity of some of the model assumptions. These included the assumptions that people would stop treatment as soon as their disease responded, even if this was after only 4 or 8\xa0weeks of treatment; that all people who relapse return to the PGA severe state, even though the time to relapse was informed by trial data that used a definition of relapse based on return to 75% baseline mTLSS; and that people receiving alitretinoin would visit a dermatologist every 4 weeks.\n\nThe ERG viewed the derived utility values used in the model as a major source of uncertainty for the cost-effectiveness analysis. It also considered that the utility estimates obtained using the directly observed relationship between PGA state and DLQI score from the Augustin study may be a more appropriate basis for modelling than the analysis of change in DLQI score calculated based on PGA state from the BAP0003 trial.\n\nThe ERG stated that there were errors in the model's VBA code. This meant that the first 4 weeks of every treatment cycle except the first cycle were omitted from the model. It also pointed out that adverse events associated with alitretinoin had been removed from the revised model that compared alitretinoin with best supportive care.\n\nThe ERG carried out an additional exploratory cost-effectiveness analysis using the manufacturer's original model. It explained that the results given by the manufacturer were not fully incremental, consisting of pairwise comparisons between alitretinoin and the comparators. The ERG explained that integrating the supportive care arm from the revised model into a fully incremental analysis was possible because the manufacturer removed adverse events from the revised model and did not report on the adverse-event profile associated with supportive care. The ERG's incremental analysis found that alitretinoin extendedly dominated ciclosporin, alitretinoin dominated PUVA, best supportive care dominated azathioprine, and the comparison of alitretinoin with best supportive care resulted in an ICER of £12,931 per QALY gained.\n\nThe ERG also conducted exploratory sensitivity analyses using the manufacturer's revised model (which compared alitretinoin with best supportive care). Using the utility estimates from the Augustin study and the assumption that people (except women of childbearing potential) see a dermatologist once every 6 weeks if they are taking alitretinoin and once every 12 weeks if they are receiving best supportive care (rather than once every 4 weeks) resulted in an ICER of £27,997 per QALY gained for alitretinoin compared with best supportive care.\n\nUsing the ERG-modified VBA code so that people with relapsing disease moved to the appropriate PGA state (30.6% of people whose disease relapsed moved to the moderate state and the remainder to the severe state) resulted in an ICER of £29,864 per QALY gained for alitretinoin compared with best supportive care. Reinstating adverse events for alitretinoin resulted in an ICER of £29,200 per QALY gained for alitretinoin compared with best supportive care.\n\nUsing all modifications described in sections 3.26 and 3.27, but keeping the utility data from the original model (taken from BAP0003), resulted in an ICER of £15,084 per QALY gained for alitretinoin compared with best supportive care. Using all modifications described in 3.26 and 3.27, including the alternative utility data from the Augustin study, resulted in an ICER of £30,918 per QALY gained for alitretinoin compared with best supportive care.\n\nFull details of all the evidence are in the manufacturer's submission and the ERG report.", 'Consideration of the evidence': "The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of alitretinoin, having considered evidence on the nature of severe chronic hand eczema and the value placed on the benefits of alitretinoin by people with the condition, those who represent them, and clinical specialists. It also took into account the effective use of NHS resources.\n\n# Clinical effectiveness\n\nThe Committee heard from the clinical specialists and patient expert that there is a need for new treatments for people with severe chronic hand eczema that is refractory to topical corticosteroids. This is because treatment options are limited and there are no licensed treatments available. The Committee also heard that severe chronic hand eczema is a very debilitating condition. This is because it can be disfiguring, can result in severe functional limitation and may be associated with depression, anxiety and social stigma.\n\nThe Committee discussed the treatment options currently available in the UK for people with severe chronic hand eczema that is refractory to topical corticosteroids. These are the immunosuppressants ciclosporin and azathioprine, and PUVA. It heard the clinical specialists' concerns about using treatments that work by suppressing the immune system because of potential adverse effects over the longer term, such as re-activation of tuberculosis. For this reason, the clinical specialists stated that they would be cautious in their use of immunosuppressants and that such treatments would be reserved for people with the most severe symptoms. The Committee also heard from the clinical specialists about concerns over the adverse effects of comparator treatments: for example, ciclosporin is associated with an increased risk of lymphoma and skin cancer, and PUVA is known to be carcinogenic. The Committee heard from the patient expert that alitretinoin would be well tolerated by most people, with limited short-term or long-term adverse effects that would be no worse than those of the current treatments. The clinical specialists confirmed that there was an increase in blood levels of triglycerides and cholesterol in some people using alitretinoin, but that these effects would be carefully monitored and medically managed in practice.\n\nThe Committee noted the subgroup analyses provided by the manufacturer for people with hyperkeratotic and/or pompholyx disease. However, it heard from the clinical specialists that it would be impractical to differentiate these subgroups in practice. The clinical specialists also stated that they would expect treatment with alitretinoin for severe chronic hand eczema to be started and monitored by specialist dermatologists with appropriate expertise in managing hand eczema.\n\nThe Committee discussed the clinical effectiveness of alitretinoin in treating severe chronic hand eczema and considered all of the available evidence. It agreed that an RCT comparing alitretinoin with the current treatments for severe chronic hand eczema would have been ideal. The Committee was aware that the alternative treatments for this disease generally lack a robust evidence base, and so the manufacturer was unable to conduct an indirect comparison of alitretinoin with the standard treatments. The Committee noted the trial comparing 10\xa0mg and 30 mg doses of alitretinoin with best supportive care, which demonstrated that alitretinoin was more clinically effective than best supportive care. The Committee therefore concluded that alitretinoin is a clinically effective treatment for severe chronic hand eczema compared with best supportive care.\n\n# Cost effectiveness\n\nThe Committee discussed the plausibility of the efficacy estimates for the comparators in the manufacturer's model. The Committee heard from the ERG that using a panel of dermatologists to determine the efficacy estimates for the comparators for the model was appropriate. However, the manufacturer did not provide details of the range of opinions obtained, whether the opinions had been weighted or whether the estimates had been adjusted to exclude the effect of placebo. The Committee therefore agreed that the estimates of efficacy for the comparators in the model should be considered with caution. The Committee also heard from the clinical specialists that the efficacy estimates for the comparators in the manufacturer's model did not reflect experience in clinical practice – in particular, azathioprine is considered to be more clinically effective than best supportive care. The specialists stated that in their experience some people's eczema would respond adequately to one of the available comparator treatments. The Committee noted comments from consultees on the side effects of treatment and the weak evidence base for azathioprine, ciclosporin and PUVA. Overall, the Committee concluded that the evidence base for the potential comparators azathioprine, ciclosporin and PUVA was weak and highly contentious. It agreed that an analysis of the cost effectiveness of alitretinoin compared with azathioprine, ciclosporin and PUVA could not be reliably considered further, given the present state of knowledge. It would therefore only consider the revised economic model comparing alitretinoin with best supportive care.\n\nThe Committee noted that the manufacturer's base case for 30 mg of alitretinoin compared with best supportive care and the corresponding ERG analysis both gave ICER estimates of approximately £13,000 per QALY gained. The Committee noted that this analysis included discontinuing treatment as soon as an adequate response (defined as hands clear or almost clear) was achieved, or after 12 weeks if the symptoms were still classed as severe, or after 24 weeks if an adequate response (hands clear or almost clear) was not achieved.\n\nThe Committee noted that the ERG had explored the following modifications to the manufacturer's model:\n\nPeople (except women of childbearing potential) would see a dermatologist once every 6 weeks with alitretinoin and once every 12 weeks with best supportive care.\n\nThe VBA code was modified so that people with disease moved to an appropriate PGA state (30.6% of people with relapsing disease moved to the moderate state and the remainder to the severe state).\n\nAdverse events associated with alitretinoin treatment were reinstated from the original model.\n\nThe Committee discussed the ERG's assumptions and modifications. Firstly, it considered the assumption in the manufacturer's model that people would stop treatment before 12\xa0weeks if an adequate response was achieved. The Committee heard from the clinical specialists that this assumption did reflect clinical practice in the UK and that people receiving alitretinoin would be seen by a dermatologist every 6 weeks. The Committee therefore accepted this assumption. The Committee then discussed whether people would be treated again only when the condition had relapsed to a severe state. The Committee heard from the clinical specialists that they may find it difficult not to begin treatment again before a person's hands had returned to the severe state. The Committee therefore accepted the ERG's assumption of earlier retreatment in a proportion of people. Finally, the Committee accepted that the adverse events associated with alitretinoin treatment needed to be reinstated in the revised model. The Committee noted that the modelling of the adverse events did not capture all monitoring and treatment related to cardiovascular risk or outcomes related to long-term effects that may result from increased blood lipid levels. However, the Committee acknowledged that, because modelling was plausible only to compare alitretinoin with best supportive care, long-term adverse effects of currently used treatments (such as an increased risk of cancer) were also not included in the modelling. For the same reason, the high cost of PUVA was not included in the economic evaluation.\n\nThe Committee discussed the relative merits and disadvantages of the methods used to estimate utility values in the BAP0003 trial and the Augustin study. The Committee acknowledged that both studies were subject to a high degree of uncertainty, as both estimated utilities indirectly. The Committee noted that the manufacturer did not use the DLQI scores from groups of people defined according to their PGA state directly, although this would have been possible. Instead, the manufacturer used a two-stage process to obtain utility estimates via DLQI scores for PGA states. In comparison, the Augustin study measured DLQI scores directly in groups of people defined according to their PGA state. However, the Augustin study identified a higher utility value for mild disease than for the state of hands clear or almost clear, which the Committee noted was counterintuitive.\n\nThe Committee noted the sensitivity analyses provided by the ERG, and that using some of the ERG's plausible assumptions would lead to small increases in the ICERs. However, it also noted that the major driver of the model was the choice of the utility values, with a much bigger utility gain from moving from the severe PGA state to the hands clear or almost clear state in the BAP0003 study (0.33) than in the Augustin study (0.14). The Committee noted that including all modifications suggested by the ERG and using the original utility values (derived from the BAP0003 trial) increased the ICER for alitretinoin compared with best supportive care to £15,000 per QALY gained. Including all modifications suggested by the ERG and using the utility values from the Augustin study increased the ICER to £31,000 per QALY gained.\n\nThe Committee then noted the concerns expressed by the patient expert and clinical specialists that the likely impact of chronic hand eczema on quality of life for people whose eczema is classified as severe may have been underestimated in the Augustin study (that is, the DLQI score estimated for the PGA severe state may not accurately reflect the impact of eczema in people who would be considered as candidates for alitretinoin in practice). In the absence of more robust data, the Committee agreed that the utility estimate for PGA-defined severe chronic hand eczema in the Augustin study may have underestimated the impact of the condition. The Committee also agreed that the benefits of moving from the state of severe chronic hand eczema to the state of hands clear or almost clear would be considerable.\n\nThe Committee agreed that the uncertainty about the relationship between DLQI score and PGA state was too great to base recommendations on PGA state alone, and that it would be appropriate to include guidance on DLQI eligibility criteria for treatment. The Committee discussed what DLQI score was appropriate to define eligibility for treatment with alitretinoin. The Committee considered concerns raised by consultees that a DLQI score of 15 was too high, but thought that this score reflected the deterioration in quality of life produced by a condition affecting the hands that is severe as defined by the PGA. The Committee noted comments from consultees advocating a DLQI score of 10, in line with the current eligibility criteria for biological treatments for psoriasis. However, the Committee considered that psoriasis and severe chronic hand eczema could have different effects on HRQoL. It also agreed, on the basis of the testimony of the patient expert, that severe chronic hand eczema is likely to be associated with a particularly high DLQI score.\n\nThe Committee discussed the implications for the cost effectiveness of alitretinoin of using different DLQI thresholds. It noted that the benefit of alitretinoin had been established in a population with severe disease for whom the manufacturer had calculated a DLQI score of 15. It concluded that the economic case had therefore been made for this population. The Committee therefore concluded that treatment with alitretinoin for people whose eczema is sufficiently severe to result in a DLQI score of 15 or more would represent a cost-effective use of NHS resources.\n\nThe Committee discussed the place of alitretinoin in the pathway of care. It heard that the different comparator treatments could be effective in achieving an adequate response in some people with severe chronic hand eczema. However, the Committee agreed that it was not appropriate to make recommendations about the place of alitretinoin in the pathway of care because robust cost-effectiveness estimates were not available for alitretinoin compared with any active comparator treatments. It also noted that azothiaprine and ciclosporin, although licensed for related conditions, do not have a marketing authorisation for severe chronic hand eczema. In addition, the Committee noted the concerns of consultees about the adverse effects associated with comparator treatments and the lack of RCT evidence of their effectiveness in treating severe chronic hand eczema.\n\nThe Committee discussed comments from consultees that treatment should not be stopped if the eczema remains severe (as defined by the PGA) at 12 weeks, because a longer time period would be needed to assess a response to treatment. However, it noted that the SPC for alitretinoin specifies that discontinuation of treatment should be considered if symptoms are still classed as severe at 12 weeks, and that such treatment discontinuation was included in the cost-effectiveness analysis. The Committee agreed with the suggestion from consultees to state in the guidance that treatment with alitretinoin should be stopped if an adequate response (hands clear or almost clear) has not been achieved by 24 weeks. The Committee also discussed the suggestion by consultees to provide specific advice about what treatments to give after 24 weeks. It agreed that this level of detail would be outside the remit for a technology appraisal.\n\nThe Committee also discussed whether only dermatologists with specialist experience in managing severe hand eczema should start and monitor treatment with alitretinoin. The Committee noted consultee comments that other clinical staff should be included, as this would enable people to receive treatment more quickly. The Committee acknowledged that specialist nurses could have an important role in the management of severe chronic hand eczema, but agreed that guidance on who should start and monitor treatment with alitretinoin should reflect the marketing authorisation for the drug. Therefore it is recommended that only dermatologists, or physicians with experience in both managing severe hand eczema the use of systemic retinoids, should start and monitor treatment with alitretinoin.\n\nIn considering the evidence and reaching its conclusions, the Committee was aware of NICE's duties under the equalities legislation, and considered whether those duties required it to alter or to add to its recommendations in any way. The Committee was aware that a number of the questions in the DLQI focus on aspects that depend on physical activity, such as shopping, working in the home or garden, or sport. The DLQI would therefore need to be used judiciously in people with a physical disability to take account of their lower baseline level of physical activity. Furthermore, sensory or learning disabilities, or other communication difficulties, could also affect the responses to the DLQI. The Committee agreed that in such cases, healthcare professionals should ensure that the DLQI continues to be a sufficiently accurate measure.\n\nThe Committee additionally heard from the clinical specialists that there may be people who, for cultural reasons, will be unable to comply with some aspects of treatment of severe chronic hand eczema (for example, wearing gloves or not carrying out certain household tasks that expose them to known irritants). However, the Committee noted that the SPC for alitretinoin states that it should not be prescribed if the patient's eczema can be adequately controlled by standard measures, including skin protection and avoidance of allergens and irritants. Therefore it was not possible for the Committee to consider this group separately.", 'Recommendations for further research ': 'The Committee recommends that phase III trials should be conducted that compare alitretinoin with ciclosporin, azathioprine and PUVA in people who have severe chronic hand eczema that is unresponsive to treatment with potent topical corticosteroids.\n\nThe Committee recommends that a study should be conducted that estimates utility values using directly observed health-related quality of life values (such as EQ-5D scores) in people with severe chronic hand eczema that is unresponsive to treatment with potent topical corticosteroids.', 'Related NICE guidance': 'Tacrolimus and pimecrolimus for atopic eczema. NICE technology appraisal guidance 82 (2004).\n\nFrequency of application of topical corticosteroids for eczema. NICE technology appraisal guidance 81 (2004).', 'Review of guidance': 'The guidance on this technology will be considered for review in August 2012. The Guidance Executive will decide whether the technology should be reviewed based on information gathered by NICE, and in consultation with consultees and commentators.\n\nAndrew DillonChief ExecutiveAugust 2009', 'Changes after publication': 'February 2014: implementation section updated to clarify that alitretinoin is recommended as an option for treating severe chronic hand eczema. Additional minor maintenance update also carried out.\n\nMarch 2012: minor maintenance', 'About this guidance': 'NICE technology appraisal guidance is about the use of new and existing medicines and treatments in the NHS in England and Wales.\n\nThis guidance was developed using the NICE single technology appraisal process.\n\nWe have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available.\n\nYour responsibility\n\nThis guidance represents the views of NICE and was arrived at after careful consideration of the evidence available. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. However, the guidance does not override the individual responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.\n\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.\n\nCopyright\n\n© National Institute for Health and Clinical Excellence 2009. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.'}	https://www.nice.org.uk/guidance/ta177	Evidence-based recommendations on alitretinoin (Toctino) for treating severe chronic hand eczema in adults.
27f4040fff3bca542bb235e581e05f58112859f8	nice	Bevacizumab (first-line), sorafenib (first- and second-line), sunitinib (second-line) and temsirolimus (first-line) for the treatment of advanced and/or metastatic renal cell carcinoma	Bevacizumab (first-line), sorafenib (first- and second-line), sunitinib (second-line) and temsirolimus (first-line) for the treatment of advanced and/or metastatic renal cell carcinoma Evidence-based recommendations on bevacizumab (Avastin), sorafenib (Nexavar), sunitinib (Sutent) and temsirolimus (Torisel) for treating advanced or metastatic renal cell carcinoma in adults. # Guidance Bevacizumab, sorafenib and temsirolimus are not recommended as first-line treatment options for people with advanced and/or metastatic renal cell carcinoma. Sorafenib and sunitinib are not recommended as second-line treatment options for people with advanced and/or metastatic renal cell carcinoma. People who are currently being treated with bevacizumab (first-line), sorafenib (first- and second-line), sunitinib (second-line) and temsirolimus (first-line) for advanced and/or metastatic renal cell carcinoma should have the option to continue their therapy until they and their clinicians consider it appropriate to stop.# Clinical need and practice Renal cell carcinoma (RCC) is a type of kidney cancer that usually originates in the lining of the tubules of the kidney and contains many blood vessels. RCC accounts for 90% of kidney cancers and approximately 3% of all adult cancers. In England and Wales, kidney cancer is the 8th most common cancer in men and the 14th most common in women. In 2004, there were 5745 cases of newly diagnosed kidney cancer registered in England and Wales. The incidence of kidney cancer begins to rise after the age of 40 and is highest in people older than 65. In England and Wales the estimated overall 5-year survival rate for RCC is 44%, but there are large differences according to the stage of disease at the time of diagnosis. The worldwide incidence of kidney cancer among both men and women has been rising steadily since the 1970s. The American Joint Committee on Cancer (AJCC) tumour node metastases (TNM) system is used to grade RCC into stages I to IV. Advanced RCC, in which the tumour is either locally advanced and/or has spread to regional lymph nodes, is generally defined as stage III. Metastatic RCC, in which the tumour has spread beyond the regional lymph nodes to other parts of the body, is generally defined as stage IV. In 2006, of people presenting with RCC in England and Wales for whom staging information was available, an estimated 26% and 17% had stage III and stage IV disease, respectively. About half of those who have curative resection for earlier stages of the disease also go on to develop advanced and/or metastatic disease. The prognosis following a diagnosis of advanced and/or metastatic RCC is poor. The 5-year survival rate for metastatic RCC is approximately 10%. There are currently no treatments that reliably cure advanced and/or metastatic RCC. The primary objectives of medical intervention are relief of physical symptoms and maintenance of function. Metastatic RCC is largely resistant to chemotherapy, radiotherapy and hormonal therapy. People with advanced and/or metastatic RCC are usually treated with either interferon alfa-2a (IFN-α) or interleukin-2 immunotherapy or a combination of IFN-α and interleukin-2. IFN-α (Roferon-A, Roche Products) is the most commonly used immunotherapy in England and Wales and has a UK marketing authorisation for treatment of people with advanced RCC. For those people receiving immunotherapies for the treatment of advanced RCC it is suggested that median overall survival is 11.4 months compared with a median overall survival of 7.6 months for those receiving control treatments. Commonly experienced adverse effects of IFN-α include flu-like symptoms, tiredness and depression. There is no standard treatment for people with advanced and/or metastatic RCC in whom first-line immunotherapy has failed, or for people who are unsuitable for immunotherapy.# The technologies # Bevacizumab Bevacizumab (Avastin, Roche Products) is a recombinant humanised monoclonal IgG1 antibody that inhibits the formation of blood vessels (angiogenesis inhibitor). It targets the biological activity of human vascular endothelial growth factor (VEGF), which stimulates new blood vessel formation in the tumour. Bevacizumab in combination with IFN-α has a UK marketing authorisation for first-line treatment of people with advanced and/or metastatic RCC. Bevacizumab is contraindicated in pregnant women, people with untreated central nervous system metastases, and people who have hypersensitivity to the active substance or to any of the excipients, to products derived from Chinese hamster ovary cell cultures or to other recombinant human or humanised antibodies. The summary of product characteristics (SPC) lists the following conditions that may be associated with bevacizumab treatment: gastrointestinal perforation, fistulae, wound healing complications, hypertension, proteinuria, arterial thromboembolism, haemorrhage, congestive heart failure and neutropenia. For full details of side effects and contraindications, see the SPC. Bevacizumab is administered as an intravenous infusion. The recommended dosage for advanced and/or metastatic RCC is 10 mg/kg body weight once every 14 days. The initial dose of bevacizumab should be delivered over 90 minutes and if the first infusion is well tolerated, the second infusion may be administered over 60 minutes. If the 60-minute infusion is well tolerated, all subsequent infusions may be administered over 30 minutes. IFN-α (Roferon-A, Roche Products) is administered by subcutaneous injection three times per week at a dose of 3 MIU for 1 week, 9 MIU for the following week and 18 MIU thereafter; if 18 MIU is not tolerated then the dose should be reduced to 9 MIU. Bevacizumab treatment is licensed for use in advanced and/or metastatic RCC until there is underlying disease progression. The price for a 400-mg vial of bevacizumab is £924.40 and the price of IFN-α is £45.19 for 9 MIU (excluding VAT; 'British National Formulary' edition 55). Assuming an average weight of 76.5 kg and no wastage, the average daily cost of bevacizumab plus IFN-α is £151.42. Over a 6-week cycle, the average total cost of drug acquisition is £5982 per patient for the first cycle and £6117 for subsequent 6-week cycles. These figures assume a typical dose of IFN-α of 9–10 MIU. The manufacturer of bevacizumab (Roche) has agreed a patient access scheme with the Department of Health for advanced and/or metastatic RCC. Costs may vary in different settings because of negotiated procurement discounts. # Sorafenib Sorafenib (Nexavar, Bayer) is a multikinase inhibitor that inhibits the development of tumour blood vessels and tumour cell proliferation. It has a dual action, inhibiting the raf cascade and VEGF/platelet-derived growth factor (PDGF) receptors on tumour cells, vascular endothelial cells and pericytes. Sorafenib has a UK marketing authorisation for the treatment of people with advanced RCC in whom IFN-α or interleukin-2-based therapy has failed or who are considered unsuitable for such therapy. Sorafenib has designated EU orphan drug status for RCC. Sorafenib is contraindicated in people who have hypersensitivity to the active substance or to any of the excipients. The SPC lists the following conditions that may be associated with sorafenib treatment: dermatological toxicities, hypertension, haemorrhage, cardiac ischaemia and/or infarction, hepatic impairment and wound healing complications. For full details of side effects and contraindications, see the SPC. Sorafenib is administered orally. The recommended dosage for advanced RCC is 400 mg twice daily. Sorafenib treatment is licensed for use in people with advanced RCC as long as clinical benefit is observed or until unacceptable adverse events occur. The current price for a pack of 200-mg tablets (112 tablets per pack) is £2980.47 (excluding VAT). The average daily cost of sorafenib treatment is £106.45, with an average 6-week cycle costing £4471. The manufacturer of sorafenib (Bayer) has agreed a patient access scheme with the Department of Health for advanced RCC. Costs of treatment cycles may vary in different settings because of negotiated procurement discounts. # Sunitinib Sunitinib (Sutent, Pfizer) is an inhibitor of a group of closely related tyrosine kinase receptors. It inhibits VEGF/PDGF receptors on cancer cells, vascular endothelial cells and pericytes, inhibiting the proliferation of tumour cells and the development of tumour blood vessels. Sunitinib has a UK marketing authorisation for the treatment of people with advanced and/or metastatic RCC. Sunitinib is contraindicated in people who have hypersensitivity to sunitinib malate or to any of the excipients. The SPC lists the following conditions that may be associated with sunitinib treatment: skin and tissue problems, gastrointestinal events, haemorrhage, hypertension, haematological problems, venous thromboembolic events, pulmonary embolism and hypothyroidism. For full details of side effects and contraindications, see the SPC. Sunitinib is administered orally. The recommended dosage is 50 mg once daily for four consecutive weeks with a 2-week rest period (that is, a complete treatment cycle of 6 weeks). The dose may be adjusted in steps of 12.5 mg according to tolerability (dose range 25–75 mg). The price for a pack of 50-mg capsules (30 capsules per pack) is £3363.00 (excluding VAT; BNF edition 55). The average daily cost of sunitinib is £74.74, with an average 6-week cycle costing £3139. The manufacturer of sunitinib (Pfizer) has agreed a patient access scheme with the Department of Health for advanced and/or metastatic RCC. Costs of treatment cycles may vary in different settings because of negotiated procurement discounts. # Temsirolimus Temsirolimus (Torisel, Wyeth Pharmaceuticals) is a selective inhibitor of the mammalian target of rapamycin (mTOR), a serine threonine kinase that regulates a signalling cascade controlling growth factor-induced cell proliferation. Temsirolimus inhibits mTOR-dependent protein translation induced by growth factor stimulation. Tumour growth may also be affected indirectly by the inhibition of other factors such as VEGF. Temsirolimus has a UK marketing authorisation for the first-line treatment of people with advanced RCC who have at least three of the six following prognostic risk factors: less than 1 year from time of initial RCC diagnosis to randomisation or initiation of treatment Karnofsky performance status of 60–70 haemoglobin less than the lower limit of normal corrected calcium greater than 10 mg/100 ml (or 2.5 mmol/litre) serum lactate dehydrogenase more than 1.5 times the upper limit of normal more than one metastatic organ site.Temsirolimus has designated EU orphan drug status for RCC. Temsirolimus is contraindicated in people who have hypersensitivity to temsirolimus, its metabolites (including sirolimus), polysorbate 80 or to any of the excipients. The SPC lists the following conditions that may be associated with temsirolimus treatment: intracerebral bleeding, renal failure, hyperglycaemia, infections, interstitial lung disease, hyperlipaemia and wound healing complications. Pre-medication with intravenous antihistamine is also recommended to minimise allergic reactions. For full details of side effects and contraindications, see the SPC. Temsirolimus is administered by intravenous infusion. The recommended dosage is 25 mg over a 30- to 60-minute period once a week. Treatment with temsirolimus should continue until there is no clinical benefit or until unacceptable toxicity occurs. The net-price for a 30-mg vial of temsirolimus is £620 (excluding VAT; BNF edition 57). Costs may vary in different settings because of negotiated procurement discounts.# Evidence and interpretation The Appraisal Committee (appendix A) considered evidence from a number of sources (appendix B). The following sections are based on the evidence received for the appraisal of 'bevacizumab, sorafenib, sunitinib and temsirolimus for the treatment of advanced and/or metastatic renal cell carcinoma'. However, the following sections do not relate specifically to the appraisal of sunitinib for the first-line treatment of advanced and/or metastatic RCC. # Clinical effectiveness The Assessment Group and manufacturers identified evidence on the clinical effectiveness of bevacizumab plus IFN-α, sorafenib, sunitinib and temsirolimus against relevant comparators within the licensed indications for each drug, and according to the appraisal scope. The following potential treatment strategies were investigated: first-line treatment for people suitable for immunotherapy (bevacizumab plus IFN-α compared with IFN-α) first-line treatment for people suitable for immunotherapy and with a poor prognosis (bevacizumab plus IFN-α and temsirolimus compared with IFN-α) first-line treatment for people unsuitable for immunotherapy (sorafenib compared with best supportive care) first-line treatment for people with a poor prognosis unsuitable for immunotherapy (sorafenib and temsirolimus compared with best supportive care) second-line treatment for people in whom immunotherapy has failed (sorafenib and sunitinib compared with best supportive care) second-line treatment for people in whom first-line treatment has failed and who are unsuitable for immunotherapy (sorafenib compared with best supportive care). ## First-line treatment for people suitable for immunotherapy One randomised controlled trial (RCT) of 649 people assessed the effect of bevacizumab plus IFN-α (n = 327) compared with IFN-α plus placebo (n = 322). In this study, the primary outcome was overall survival. The study was unblinded after a pre-planned interim analysis based on approximately 250 deaths, and participants in the IFN-α arm who had not progressed were offered bevacizumab plus IFN-α. IFN-α was given for a maximum of 1 year. The study included predominantly people with clear cell RCC who had risk factors suggestive of a favourable or intermediate prognosis. All participants had undergone a previous nephrectomy. Median overall survival had not been reached in the bevacizumab plus IFN-α treatment arm at the time of data analysis and was 19.8 months in the IFN-α plus placebo arm. There was no statistically significant difference in overall survival between bevacizumab plus IFN-α compared with IFN-α plus placebo (hazard ratio 0.79, 95% confidence interval 0.62 to 1.02, p = 0.0670). Progression-free survival was defined as the time between randomisation and first documented disease progression or death from any cause. There was a statistically significant difference in median progression-free survival for bevacizumab plus IFN-α (10.2 months) compared with IFN-α plus placebo (5.4 months); HR 0.63, 95% CI 0.52 to 0.75. Tumour response rate was measured as a partial or complete reduction in tumour size. The overall tumour response rate in the bevacizumab plus IFN-α arm was 31% compared with 13% in the IFN-α plus placebo arm (p = 0.0001). Approximately half of all the trial participants achieved stable disease. Adverse events were taken from the 'safety population' (that is, people were assigned to treatments in the analysis based on what they actually received, for example patients in the IFN-α plus placebo arm receiving one or more doses of bevacizumab were assigned to the bevacizumab arm). No significant differences between the treatment and control arms were reported. A total of 28% of participants discontinued treatment in the bevacizumab plus IFN-α arm because of adverse events compared with 12% in the IFN-α plus placebo arm. Health-related quality of life was not measured in the study. ## First-line treatment for people suitable for immunotherapy with at least three of six factors indicating poor prognosis One RCT with 626 participants investigated the effectiveness of temsirolimus (n = 209), temsirolimus plus IFN-α (n = 210) and IFN-α alone (n = 207) as first-line treatments of RCC in people who were suitable for immunotherapy and had at least three of six factors indicating poor prognosis. The combination of temsirolimus plus IFN-α does not have a UK marketing authorisation and so data from this group were not considered. The primary outcome in this temsirolimus study was overall survival. Approximately 80% of participants had a Karnofsky performance status of 70 or less and clear cell carcinoma. Approximately 66% of participants had undergone prior nephrectomy. Interim and final analyses were presented. In the temsirolimus study, there were statistically significant differences in median overall survival with temsirolimus (10.9 months) compared with IFN-α (7.3 months), in both the interim (HR 0.73, 95% CI 0.58 to 0.92; p = 0.008) and final analyses (HR 0.78, 95% CI 0.63 to 0.97; p = 0.0252). Some participants had not undergone prior nephrectomy and some had non-clear cell carcinoma. Subgroup analyses suggested that temsirolimus compared with IFN-α significantly improved overall survival for those who had not undergone prior nephrectomy (HR 0.61, 95% CI 0.41 to 0.91) and for those with non-clear-cell carcinoma (HR 0.55, 95% CI 0.33 to 0.90). No significant improvements in overall survival were observed for those who had undergone prior nephrectomy (HR 0.84, 95% CI 0.63 to 1.11) and those who had clear cell carcinoma (HR 0.85, 95% CI 0.64 to 1.08). In the interim analyses, median progression-free survival was assessed by both site investigators and blinded independent assessment. For those receiving temsirolimus, the median progression-free survival was 3.8 months and 5.5 months as assessed by site investigators and blinded independent assessment, respectively. For those receiving IFN-α, the median progression-free survival was 1.9 months and 3.1 months, respectively. No statistical analysis was reported for the interim analyses. In the final analyses, the median progression-free survival was 3.8 months and 5.6 months as assessed by site investigators and blinded independent assessment, respectively. For those receiving IFN-α, median progression-free survival was 1.9 months and 3.2 months, respectively. There was a statistically significant difference in median progression-free survival with temsirolimus compared with IFN-α according to the independent assessment (HR 0.74, 95% CI 0.60 to 0.91; p = 0.0042) and the investigators' assessment (HR 0.74, 95% CI 0.60 to 0.90; p = 0.0028). Compared with IFN-α, temsirolimus improved progression-free survival for those who had not undergone prior nephrectomy (HR 0.62, 95% CI 0.43 to 0.88) and for those who had undergone prior nephrectomy (HR 0.72, 95% CI 0.55 to 0.93). Compared with IFN-α, temsirolimus improved progression-free survival for those who had non-clear-cell carcinoma (HR 0.36, 95% CI 0.22 to 0.59), and there was a non-statistically significant difference for those who had clear cell carcinoma (HR 0.84, 95% CI 0.67 to 1.05). The temsirolimus study measured objective tumour response rate. The manufacturer of temsirolimus (Wyeth Pharmaceuticals) stated that no statistically significant differences were observed; the objective partial tumour response rate was 8.6% (18 participants) for those who received temsirolimus compared with 4.8% (10 participants) for those who received IFN-α. There was a statistically significant difference in the number of participants that achieved stable disease for at least 8 weeks with temsirolimus (131 participants, 62.7%) compared with IFN-α (80 participants, 38.6%). In the temsirolimus study, time without symptoms and toxicity (TWiST) and quality-adjusted survival and toxicity (Q-TWiST) were reported as pre-defined endpoints. The reported results included some participants from the third treatment arm (temsirolimus plus IFN-α). Participants receiving temsirolimus had a significantly longer time in both TWiST and Q-TWiST health states (6.5 months and 7.0 months, respectively) compared with participants receiving IFN-α alone (4.7 months and 5.7 months, respectively). In the temsirolimus study, 67% of participants receiving temsirolimus and 78% of those receiving IFN-α alone reported a grade 3 or 4 adverse event (p = 0.02). Anaemia was the most commonly reported grade 3 or 4 adverse event in the temsirolimus arm (20%) and asthenia (loss of strength) in the IFN-α alone arm (26%). A total of 7% (n = 15) of participants in the temsirolimus arm discontinued treatment because of adverse events compared with 14% (n = 29) in the IFN-α alone arm. According to the Memorial Sloan-Kettering Cancer Center (MSKCC) risk classification, 31% of participants in the temsirolimus arm and 24% in the IFN-α alone arm had an intermediate rather than a poor prognosis. In the bevacizumab study (see section 4.1.2), 9% of participants receiving bevacizumab plus IFN-α and 8% of those receiving IFN-α plus placebo were defined as having a poor prognosis. Only progression-free survival was reported according to this subgroup. There was no statistically significant difference in median progression-free survival between bevacizumab plus IFN-α (2.2 months) and IFN-α alone (2.1 months) for participants with at least three MSKCC risk factors for poor prognosis (HR 0.81, 95% CI 0.46 to 1.42). ## First-line treatment for people unsuitable for immunotherapy The Assessment Group did not identify any full reports of RCTs assessing sorafenib as first-line treatment for people with advanced and/or metastatic RCC who were unsuitable for immunotherapy. One RCT was identified with a small population subgroup (17% of the total number of participants) that was unsuitable for immunotherapy. However, these participants did not receive sorafenib as a first-line treatment because the RCT only included people who had received at least one prior systemic therapy. Further details of the sorafenib RCT are given in section 4.1.15. The manufacturer of sorafenib (Bayer) submitted data on first-line treatment of people unsuitable for immunotherapy from two expanded access programmes conducted in Europe (318 participants unsuitable for immunotherapy) and North America (224 participants unsuitable for immunotherapy). Both were in effect single-arm studies and the results were reported only in abstract form. The expanded access studies reported median progression-free survival of 6.0 months and 8.1 months, respectively. ## First-line treatment for people with poor prognosis unsuitable for immunotherapy The Assessment Group did not identify any data on the clinical effectiveness of sorafenib or temsirolimus as first-line treatment for people with advanced and/or metastatic RCC who had a poor prognosis and were unsuitable for immunotherapy. In order to inform a cost-effectiveness estimate for this population, the manufacturer of temsirolimus (Wyeth Pharmaceuticals) performed an indirect comparison of temsirolimus with best supportive care. Data were taken from the temsirolimus RCT and an RCT that compared IFN-α with medroxyprogresterone (MPA). No further details on clinical effectiveness were presented. ## Second-line treatment for people in whom immunotherapy has failed One RCT with 903 participants investigated the effectiveness of sorafenib (n = 451) compared with placebo, which was considered equivalent to best supportive care (n = 452). The RCT included people who had experienced disease progression after one systemic treatment within the previous 8 months. All participants in the RCT had clear cell carcinoma with an ECOG performance status of 0 or 1 and a favourable or intermediate MSKCC prognostic score. A total of 83% of participants had received previous immunotherapy and the remaining 17% of participants were unsuitable for immunotherapy so had received other first-line therapies. The primary outcome of the RCT was overall survival. The RCT was terminated early, on ethical grounds, after an independent review decided that sorafenib should be offered to participants who were receiving placebo. For the whole trial population, at the time of the first interim analyses, the median overall survival in the sorafenib RCT had not been reached in the sorafenib arm, and was 14.7 months in the placebo arm (HR 0.72, 95% CI 0.54 to 0.94; p = 0.02). The difference was not considered statistically significant because it did not reach the pre-specified O'Brien–Fleming threshold of less than or equal to 0.0005. From the whole trial population of the sorafenib RCT, results were reported of a pre-planned interim analysis and an unplanned updated analysis (at the point of crossover) for progression-free survival. For the pre-planned analyses, both the independent and investigator assessments resulted in statistically significant differences in median progression-free survival. The independent assessment of median progression-free survival was 5.5 months in the sorafenib arm compared with 2.8 months in the placebo arm (HR 0.44, 95% CI 0.35 to 0.55). The investigator assessment of median progression-free survival was 5.9 months in the sorafenib arm compared with 2.8 months in the placebo arm (p < 0.001). The unplanned investigator assessment of median progression-free survival at the time of crossover was 5.5 months in the sorafenib arm compared with 2.8 months in the placebo arm (HR 0.51, 95% CI 0.43 to 0.60). The sorafenib RCT measured tumour response rate. Out of the whole trial population, one participant who received sorafenib achieved a complete tumour response compared with none who received placebo. A total of 43 (10%) participants receiving sorafenib and 8 (2%) receiving placebo achieved a partial response, and 333 (74%) participants receiving sorafenib and 239 (53%) receiving placebo achieved stable disease. This difference was statistically significant (p < 0.001). Health-related quality of life was measured in the whole trial population of the sorafenib RCT using the FACT-G and FKSI indices. There was no significant difference between the placebo and sorafenib groups in mean FACT-G physical well-being score nor was there any statistically significant difference in mean FKSI-10 total score between groups over the first 32 weeks of treatment (p = 0.83 and p = 0.98, respectively). However, median time to health status deterioration, as defined by a four-point or more drop in FKSI-10 total score, was significantly greater for those receiving sorafenib compared with those receiving placebo (p < 0.0001). On the following items of the FKSI-15 index, those people who had received sorafenib scored significantly better than those who had received placebo: coughing (p < 0.0001); fever (p = 0.0015); worry about their disease (p = 0.0004); ability to enjoy life (p = 0.0119). However, a significantly greater number of people receiving sorafenib reported 'bothersome side effects of treatment' than those receiving placebo (p < 0.0001). Skin rashes, hypertension, diarrhoea and hand–foot syndrome were more common in the sorafenib arm. One randomised discontinuation trial was also identified that compared sorafenib with best supportive care. The randomised discontinuation trial included 65 people with advanced and/or metastatic RCC. In most participants immunotherapy had failed. Most participants in this trial had an ECOG performance status of 0 or 1 and had undergone prior nephrectomy. The median progression-free survival in the sorafenib randomised discontinuation trial was significantly longer for participants receiving sorafenib (24 weeks) compared with those receiving placebo (6 weeks); p = 0.0087. At 24 weeks, a greater proportion of participants who had received sorafenib had no evidence of disease progression compared with those who had received placebo (50% and 18%, respectively; p = 0.0077). Overall survival, health-related quality of life and adverse events were not assessed in the randomised discontinuation trial. Two single-arm phase II studies, of 63 and 106 participants, investigated the effectiveness of sunitinib as second-line treatment following prior nephrectomy and at least one course of cytokine-based therapy. A total of 57% of the pooled population had an ECOG performance status of 0. In both studies, sunitinib was given until disease progression, and dose reductions were allowed if adverse effects were observed. In both studies, the primary outcome was objective tumour response. The median overall survival in the smaller sunitinib study was 16.4 months (95% CI 10.8 to 'not reached') and 23.9 months (95% CI 14.1 to 30.7) in the larger sunitinib study. The median progression-free survival in the smaller sunitinib study was 8.7 months (95% CI 5.5 to 10.7) and 8.8 months (95% CI 7.8 to 13.5) in the larger sunitinib study. No participants achieved a complete tumour response in either of the sunitinib studies. A total of 40% in the smaller sunitinib study and 33% in the larger sunitinib study achieved partial tumour responses. Approximately equal proportions of the remaining participants in both studies experienced stable disease or progressive disease. Informal analysis comparing the pooled sunitinib studies with the best supportive care arm of the sorafenib RCT suggests that sunitinib may be clinically effective compared with best supportive care. ## Second-line treatment for people unsuitable for immunotherapy The Assessment Group did not identify any full reports of RCTs assessing sorafenib as a second-line treatment for people with advanced and/or metastatic RCC who were unsuitable for immunotherapy. The manufacturer of sorafenib (Bayer) submitted data from an RCT with a small population subgroup (17% of the total number of participants) who were unsuitable for immunotherapy but had received other first-line treatments. This was a trial of sorafenib compared with placebo, which was assumed to be equivalent to best supportive care. Further details of the sorafenib RCT are given in section 4.1.15. The Assessment Group did not consider the results from this subgroup because it was unclear whether the subgroups were defined at the start of the study and the size of the subgroup was small. The results of the trial for this subgroup were marked as academic in confidence. Therefore they are not presented in this document. ## Summary of clinical effectiveness The Assessment Group concluded from a summary of the data on the clinical effectiveness of first-line treatments for people who are suitable for immunotherapy, that bevacizumab plus IFN-α appears to have significant benefits compared with IFN-α alone in terms of progression-free survival and tumour response. For people with poor prognosis, temsirolimus appears to have significant benefits compared with IFN-α in terms of overall survival, progression-free survival and tumour response rate. There is some evidence to suggest that temsirolimus may have a differential effect on people who have non-clear-cell carcinoma and who have not undergone nephrectomy. The frequency of adverse events associated with bevacizumab and temsirolimus is comparable to that associated with IFN-α monotherapy, but the adverse event profiles differ between treatments. The Assessment Group concluded that for second-line treatment for people in whom immunotherapy had failed, sorafenib demonstrated clinically and statistically significant benefits compared with best supportive care in terms of progression-free survival and tumour response rate. Sorafenib was associated with more adverse events than best supportive care, particularly hand–foot skin reactions and hypertension. The Assessment Group also stated that although an informal comparison suggests that sunitinib may be beneficial compared with best supportive care, no definitive conclusions could be drawn because of the absence of any comparator in the studies. # Cost effectiveness No published studies of the cost effectiveness of bevacizumab, sorafenib, sunitinib or temsirolimus were identified. The manufacturers of each of the drugs submitted cost-effectiveness models and the Assessment Group developed a model for each treatment question. ## Manufacturers' models The manufacturer of bevacizumab (Roche Products) submitted a simple state-transition model with three health states: progression-free survival, progressive disease and death. The model compared bevacizumab plus IFN-α with IFN-α plus placebo as a first-line treatment for people suitable for immunotherapy. Patient-level data were taken from the bevacizumab trial (see section 4.1.2) and IFN-α use was limited to 1 year in both treatment arms as in the trial. Gompertz survival curves were fitted to the overall and progression-free survival data from the IFN-α plus placebo arm in the trial and the progression-free survival curve for the bevacizumab plus IFN-α arm. Because median overall survival was not reached in the bevacizumab plus IFN-α arm, the hazard ratio from the stratified 'safety population' was applied to the baseline IFN-α plus placebo overall survival Gompertz curve. The treatment-specific (that is, different utility scores calculated for the different trial arms) utility data from an RCT of sunitinib compared with IFN-α were averaged and the following values assigned: progression-free survival = 0.78 and progressive disease = 0.705. Drug costs were adjusted according to RCT data on dose intensity (that is, the amount of drug administered in a clinical trial as a proportion of the amount that would have been administered if there had been no withdrawals of participants or dose reductions). The cost adjustment of bevacizumab was estimated as 62%; that of IFN-α was estimated as 80% and 63% when used with bevacizumab and as monotherapy, respectively. A 'dose cap' pricing strategy was applied with bevacizumab being free to the NHS once 10 g has been purchased for a patient within a year of initiation of treatment. With discounting at 3.5% per annum, the comparison of bevacizumab plus IFN-α with IFN-α plus placebo produced a base-case incremental cost-effectiveness ratio (ICER) of £74,999 per quality-adjusted life year (QALY) gained. One-way sensitivity analyses consisted only of exploring the effects of using an alternative log–logistic survival curve in the extrapolation of trial results. The use of this model reduced the ICER to £39,978 per QALY gained. The manufacturer of bevacizumab acknowledged that this sensitivity analysis may be implausible because the use of a log–logistic model resulted in a longer life expectancy (20 years) than would be expected for people with advanced and/or metastatic RCC. The manufacturer of temsirolimus (Wyeth Pharmaceuticals) submitted a state-transition model with three health states: progression-free survival, post-progression and death. The progression-free survival state was then subdivided into stable disease, complete/partial response and progressive disease. The model compared temsirolimus with IFN-α as a first-line treatment for people with at least three of six risk factors for poor prognosis, who were suitable for immunotherapy. Patient-level data were taken from the temsirolimus trial described in section 4.1.7. Weibull regression models were applied to progression-free survival and overall survival data to calculate the time-dependent state transition probabilities. The following health-state utility values, derived from the temsirolimus trial, were applied: 0.658 for complete/partial response, 0.600 for stable disease and 0.446 for progressive disease and post-progression. Drug costs were adjusted according to RCT data on dose intensity and estimated as 92% for temsirolimus and 56% for IFN-α. At the time of the original submission, the manufacturer used a price of £515 (excluding VAT) for a 30-mg vial of temsirolimus (see section 4.2.18) and no wastage was assumed. With discounting at 3.5% per annum, the comparison of temsirolimus with IFN-α produced an ICER of £55,814 per QALY gained in the base case. The one-way sensitivity analyses demonstrated that the ICER was most sensitive to the drug-related treatment costs and when these were explored the ICERs ranged from £39,977 to £65,542 per QALY gained. In subgroup analyses, the ICER for the subgroup with clear cell carcinoma was £57,731 per QALY gained, £51,159 per QALY gained for the subgroup with non-clear-cell carcinoma, £60,575 per QALY gained for those with prior nephrectomy and £49,690 per QALY gained for those without prior nephrectomy. The manufacturer of temsirolimus (Wyeth Pharmaceuticals) submitted an indirect comparison of temsirolimus with best supportive care. The model described in section 4.2.4 was used. Data were taken from the temsirolimus RCT and an RCT that compared IFN-α with medroxyprogresterone (MPA). With discounting at 3.5% per annum, the indirect comparison of temsirolimus with best supportive care produced an ICER of £81,201 per QALY gained. No sensitivity analyses were conducted. The manufacturer of sorafenib (Bayer) submitted a simple state-transition model with three health states: progression-free survival, progressed disease and death. The model compared sorafenib with best supportive care for people in whom immunotherapy had failed or who were unsuitable for immunotherapy. Patient-level data were taken from the sorafenib RCT (see section 4.1.15). For progression-free survival, the trial data were used directly for both the sorafenib and placebo arms. However, because of a short follow-up period, the data for overall survival were immature and were extrapolated over time by using an exponential function. Analysis was presented according to the following subgroups: people receiving sorafenib as second-line treatment after failure of immunotherapy; people receiving sorafenib as a second-line treatment who were unsuitable for immunotherapy and in whom a non-immunotherapy-based first-line treatment had failed; and a combination of the two subgroups. An exploratory analysis comparing sorafenib with sunitinib as second-line treatments was also presented. However, because the subgroup data and indirect comparison were marked as academic in confidence, only the data for the whole population are presented in this document. The following health-state utility values, taken from an unpublished survey of physicians, were applied: 0.737 for progression-free survival and 0.548 for progressed disease. The model assumed a sorafenib dose intensity of 100%. The manufacturer used a price of £2504.60 (excluding VAT) for a pack of 200-mg tablets (112 per pack). With discounting at 3.5% per annum, the comparison of sorafenib with best supportive care produced an ICER of £90,630 per QALY gained for the combined group in the base case. The one-way sensitivity analyses did not produce an ICER lower than £60,000 per QALY gained as demonstrated by Tornado diagrams reported in the manufacturer's submission. The ICERs were most sensitive to health utility values for progression-free survival and progressed disease, and the resource associated with the number of inpatient days required when receiving sorafenib and best supportive care. The manufacturer of sorafenib submitted revised cost-effectiveness analyses for the whole trial population and for the 83% of the trial participants in whom immunotherapy had failed. The revised cost-effectiveness estimates also incorporated a patient access scheme in which the first pack of sorafenib is free to the NHS. The Department of Health considered that this patient access scheme does not constitute an excessive administrative burden on the NHS. Details of the new price of sorafenib of £2980.47 for a pack of 112 200-mg tablets, which was agreed in the context of the Pharmaceutical Price Regulation Scheme (PPRS), were also provided. In the revised analyses, the progression-free and overall survival curves for both sorafenib and best supportive care were modelled by fitting independent Weibull distributions to each separate curve (rather than exponential extrapolation as in the original submission). The manufacturer stated that this approach was justified because it was more consistent with the distributions used in the Assessment Group's economic model. The manufacturer also made further amendments to the cost and utility assumptions to more closely reflect the original model developed by the Assessment Group. The revised ICER (taking into account the patient access scheme and new price) for the whole trial population was £72,546 per QALY gained. The revised ICER (taking into account the patient access scheme and new price) for the subgroup of participants in whom immunotherapy had failed was £62,256 per QALY gained. No sensitivity analyses of the revised cost-effectiveness estimates were presented by the manufacturer of sorafenib. In the original submission, the manufacturer of sorafenib (Bayer) also submitted a cost-effectiveness estimate of sorafenib as second-line treatment for people who were unsuitable for immunotherapy compared with best supportive care. Patient-level data were taken from a small population subgroup of 17% of participants in the sorafenib RCT (described in section 4.1.15). The cost-effectiveness estimates for this subgroup were marked as academic in confidence. Therefore they are not presented in this document. The manufacturer of sunitinib (Pfizer) submitted a simple state-transition model with three health states: progression-free survival, progressed disease and death. The model compared sunitinib with best supportive care as second-line therapies. Patient-level data on the effectiveness of sunitinib were taken from the smaller of the two single-arm phase II trials (see section 4.1.21). Data for best supportive care were taken from a pooled analysis of a review and Medicare data. Survival analysis was used to model disease progression, survival and treatment effect, with Weibull survival curves used to extrapolate independent data from different sources. The health-state utilities used were taken from EQ-5D data collected in the single-arm phase II trial with different utility values assigned according to treatment and health state: sunitinib/progression-free survival = 0.803; best supportive care/progression-free survival = 0.758; sunitinib/progressed disease and best supportive care/progressed disease = 0.683. The cost-effectiveness estimates also incorporated a patient access scheme in which the first pack of sunitinib is free to the NHS. The Department of Health considered that this patient access scheme does not constitute an excessive administrative burden on the NHS. With discounting at 3.5% per annum, the comparison of sunitinib with best supportive care produced an ICER of £37,519 per QALY gained in the base case. The one-way sensitivity analyses demonstrated that the ICER was most sensitive to time spent in progression and the data source for best supportive care. The ICERs ranged from £27,935 to £206,962 per QALY gained when these parameters were explored. ## Assessment Group model The Assessment Group model was developed to estimate the cost effectiveness of bevacizumab plus IFN-α, sorafenib, sunitinib and temsirolimus against relevant comparators within the licensed indications for each drug, and according to the appraisal scope. The Markov model considered three treatment strategy questions: first-line treatment (bevacizumab plus IFN-α compared with IFN-α); first-line treatment of people with a poor prognosis (temsirolimus compared with IFN-α) and second-line treatment (sorafenib compared with best supportive care) using similar model structures but with different model parameter data for each question. The model used three distinct health states: progression-free survival, progressive disease and death. For first-line treatment of people suitable for immunotherapy, baseline disease progression (IFN-α alone) was taken from the bevacizumab study (see section 4.1.2). Data for progression-free survival and overall survival for people receiving IFN-α were read directly from reported Kaplan–Meier curves, and Weibull curves were then fitted for use in the model. The disease progression for bevacizumab plus IFN-α was estimated using the ITT hazard ratios from the bevacizumab trial. For first-line treatment of people with at least three of six factors indicating poor prognosis and who are suitable for immunotherapy, baseline disease progression (IFN-α alone) for progression-free survival and overall survival were estimated by fitting Weibull curves to empirical data from the temsirolimus study (see section 4.1.7). The disease progression for temsirolimus was estimated by applying the hazard ratios for progression-free and overall survival from the temsirolimus study. The following subgroup analyses were also performed: clear cell and non-clear-cell carcinoma; prior nephrectomy and no prior nephrectomy; a poor prognosis according to the MSKCC score (approximately 75% of participants in the temsirolimus study). The cost effectiveness of bevacizumab plus IFN-α for people with a poor prognosis was not estimated because of the small number of participants with a poor prognosis in the bevacizumab study. For second-line treatment, baseline disease progression was modelled by fitting Weibull curves to the empirical progression-free survival and overall survival curves from the best supportive care arm of the sorafenib RCT. Disease progression for participants receiving sorafenib was estimated by applying the hazard ratios from the sorafenib RCT. No subgroup analyses were presented in the Assessment Group model as it was not clear whether the subgroups were defined a priori and the sample size calculations were based on the entire trial population. The cost effectiveness of sunitinib as a second-line treatment compared with best supportive care was not evaluated in the Assessment Group model because the data came from two single-arm trials and were considered inadequate by the Assessment Group. The health-state utilities used in the Assessment Group model were derived from trial data in the manufacturer submissions and UK EQ-5D tariffs. Participants were assumed to be similar at baseline in terms of health-state value. Therefore treatment-specific health-state values were not applied. People who receive first-line treatments were assumed to have a utility of 0.78 when in the PFS state and 0.70 when in the PD state; these assumptions came from the data submitted by the manufacturer of sunitinib and used in the appraisal of sunitinib as a first-line treatment for advanced and/or metastatic RCC. People with a poor prognosis who can receive first-line treatments were assumed to have a utility of 0.60 when in the PFS state and 0.45 when in the PD state; these assumptions came from the Wyeth submission. People who were receiving second-line treatments were assumed to have a utility of 0.76 when in the PFS state and 0.68 when in the PD state; these assumptions came from the Pfizer submission. In the Assessment Group model, drug acquisition costs (except for sorafenib) were modified according to dose intensities reported in the relevant RCTs. Current list prices were taken from the BNF (edition 55), and the agreed patient access scheme of the first pack of sorafenib being free to the NHS was applied. All other costs were inflated to 2007–8 values. Because temsirolimus had no BNF list price at the time of the submission, the price of a 30-mg vial was inferred from the price of a 25-mg dose of temsirolimus as submitted by the manufacturer, and calculated as £618. However, the price stated by the manufacturer in their original submission of £515 was included in the sensitivity analyses. The patient access scheme for bevacizumab, which was described by the manufacturer, was included in sensitivity analyses only. It was assumed that 100% of IFN-α monotherapy was administered at home, with 75% being self-administered. Additional resource uses associated with outpatient monitoring, scans and tests were used in the model for people in the PFS health state on drug treatment. In the PFS state, the medical management cost per cycle was £81 for best supportive care and £223 for all other drug treatments. In the PD state, the cost for each cycle was £435 for all treatments. A number of one-way and multi-way sensitivity analyses were performed to test the sensitivity of the cost-effectiveness analyses. The key sensitivity analyses investigated the assumptions that were made on clinical effectiveness, drug acquisition and administration costs, best supportive care and management costs and health-state utility values. In particular, the Assessment Group highlighted a paucity of data surrounding accurate health-state utility values and best supportive care costs. The Assessment Group performed sensitivity analyses on their own model by varying their own assumptions and also by incorporating the manufacturers' parameters. The Assessment Group also performed sensitivity analyses on the manufacturers' models by incorporating the Assessment Group's parameters and assumptions. With discounting at 3.5% per annum, the comparison of bevacizumab plus IFN-α with IFN-α alone produced an ICER of £171,301 per QALY gained. The deterministic sensitivity analyses demonstrated that estimates of treatment effectiveness, drug pricing (including dose intensity data) and health-state utility input parameters were the key drivers affecting the ICERs. The ICERs were particularly sensitive to variations in estimates of the hazard ratio for overall survival, with ICERs ranging from £90,693 (HR for overall survival = 0.58) to £868,881 (HR for overall survival = 0.97) per QALY gained for bevacizumab plus IFN-α compared with IFN-α alone. With discounting at 3.5% per annum and using a vial price of £618, the comparison of temsirolimus with IFN-α produced an ICER of £94,385 per QALY gained. In the subgroup analyses for temsirolimus (clear cell, non-clear-cell carcinoma; nephrectomy, no nephrectomy; and only participants with a poor prognosis according to the Motzer criteria), the ICERs ranged from £74,184 to £154,334 per QALY gained. The only subgroup that demonstrated a lower ICER than the base-case analysis was the subgroup with no prior nephrectomy, at £74,184 per QALY gained. The deterministic sensitivity analyses demonstrated that estimates of treatment effectiveness, cost of acquisition and administration of temsirolimus, and health-state utility input parameters were the key drivers affecting the ICERs. The ICER was particularly sensitive to variations in estimates of the hazard ratio for overall survival, with ICERs ranging from £56,452 (HR for overall survival = 0.58) to £253,443 (HR for overall survival = 0.92) per QALY gained in the Assessment Group's initial analyses. With discounting at 3.5% per annum and using the original price of £2504.60, the comparison of sorafenib with best supportive care produced an ICER of £102,498 per QALY gained for all patients. The deterministic sensitivity analyses demonstrated that estimates of treatment effectiveness and cost of sorafenib (dose intensity assumption) were the key drivers affecting the ICERs. The health-state utility parameters affected the ICER marginally. The ICER was particularly sensitive to variations in estimates of the hazard ratio for overall survival, with ICERs ranging from £55,585 (HR for overall survival = 0.54) to £368,830 (HR for overall survival = 0.94) per QALY gained. All ICERs were higher when using the Assessment Group model than the manufacturers' models. In general, the model structures used by the Assessment Group and the manufacturers were similar. However, there were some differences in assumptions and data inputs that have been highlighted by the Assessment Group. In relation to the economic model submitted by Roche Products (bevacizumab plus IFN-α compared with IFN-α plus placebo), the Assessment Group stated that it was essentially the assumptions about costs (especially drug-related costs) that were associated with different cost-effectiveness estimates. If the original 'dose cap' patient access scheme detailed by the manufacturer was applied in the Assessment Group model, the ICER in the Assessment Group model was reduced from £171,301 to £90,584 per QALY gained. Similarly, if the original 'dose cap' patient access scheme was removed from the manufacturer's model, the ICER increased from £74,999 to £108,329 per QALY gained. Another important difference between the manufacturer's and Assessment Group models is the use of data on dose intensity. Incorporating the Assessment Group's higher dose intensity estimates into the manufacturer economic model further increased the ICER from £74,999 to £117,000 per QALY gained. In relation to the economic model submitted by Wyeth Pharmaceuticals (temsirolimus compared with IFN-α), the Assessment Group stated that the key differences were the assumptions made on resource use and costs, particularly costs associated with the acquisition of temsirolimus and the administration of IFN-α. If the Assessment Group's assumptions of lower costs of administration of IFN-α were incorporated into the Wyeth model (which used a vial price of £515), the Wyeth base case ICER increased from £55,814 to £102,000 per QALY gained. The ICERs for the different subgroups also increased: from £51,159 to £63,100 per QALY gained for the subgroup with non-clear-cell carcinoma; from £57,731 to £121,300 per QALY gained for the subgroup with clear cell carcinoma; from £49,690 to £84,000 per QALY gained for the subgroup with no prior nephrectomy; and from £60,575 to £117,000 per QALY gained for the subgroup with prior nephrectomy. Following consultation on the draft guidance, the Assessment Group and the Decision Support Unit (DSU) were requested to explore the issues raised during the consultation. The manufacturer of bevacizumab (Roche Products) requested that the following parameters were altered in the Assessment Group's economic model: The hazard ratio for overall survival should be reduced from 0.75 to 0.613. This is because 28% of the participants in the bevacizumab plus IFN-α arm and 18% of the participants in the IFN-α plus placebo arm of the trial received second-line treatments. The hazard ratio of 0.613 represents the effect of bevacizumab plus IFN-α compared with IFN-α plus placebo on overall survival when the participants who received any second-line treatments were censored from the analysis. The average cumulative dose of bevacizumab per participant should be based on the empirical trial data; that is, an average dose of 756.7 mg of bevacizumab per administration (the Assessment Group's base case assumed an average bevacizumab dose intensity of 88% over 12 months, which was based on the dosage implied by the trial protocol). The average number of bevacizumab administrations per participant should be based on empirical trial data; that is, an average duration of bevacizumab treatment of 7.36 months (the Assessment Group's base case assumed a treatment duration of 12 months, based on the interpretation of the trial protocol). The cost of bevacizumab administration should be reduced from £197 to £98 because of the reduced time needed to administer intravenous bevacizumab. Applying these parameter changes to the Assessment Group's base case reduced the cost-effectiveness estimate of bevacizumab plus IFN-α compared with IFN-α plus placebo. Applying the revised hazard ratio for overall survival reduced the ICER from £171,301 per QALY gained to £101,340 per QALY gained. Using the empirical trial data on dosage of bevacizumab and number of administrations reduced the base-case ICER from £171,301 to £114,624 per QALY gained and reduced the revised ICER (with a hazard ratio for overall survival of 0.613) from £101,340 to £68,561 per QALY gained. Reducing the cost of bevacizumab administration further reduced the base-case ICER from £114,624 to £108,835 per QALY gained and the revised ICER (with a hazard ratio for overall survival of 0.613) from £68,561 to £65,213 per QALY gained. The DSU highlighted concerns that the revised hazard ratio for overall survival as presented by Roche (0.613) was now lower than the hazard ratio for progression-free survival (0.63). The DSU performed additional analysis of the parameter changes that set the hazard ratio for overall survival equal to that of progression-free survival (that is, hazard ratios of 0.63 for both). This reduced the original Assessment Group base-case ICER from £171,301 to £107,489 per QALY gained. Following consultation on the parameter changes made to the Assessment Group model by the DSU, the manufacturer of bevacizumab responded stating that the dose intensity should be revised to 92%. A revised cost of bevacizumab administration of £170 per dose was also suggested by the manufacturer of bevacizumab. The DSU was requested to calculate an updated cost-effectiveness estimate for bevacizumab plus IFN-α compared with IFN-α in the Assessment Group's model. The DSU was asked to use the following parameters: a corrected bevacizumab dose intensity of 92%; a bevacizumab administration cost of £170; and a hazard ratio for overall survival of 0.63 (equal to that of progression-free survival). Using these parameters in the Assessment Group's model resulted in an ICER of £82,732 per QALY gained for bevacizumab plus IFN-α compared with IFN-α. Following further consultation, the manufacturer of bevacizumab (Roche) included details of an updated patient access scheme which had been agreed with the Department of Health. The patient access scheme includes a rebate of the costs of bevacizumab after 10 g has been given to a patient in a 12-month period and a rebate of all costs of IFN-α when it is given with bevacizumab. The Department of Health considered that this patient access scheme does not constitute an excessive administrative burden to the NHS. The DSU was asked to provide a revised cost-effectiveness estimate using the Assessment Group model, incorporating the parameter changes requested by the manufacturer of bevacizumab (see section 4.2.27) and the costs with the patient access scheme. Applying the parameter changes and including the costs from the patient access scheme reduced the cost-effectiveness estimate of bevacizumab plus IFN-α compared with IFN-α plus placebo from £82,732 to £53,820 per QALY gained. The manufacturer of sorafenib (Bayer) provided a late submission, which revised their original analysis of the whole trial population and the 83% of participants in whom first-line immunotherapy had failed. No revised analyses were provided of the 17% in whom other first-line (non-immunotherapy) treatments had failed. The revised analyses also included details of a patient access scheme in which the first pack of sorafenib is free to the NHS. The manufacturer also presented information about the new price of sorafenib in the context of the PPRS. The DSU was asked to appraise the approach used by the manufacturer and provide cost-effectiveness estimates using the Assessment Group model, incorporating costs with the scheme and the new increased price. In relation to the approach used by the manufacturer. The DSU acknowledged that the alternative modelling approach, utility values and costs had been changed by the manufacturer to reflect those used in the Assessment Group model and that a more complete dataset for the people in whom immunotherapy had failed was used in the revised analyses. The DSU also agreed with the manufacturer that the assumption of proportional hazards was not valid and this resulted in a large reduction in the ICERs. However, the DSU noted that the revised analysis resulted in ICERs for people in whom immunotherapy had failed which were lower than the total group ICERs and this was markedly different from the original (confidential) analyses presented by the manufacturer of sorafenib, where the subgroup ICER was higher than the total group ICER. The DSU also highlighted that the follow-up of the participants randomised to receive sorafenib was much longer than that of the participants randomised to receive best supportive care. This was because participants were allowed to crossover from best supportive care to sorafenib treatment after the study was terminated early on ethical grounds. There were also no details about whether participants randomised to receive sorafenib received any subsequent treatments. Therefore the DSU stated that a more appropriate approach would have been to censor both arms at the same point. The DSU noted that this approach was presented in the main publication of the trial. The DSU then calculated the respective cost-effectiveness estimates using the Assessment Group's economic model. The DSU accepted arguments presented by the manufacturer of sorafenib that the proportional hazards assumption did not hold and that independent curve modelling should be used. In order to address the concerns surrounding the censoring approach used by the manufacturer, the DSU censored both arms at the same point (that is, at the point of trial termination). The DSU then modelled the progression-free and overall survival curves for sorafenib and best supportive care using independent Weibull curves. The revised ICER for the whole trial population (including costs with the patient access scheme and new price) was £74,915 per QALY gained. The revised ICER (including costs with the patient access scheme and new price) for the subgroup of participants in whom immunotherapy had failed was £65,929 per QALY gained. # Consideration of the evidence The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of bevacizumab (first-line), sorafenib (first- and second-line), sunitinib (second-line) and temsirolimus (first-line), having considered evidence on the nature of the condition and the value placed on the benefits of bevacizumab (first-line), sorafenib (first- and second-line), sunitinib (second-line) and temsirolimus (first-line) by people with advanced and/or metastatic RCC, those who represent them, and clinical specialists. It was also mindful of the need to take account of the effective use of NHS resources. The Committee heard from clinical specialists and patient experts that there are limited treatment options for people with advanced and/or metastatic RCC. The Committee noted that the only current standard first-line treatment is immunotherapy and there are no current treatment options for people in whom immunotherapy has failed or who are considered unsuitable for immunotherapy. Moreover, there are no current standard second-line treatment options. The Committee heard from people with RCC and patient experts that immunotherapy is associated with limited effectiveness and high toxicity. The Committee also heard that RCC does not respond well to conventional chemotherapies and that bevacizumab (first-line), sorafenib (first- and second-line), sunitinib (second-line) and temsirolimus (first-line) represent improvements in the treatment of advanced and/or metastatic RCC. The Committee heard from people with RCC and patient experts that advanced and/or metastatic RCC is a relatively rare cancer and noted the views of both patient and clinical experts concerning the severity of the disease. The Committee also heard from clinical experts, the Assessment Group and manufacturers that there is a paucity of data on the utility values associated with living with advanced and/or metastatic RCC. The Committee noted that it may be difficult to fully capture the effects of bevacizumab (first-line), sorafenib (first- and second-line), sunitinib (second-line) and temsirolimus (first-line) on health-related quality of life. The Committee acknowledged the comments that were received from people with RCC and the public, stating that some people with RCC had experienced significant improvements in their quality of life as a result of using the drugs. The Committee was aware of the supplementary advice from NICE that should be taken into account when appraising treatments which may extend the life of people with a short life expectancy and which are licensed for indications that affect small numbers of people with incurable illnesses. For this advice to be applied, all the following criteria must be met: The treatment is indicated for patients with a short life expectancy, normally less than 24 months. There is sufficient evidence to indicate that the treatment offers an extension to life, normally of at least an additional 3 months, compared with current NHS treatment. No alternative treatment with comparable benefits is available through the NHS. The treatment is licensed or otherwise indicated for a small patient population.In addition, when taking these into account the Committee must be persuaded that the estimates of the extension to life are robust and the assumptions used in the reference case economic modelling are plausible, objective and robust. ## First-line treatment for people suitable for immunotherapy The Committee reviewed the evidence of clinical effectiveness from the bevacizumab study. The Committee noted that bevacizumab plus IFN-α demonstrated a statistically significant gain in terms of progression-free survival compared with IFN-α plus placebo. The Committee was aware that the data presented on overall survival were immature because median overall survival had not been reached. The Committee was persuaded that bevacizumab plus IFN-α is a clinically effective first-line treatment. However, the Committee heard testimony from clinical specialists and people with RCC that IFN-α is associated with high toxicity, is poorly tolerated and is administered by subcutaneous injection. Therefore the Committee was mindful of the concerns highlighted by patient experts and clinical specialists associated with the combination of bevacizumab and IFN-α. The Committee considered the estimates of cost effectiveness of bevacizumab plus IFN-α. It noted that the models from the manufacturer and the Assessment Group were similar in terms of structure and data sources; the models differed chiefly in the drug acquisition costs. These differences resulted in different estimates of cost effectiveness between the manufacturer and the Assessment Group of £75,000 and £171,000 per QALY gained, respectively. The Committee noted that when the original patient access scheme was applied to the Assessment Group cost-effectiveness estimate, the Assessment Group base-case ICER was reduced from £171,000 to £90,500 per QALY gained. The Committee noted that the original patient access scheme was not agreed by the Department of Health and that the final agreed patient access scheme had an additional component which would further reduce these ICERs. The Committee considered the parameter changes suggested by the manufacturer of bevacizumab for insertion into the Assessment Group's model (see section 4.2.27). Although the first suggestion to censor participants once second-line treatments were received was appropriate in principle, the Committee noted that its application produced some anomalous findings: there were more participants in the bevacizumab arm than the IFN-α arm that were censored. Although the Committee noted that, on average, the participants in the bevacizumab plus IFN-α arm had received treatment for almost twice as long as those in the IFN-α plus placebo arm, the Committee considered that the cause of the greater censoring was likely to be the withdrawal of more participants from bevacizumab plus IFN-α treatment than IFN-α plus placebo treatment because of the adverse effects of bevacizumab plus IFN-α. It also noted that the revised hazard ratio for overall survival was now lower than the original hazard ratio for progression-free survival. The Committee considered that a reduced hazard ratio for overall survival was plausible, but that it would not be expected to be lower than the hazard ratio for progression-free survival. The Committee then reviewed the bevacizumab dosages and quantity and cost of bevacizumab administrations applied in the economic model. The Committee accepted that it was plausible that in the trial participants may have stopped treatment before 12 months, but considered that the trial protocol and exact interpretation of treatment duration was unclear. The Committee also considered that lower costs of bevacizumab administration were plausible, although noted that the costs of administration were unlikely to be halved. The Committee noted and accepted the revised dose intensity estimate of 92% and bevacizumab administration cost of £170 as provided by the manufacturer of bevacizumab. The Committee then discussed the fact that bevacizumab was licensed to be given to people with advanced and/or metastatic RCC in combination with IFN-α. It noted that the health-state utilities used in calculating the cost-effectiveness estimate of bevacizumab plus IFN-α compared with IFN-α plus placebo were obtained from an RCT of sunitinib compared with IFN-α (see section 4.2.2), and that the health-state utilities were not treatment specific. The Committee was aware that the costs of adverse effects had been included in the economic model, although these were negligible. It considered that there would be disutility associated with the high toxicity, poor tolerance and issues with the administration of bevacizumab plus IFN-α, that had been highlighted by clinical specialists and patient experts, and that this disutility had not been incorporated into the cost-effectiveness estimate of bevacizumab plus IFN-α compared with IFN-α. Taking these concerns that had been highlighted into account the Committee agreed that the ICER was likely to be an underestimate and therefore the Committee concluded that the lowest plausible ICER estimate was £53,800 per QALY gained. The Committee next discussed whether bevacizumab plus IFN-α for the treatment of advanced and/or metastatic RCC fulfilled the criteria for a life-extending, end-of-life treatment. The Committee noted from the clinical trials that life expectancy with IFN-α treatment alone was unlikely to be greater than 24 months and was potentially as low as 12 months. The Committee agreed that it was likely that bevacizumab plus IFN-α would increase overall survival by more than 3 months in comparison with IFN-α alone. It had heard that RCC does not respond well to IFN-α alone, but considered that bevacizumab plus IFN-α does represent a marked change in the treatment of advanced and/or metastatic RCC. The Committee was aware that the total number of people with advanced and/or metastatic RCC in England and Wales was approximately 4000. However, the Committee understood that it should take into account the cumulative population for each product in considering the strength of any case, for justifying decisions which employ, in whole or part, the supplementary criteria for appraising life-extending, end-of-life treatments. It noted that bevacizumab was licensed for a number of other indications involving much larger patient groups. The Committee noted that the manufacturer argued that the use of bevacizumab was restricted in the UK and that, in effect, the valid patient population for bevacizumab is small. However the Committee considered that this point did not override its view that bevacizumab is licensed for a relatively large population across its range of indications. In summary, the Committee was not persuaded that bevacizumab plus IFN-α meets all the criteria for a life-extending end-of-life treatment, given the size of the patient populations (in RCC and other cancers) for whom it is licensed. The Committee considered the lowest plausible cost-effectiveness estimate of bevacizumab plus IFN-α of £53,800 per QALY gained and concluded that bevacizumab plus IFN-α as a first-line treatment for people with advanced and/or metastatic RCC would not be a cost-effective use of NHS resources. ## First-line treatment for people suitable for immunotherapy with three of six factors indicating poor prognosis The Committee reviewed the evidence of clinical effectiveness from the temsirolimus study. The Committee was mindful that the criteria used for defining poor prognosis in the temsirolimus trial were different from those commonly used in clinical practice. It noted that temsirolimus demonstrated a statistically significant gain in terms of overall survival, progression-free survival and tumour response rate compared with IFN-α. The Committee discussed the available subgroup data, but had concerns as to whether the data were robust enough to distinguish particular subgroup responses. Some of the subgroups were very small, in particular one of the subgroups highlighted by the manufacturer, non-clear-cell carcinoma, was based on less than 20% (n=73) of the trial population. This subgroup was also defined imprecisely as 'non-clear-cell carcinoma and 'indeterminate histologies' in the trial. It was also unclear whether all of the subgroup analyses had been defined a priori. However, the Committee was persuaded that in general temsirolimus is a clinically effective first-line treatment for people with a poor prognosis, and was minded to consider the cost-effectiveness evidence, including the subgroups who might gain greater benefit. Therefore the Committee considered the estimates of cost effectiveness of temsirolimus. It noted that the original models from the manufacturer and the Assessment Group were similar in terms of structure and data sources; the models differed chiefly in the acquisition cost of temsirolimus and costs associated with the administration of IFN-α. However, the Committee heard from clinical specialists that most people would be able to self-administer IFN-α at home and that the proportion needing help with administration assumed by the Assessment Group was considered reasonable. The Committee acknowledged consultation responses from the manufacturer that highlighted that the duration of temsirolimus treatment had been overestimated in the Assessment Group economic model by the use of hazard ratios for deriving survival curves. Therefore the Committee considered that the most appropriate ICERs were those calculated by the manufacturer, but with the Assessment Group's costs for IFN-α administration incorporated and the manufacturer's initial cost for the acquisition of temsirolimus. These resulted in a base-case ICER of £102,000 per QALY gained and subgroup ICERs ranging from £63,100 ('non-clear-cell carcinoma and indeterminate histologies') to £121,300 (clear-cell carcinoma) per QALY gained. However, The Committee noted the recently published price of £620 for a vial of temsirolimus and was aware that these ICER estimates were derived using an underestimate of the price of a vial of temsirolimus of £515. Therefore it concluded that the ICERs were underestimates and would all increase if the recently published price of temsirolimus was incorporated into the cost-effectiveness analyses. The Committee next discussed whether temsirolimus for the treatment of advanced and/or metastatic RCC fulfilled the criteria for a life-extending, end-of-life treatment. The Committee noted from the clinical trials that life expectancy with IFN-α treatment alone was unlikely to be greater than 24 months and was potentially as low as 7 months for patients with a poor prognosis. The Committee considered that evidence from the temsirolimus trial suggested that temsirolimus increased survival by more than 3 months compared with IFN-α alone and it considered temsirolimus to be an improvement in treatment for advanced and/or metastatic RCC. It was aware that the total number of people with advanced and/or metastatic RCC in England and Wales was approximately 4000 and that temsirolimus was licensed for people with a poor prognosis and so had a very small patient population. The Committee agreed that the criterion for the robustness of evidence was convincing for the overall trial data, but not for the subgroup data. In summary, the Committee was satisfied that temsirolimus met the criteria for being a life-extending, end-of-life treatment for the whole trial population. The Committee then considered the cost-effectiveness estimate of temsirolimus of £102,000 per QALY gained (noting that this was an underestimate because of the underestimated price of temsirolimus), in light of the appraisal of a life-extending, end-of-life treatment. The Committee was aware that the patient population eligible for temsirolimus treatment was very small, but noted that NICE had not received direction from the Department of Health that 'ultra-orphan' conditions should be appraised differently from any other appraisal; including those that meet the end-of-life criteria. The Committee considered that the additional weight that would need to be assigned to the original QALY benefits in this patient group for the cost effectiveness of temsirolimus to fall within the current threshold range would be too great. The subgroup data were not considered to be robust enough to apply a consideration of additional weight that would need to be assigned to the original QALY benefits in these subgroups. Therefore the Committee concluded that temsirolimus as a first-line treatment for people with advanced RCC and a poor prognosis would not be a cost-effective use of NHS resources. Very few data were presented to the Committee on the clinical effectiveness of bevacizumab plus IFN-α compared with IFN-α plus placebo as a first-line treatment for people with a poor prognosis, suitable for immunotherapy. The Committee noted that only a small subgroup of the bevacizumab RCT (see section 4.1.2) had a poor prognosis and the data available confirmed no benefit in terms of progression-free survival. The Committee concluded that with such limited evidence, it could not consider bevacizumab plus IFN-α as a clinically effective first-line treatment for people with poor prognosis, suitable for immunotherapy with advanced and/or metastatic RCC. ## First-line treatment for people unsuitable for immunotherapy The only data presented to the Committee for the first-line treatment of people unsuitable for immunotherapy came from two single-arm studies of sorafenib which were presented in abstract form only. The Committee concluded that, with such weak evidence, it could not consider sorafenib as a clinically effective first-line treatment for people with advanced RCC who were unsuitable for immunotherapy. ## First-line treatment for people unsuitable for immunotherapy with three of six factors indicating poor prognosis The Committee reviewed the evidence of clinical and cost effectiveness for temsirolimus compared with best supportive care as presented by the manufacturer (Wyeth Pharmaceuticals). The Committee was aware that the data informing the comparisons came from an indirect comparison. Limited information on the trial used in the comparison was presented and the Committee heard that the best supportive care in the trial was unlikely to be offered as current clinical practice. The Committee concluded that temsirolimus had not been shown to be a clinically effective first-line treatment for people with advanced RCC and a poor prognosis and who were unsuitable for immunotherapy. No data were presented to the Committee on the clinical or cost effectiveness of sorafenib compared with best supportive care as a first-line treatment for people with a poor prognosis who were unsuitable for immunotherapy. The Committee noted that the sorafenib RCT included only people with an ECOG performance status of 0 or 1 and therefore did not include people with a poor performance. The Committee concluded that, in the absence of evidence, sorafenib had not been shown to be a clinically effective first-line treatment for people with advanced RCC and a poor prognosis and who were unsuitable for immunotherapy. ## Second-line treatment for people in whom immunotherapy has failed The Committee reviewed the clinical effectiveness of sorafenib for people in whom immunotherapy has failed. The Committee noted that sorafenib demonstrated a clinically relevant and statistically significant advantage over best supportive care in terms of progression-free survival and tumour response for the 83% of the trial participants in whom immunotherapy had failed. The Committee was persuaded that sorafenib is a clinically effective therapy for second-line treatment of RCC for people in whom immunotherapy has failed. The Committee then reviewed the cost-effectiveness estimates for the subgroup in whom immunotherapy had failed. The Committee noted that the trial was not stratified according to prior treatments, but acknowledged responses from consultation that the subgroup was pre-specified, and considered that the subgroup represented most of the trial participants and was relatively large. The Committee noted comments from the DSU that the reduced ICERs, presented by the manufacturer of sorafenib in the revised analyses, were derived using appropriate modelling techniques, similar to that used by the Assessment Group. However, the Committee agreed that due to the concerns raised by the DSU about the change in direction of the subgroup ICER as presented by the manufacturer of sorafenib that the most reasonable subgroup estimate came from the DSU revised analysis using the Assessment Group's economic model. The Committee, noting instructions from the Department of Health that all of the cost-effectiveness estimates should include the first pack of sorafenib as free to the NHS and the new increased price of sorafenib, accepted that the most plausible ICER for sorafenib compared with best supportive care for people in whom immunotherapy had failed was £65,900 per QALY gained. The Committee next discussed whether sorafenib for the treatment of advanced RCC fulfilled the criteria for consideration as a life-extending, end-of-life treatment. The Committee noted from the clinical trials that life expectancy with best supportive care alone was unlikely to be greater than 24 months and was potentially as low as 6 months. The Committee considered that even though the sorafenib trial was terminated early, this was done after a report of increased progression-free survival in the sorafenib arm. The Committee considered that it was likely that sorafenib would increase overall survival by more than 3 months in comparison with best supportive care. It also agreed that sorafenib provided an improvement in the treatment of advanced RCC. It was aware that the total number of people with advanced and/or metastatic RCC in England and Wales was approximately 4000. Therefore the Committee was satisfied that sorafenib meets the criteria for being a life-extending, end-of-life treatment and that the trial evidence presented for this consideration was robust. The Committee then considered the most plausible cost effectiveness of sorafenib for people in whom immunotherapy had failed, of £65,900 per QALY gained, in light of the appraisal of a life-extending, end-of-life treatment. It considered that the magnitude of additional weight that would need to be assigned to the original QALY benefits in this patient group for the cost effectiveness of the drug to fall within the current threshold range would be too great. Therefore the Committee concluded that sorafenib as a second-line treatment for people with advanced RCC in whom immunotherapy has failed would not be a cost-effective use of NHS resources. The Committee then reviewed the clinical and cost effectiveness for sunitinib as a second-line treatment compared with best supportive care for people in whom immunotherapy had failed. The Committee was concerned that the data informing the comparisons came from two small single-arm trials. The Committee acknowledged that the comparison with best supportive care suggested that sunitinib may be clinically effective compared with best supportive care. However, in the absence of further robust data, the Committee concluded that sunitinib could not be considered a clinically effective second-line treatment for people with advanced and/or metastatic RCC in whom immunotherapy had failed. ## Second-line treatment for people in whom non-immunotherapy first-line treatment has failed and who are unsuitable for immunotherapy The Committee reviewed the academic-in-confidence evidence on the clinical effectiveness of sorafenib compared with best supportive care for people unsuitable for immunotherapy as presented by the manufacturer (Bayer). The Committee noted that the subgroup constituted a small proportion (17%) of the sorafenib RCT, but that the overall trial population was relatively large. Following consultation, the Committee heard that the data informing the comparison came from a pre-planned subgroup from the sorafenib RCT, although it was unclear what prior therapies the subgroup had received. The Committee concluded that, although the data were limited, sorafenib could be considered as a clinically effective second-line treatment for those unsuitable for immunotherapy with advanced RCC. The Committee then reviewed the estimates of cost effectiveness of sorafenib as a second-line treatment for people unsuitable for immunotherapy. The Committee noted that the manufacturer of sorafenib (Bayer) had not provided revised ICERs for this subgroup. The Committee noted that, overall, the revised models submitted by the manufacturer and the Assessment Group were generally similar in terms of structure, data sources and assumptions. The resulting estimates of cost effectiveness were broadly similar with a revised manufacturer base-case ICER for the whole trial population of £72,500, per QALY gained and a DSU revised Assessment Group base-case ICER of £74,900 per QALY gained. The Committee noted that the subgroup ICER for the 83% of trial participants in whom immunotherapy had failed was lower than these ICERs for the whole trial population. The Committee therefore agreed that the most plausible subgroup ICER for the 17% of trial participants who were unsuitable for immunotherapy must be higher than the ICER for the whole trial population of £72,500 or £74,900 per QALY gained. The Committee agreed that the criterion for the robustness of evidence for this subgroup was not convincing therefore the Committee did not discuss whether sorafenib for the second-line treatment of people with advanced RCC who are unsuitable for immunotherapy fulfilled the criteria for consideration as a life-extending, end-of-life treatment. This was because it was not clear what prior therapies the people in the subgroup had received and no cost-effectiveness estimates were provided. The Committee considered the most plausible ICERs that were higher than £72,500 and £74,900 per QALY gained and concluded that sorafenib as second-line treatment for people in whom non-immunotherapy first-line treatment has failed and who are unsuitable for immunotherapy with advanced RCC would not be a cost-effective use of NHS resources. ## Second-line treatment for people in whom sunitinib has failed The Committee noted the suggestion made by the manufacturer of sorafenib that consideration should be given to the sequencing of treatments (particularly sunitinib as a first-line treatment followed by sorafenib as second-line treatment). It also noted that the marketing authorisation of sorafenib was for people in whom immunotherapy had failed or who were unsuitable for immunotherapy. Therefore the Committee considered that the use of sorafenib after sunitinib would be relevant only for people who had received sunitinib as a first-line treatment and were unsuitable for immunotherapy. The Committee noted that the evidence base for this treatment pathway was absent, because participants were excluded from the sorafenib RCT if they had received sunitinib as a first-line treatment and the sunitinib RCT only included people who were suitable for immunotherapy. In the absence of robust data, the Committee could not reach any conclusions on whether sorafenib could be considered a clinically effective second-line treatment for people with advanced RCC who had received sunitinib as a first-line treatment. ## The Institute's duties under the equalities legislation In carrying out its consideration of the evidence and reaching its conclusions, the Committee was aware of the Institute's duties under the equalities legislation and considered whether those duties required the Committee to alter or to add to its recommendations in any way. However, the Committee did not identify any way in which its guidance would have a particular impact on any of the groups whose interests are protected by the equalities legislation. It noted that in relation to first-line treatment for people who are unsuitable for immunotherapy and second-line treatment for people who are unsuitable for immunotherapy its recommendations are based on the view that there is limited or no evidence of clinical effectiveness for any patient group. For the other patient populations the Committee's conclusions are based on the view that the treatments are not cost effective for any patient group. The guidance does not recommend the availability of the treatments to some patients and not to others. The recommendations apply to all patients with renal cell carcinomas and all such patients are affected by the guidance in the same way.# Recommendations for further research There are a number of ongoing trials which are actively recruiting participants and which are relevant to this appraisal. Some of these trials are investigating the optimum sequences of treatment. Full details of ongoing research can be found at the National Institute for Health Research Clinical Research Network, ClinicalTrials.gov and Current Controlled Trials. The Assessment Group considered that the following well-conducted RCTs reporting health-related utility values in accordance with the NICE methods guide could be of value: RCTs to investigate the effectiveness of temsirolimus and sorafenib as first-line treatments (both as monotherapy) compared with best supportive care in people who are unsuitable or have contraindications for immunotherapy and who have a poor or intermediate prognosis. RCTs of sunitinib as a second-line treatment in people in whom immunotherapy has failed. RCTs of sorafenib as a second-line treatment in whom first-line non-immunotherapy treatment (including sunitinib) has failed and who are unsuitable or have contraindications to immunotherapy.# Related NICE guidance Sunitinib for the first-line treatment of advanced and/or metastatic renal cell carcinoma. NICE technology appraisal guidance 169 (2009). Percutaneous radiofrequency ablation of renal cancer. NICE interventional procedure guidance 91 (2004). Improving outcomes in urological cancers. NICE cancer service guidance (2002).# Review of guidance The review date for a technology appraisal refers to the month and year in which the Guidance Executive will consider whether the technology should be reviewed. This decision will be taken in the light of information gathered by the Institute, and in consultation with consultees and commentators. The guidance on this technology will be considered for review by June 2011. Andrew DillonChief ExecutiveAugust 2009# Changes after publication February 2014: minor maintenance March 2012: minor maintenance# About this guidance NICE technology appraisal guidance is about the use of new and existing medicines and treatments in the NHS in England and Wales. This guidance was developed using the NICE multiple technology appraisal process. We have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available. Your responsibility This guidance represents the views of NICE and was arrived at after careful consideration of the evidence available. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. However, the guidance does not override the individual responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or guardian or carer. Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties. Copyright © National Institute for Health and Clinical Excellence 2009. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.	{'Guidance': 'Bevacizumab, sorafenib and temsirolimus are not recommended as first-line treatment options for people with advanced and/or metastatic renal cell carcinoma.\n\nSorafenib and sunitinib are not recommended as second-line treatment options for people with advanced and/or metastatic renal cell carcinoma.\n\nPeople who are currently being treated with bevacizumab (first-line), sorafenib (first- and second-line), sunitinib (second-line) and temsirolimus (first-line) for advanced and/or metastatic renal cell carcinoma should have the option to continue their therapy until they and their clinicians consider it appropriate to stop.', 'Clinical need and practice': 'Renal cell carcinoma (RCC) is a type of kidney cancer that usually originates in the lining of the tubules of the kidney and contains many blood vessels. RCC accounts for 90% of kidney cancers and approximately 3% of all adult cancers. In England and Wales, kidney cancer is the 8th most common cancer in men and the 14th most common in women. In 2004, there were 5745 cases of newly diagnosed kidney cancer registered in England and Wales. The incidence of kidney cancer begins to rise after the age of 40 and is highest in people older than 65. In England and Wales the estimated overall 5-year survival rate for RCC is 44%, but there are large differences according to the stage of disease at the time of diagnosis. The worldwide incidence of kidney cancer among both men and women has been rising steadily since the 1970s.\n\nThe American Joint Committee on Cancer (AJCC) tumour node metastases (TNM) system is used to grade RCC into stages I to IV. Advanced RCC, in which the tumour is either locally advanced and/or has spread to regional lymph nodes, is generally defined as stage III. Metastatic RCC, in which the tumour has spread beyond the regional lymph nodes to other parts of the body, is generally defined as stage IV.\n\nIn 2006, of people presenting with RCC in England and Wales for whom staging information was available, an estimated 26% and 17% had stage III and stage IV disease, respectively. About half of those who have curative resection for earlier stages of the disease also go on to develop advanced and/or metastatic disease. The prognosis following a diagnosis of advanced and/or metastatic RCC is poor. The 5-year survival rate for metastatic RCC is approximately 10%.\n\nThere are currently no treatments that reliably cure advanced and/or metastatic RCC. The primary objectives of medical intervention are relief of physical symptoms and maintenance of function. Metastatic RCC is largely resistant to chemotherapy, radiotherapy and hormonal therapy. People with advanced and/or metastatic RCC are usually treated with either interferon alfa-2a (IFN-α) or interleukin-2 immunotherapy or a combination of IFN-α and interleukin-2. IFN-α (Roferon-A, Roche Products) is the most commonly used immunotherapy in England and Wales and has a UK marketing authorisation for treatment of people with advanced RCC. For those people receiving immunotherapies for the treatment of advanced RCC it is suggested that median overall survival is 11.4 months compared with a median overall survival of 7.6 months for those receiving control treatments. Commonly experienced adverse effects of IFN-α include flu-like symptoms, tiredness and depression. There is no standard treatment for people with advanced and/or metastatic RCC in whom first-line immunotherapy has failed, or for people who are unsuitable for immunotherapy.', 'The technologies': "# Bevacizumab\n\nBevacizumab (Avastin, Roche Products) is a recombinant humanised monoclonal IgG1 antibody that inhibits the formation of blood vessels (angiogenesis inhibitor). It targets the biological activity of human vascular endothelial growth factor (VEGF), which stimulates new blood vessel formation in the tumour. Bevacizumab in combination with IFN-α has a UK marketing authorisation for first-line treatment of people with advanced and/or metastatic RCC.\n\nBevacizumab is contraindicated in pregnant women, people with untreated central nervous system metastases, and people who have hypersensitivity to the active substance or to any of the excipients, to products derived from Chinese hamster ovary cell cultures or to other recombinant human or humanised antibodies. The summary of product characteristics (SPC) lists the following conditions that may be associated with bevacizumab treatment: gastrointestinal perforation, fistulae, wound healing complications, hypertension, proteinuria, arterial thromboembolism, haemorrhage, congestive heart failure and neutropenia. For full details of side effects and contraindications, see the SPC.\n\nBevacizumab is administered as an intravenous infusion. The recommended dosage for advanced and/or metastatic RCC is 10 mg/kg body weight once every 14 days. The initial dose of bevacizumab should be delivered over 90 minutes and if the first infusion is well tolerated, the second infusion may be administered over 60 minutes. If the 60-minute infusion is well tolerated, all subsequent infusions may be administered over 30 minutes. IFN-α (Roferon-A, Roche Products) is administered by subcutaneous injection three times per week at a dose of 3 MIU for 1 week, 9 MIU for the following week and 18 MIU thereafter; if 18 MIU is not tolerated then the dose should be reduced to 9 MIU. Bevacizumab treatment is licensed for use in advanced and/or metastatic RCC until there is underlying disease progression. The price for a 400-mg vial of bevacizumab is £924.40 and the price of IFN-α is £45.19 for 9 MIU (excluding VAT; 'British National Formulary' [BNF] edition 55). Assuming an average weight of 76.5 kg and no wastage, the average daily cost of bevacizumab plus IFN-α is £151.42. Over a 6-week cycle, the average total cost of drug acquisition is £5982 per patient for the first cycle and £6117 for subsequent 6-week cycles. These figures assume a typical dose of IFN-α of 9–10 MIU. The manufacturer of bevacizumab (Roche) has agreed a patient access scheme with the Department of Health for advanced and/or metastatic RCC. Costs may vary in different settings because of negotiated procurement discounts.\n\n# Sorafenib\n\nSorafenib (Nexavar, Bayer) is a multikinase inhibitor that inhibits the development of tumour blood vessels and tumour cell proliferation. It has a dual action, inhibiting the raf cascade and VEGF/platelet-derived growth factor (PDGF) receptors on tumour cells, vascular endothelial cells and pericytes. Sorafenib has a UK marketing authorisation for the treatment of people with advanced RCC in whom IFN-α or interleukin-2-based therapy has failed or who are considered unsuitable for such therapy. Sorafenib has designated EU orphan drug status for RCC.\n\nSorafenib is contraindicated in people who have hypersensitivity to the active substance or to any of the excipients. The SPC lists the following conditions that may be associated with sorafenib treatment: dermatological toxicities, hypertension, haemorrhage, cardiac ischaemia and/or infarction, hepatic impairment and wound healing complications. For full details of side effects and contraindications, see the SPC.\n\nSorafenib is administered orally. The recommended dosage for advanced RCC is 400 mg twice daily. Sorafenib treatment is licensed for use in people with advanced RCC as long as clinical benefit is observed or until unacceptable adverse events occur. The current price for a pack of 200-mg tablets (112 tablets per pack) is £2980.47 (excluding VAT). The average daily cost of sorafenib treatment is £106.45, with an average 6-week cycle costing £4471. The manufacturer of sorafenib (Bayer) has agreed a patient access scheme with the Department of Health for advanced RCC. Costs of treatment cycles may vary in different settings because of negotiated procurement discounts.\n\n# Sunitinib\n\nSunitinib (Sutent, Pfizer) is an inhibitor of a group of closely related tyrosine kinase receptors. It inhibits VEGF/PDGF receptors on cancer cells, vascular endothelial cells and pericytes, inhibiting the proliferation of tumour cells and the development of tumour blood vessels. Sunitinib has a UK marketing authorisation for the treatment of people with advanced and/or metastatic RCC.\n\nSunitinib is contraindicated in people who have hypersensitivity to sunitinib malate or to any of the excipients. The SPC lists the following conditions that may be associated with sunitinib treatment: skin and tissue problems, gastrointestinal events, haemorrhage, hypertension, haematological problems, venous thromboembolic events, pulmonary embolism and hypothyroidism. For full details of side effects and contraindications, see the SPC.\n\nSunitinib is administered orally. The recommended dosage is 50 mg once daily for four consecutive weeks with a 2-week rest period (that is, a complete treatment cycle of 6 weeks). The dose may be adjusted in steps of 12.5 mg according to tolerability (dose range 25–75 mg). The price for a pack of 50-mg capsules (30 capsules per pack) is £3363.00 (excluding VAT; BNF edition 55). The average daily cost of sunitinib is £74.74, with an average 6-week cycle costing £3139. The manufacturer of sunitinib (Pfizer) has agreed a patient access scheme with the Department of Health for advanced and/or metastatic RCC. Costs of treatment cycles may vary in different settings because of negotiated procurement discounts.\n\n# Temsirolimus\n\nTemsirolimus (Torisel, Wyeth Pharmaceuticals) is a selective inhibitor of the mammalian target of rapamycin (mTOR), a serine threonine kinase that regulates a signalling cascade controlling growth factor-induced cell proliferation. Temsirolimus inhibits mTOR-dependent protein translation induced by growth factor stimulation. Tumour growth may also be affected indirectly by the inhibition of other factors such as VEGF. Temsirolimus has a UK marketing authorisation for the first-line treatment of people with advanced RCC who have at least three of the six following prognostic risk factors:\n\nless than 1 year from time of initial RCC diagnosis to randomisation or initiation of treatment\n\nKarnofsky performance status of 60–70\n\nhaemoglobin less than the lower limit of normal\n\ncorrected calcium greater than 10 mg/100 ml (or 2.5 mmol/litre)\n\nserum lactate dehydrogenase more than 1.5 times the upper limit of normal\n\nmore than one metastatic organ site.Temsirolimus has designated EU orphan drug status for RCC.\n\nTemsirolimus is contraindicated in people who have hypersensitivity to temsirolimus, its metabolites (including sirolimus), polysorbate 80 or to any of the excipients. The SPC lists the following conditions that may be associated with temsirolimus treatment: intracerebral bleeding, renal failure, hyperglycaemia, infections, interstitial lung disease, hyperlipaemia and wound healing complications. Pre-medication with intravenous antihistamine is also recommended to minimise allergic reactions. For full details of side effects and contraindications, see the SPC.\n\nTemsirolimus is administered by intravenous infusion. The recommended dosage is 25 mg over a 30- to 60-minute period once a week. Treatment with temsirolimus should continue until there is no clinical benefit or until unacceptable toxicity occurs. The net-price for a 30-mg vial of temsirolimus is £620 (excluding VAT; BNF edition 57). Costs may vary in different settings because of negotiated procurement discounts.", 'Evidence and interpretation': "The Appraisal Committee (appendix A) considered evidence from a number of sources (appendix B). The following sections are based on the evidence received for the appraisal of 'bevacizumab, sorafenib, sunitinib and temsirolimus for the treatment of advanced and/or metastatic renal cell carcinoma'. However, the following sections do not relate specifically to the appraisal of sunitinib for the first-line treatment of advanced and/or metastatic RCC.\n\n# Clinical effectiveness\n\nThe Assessment Group and manufacturers identified evidence on the clinical effectiveness of bevacizumab plus IFN-α, sorafenib, sunitinib and temsirolimus against relevant comparators within the licensed indications for each drug, and according to the appraisal scope. The following potential treatment strategies were investigated:\n\nfirst-line treatment for people suitable for immunotherapy (bevacizumab plus IFN-α compared with IFN-α)\n\nfirst-line treatment for people suitable for immunotherapy and with a poor prognosis (bevacizumab plus IFN-α and temsirolimus [as monotherapy] compared with IFN-α)\n\nfirst-line treatment for people unsuitable for immunotherapy (sorafenib compared with best supportive care)\n\nfirst-line treatment for people with a poor prognosis unsuitable for immunotherapy (sorafenib and temsirolimus [both as monotherapy] compared with best supportive care)\n\nsecond-line treatment for people in whom immunotherapy has failed (sorafenib and sunitinib [both as monotherapy] compared with best supportive care)\n\nsecond-line treatment for people in whom first-line treatment has failed and who are unsuitable for immunotherapy (sorafenib [as monotherapy] compared with best supportive care).\n\n## First-line treatment for people suitable for immunotherapy\n\nOne randomised controlled trial (RCT) of 649 people assessed the effect of bevacizumab plus IFN-α (n = 327) compared with IFN-α plus placebo (n = 322). In this study, the primary outcome was overall survival. The study was unblinded after a pre-planned interim analysis based on approximately 250 deaths, and participants in the IFN-α arm who had not progressed were offered bevacizumab plus IFN-α. IFN-α was given for a maximum of 1 year. The study included predominantly people with clear cell RCC who had risk factors suggestive of a favourable or intermediate prognosis. All participants had undergone a previous nephrectomy.\n\nMedian overall survival had not been reached in the bevacizumab plus IFN-α treatment arm at the time of data analysis and was 19.8 months in the IFN-α plus placebo arm. There was no statistically significant difference in overall survival between bevacizumab plus IFN-α compared with IFN-α plus placebo (hazard ratio [HR] 0.79, 95% confidence interval [CI] 0.62 to 1.02, p = 0.0670).\n\nProgression-free survival was defined as the time between randomisation and first documented disease progression or death from any cause. There was a statistically significant difference in median progression-free survival for bevacizumab plus IFN-α (10.2 months) compared with IFN-α plus placebo (5.4 months); HR 0.63, 95% CI 0.52 to 0.75.\n\nTumour response rate was measured as a partial or complete reduction in tumour size. The overall tumour response rate in the bevacizumab plus IFN-α arm was 31% compared with 13% in the IFN-α plus placebo arm (p = 0.0001). Approximately half of all the trial participants achieved stable disease.\n\nAdverse events were taken from the 'safety population' (that is, people were assigned to treatments in the analysis based on what they actually received, for example patients in the IFN-α plus placebo arm receiving one or more doses of bevacizumab were assigned to the bevacizumab arm). No significant differences between the treatment and control arms were reported. A total of 28% of participants discontinued treatment in the bevacizumab plus IFN-α arm because of adverse events compared with 12% in the IFN-α plus placebo arm. Health-related quality of life was not measured in the study.\n\n## First-line treatment for people suitable for immunotherapy with at least three of six factors indicating poor prognosis\n\nOne RCT with 626 participants investigated the effectiveness of temsirolimus (n = 209), temsirolimus plus IFN-α (n = 210) and IFN-α alone (n = 207) as first-line treatments of RCC in people who were suitable for immunotherapy and had at least three of six factors indicating poor prognosis. The combination of temsirolimus plus IFN-α does not have a UK marketing authorisation and so data from this group were not considered. The primary outcome in this temsirolimus study was overall survival. Approximately 80% of participants had a Karnofsky performance status of 70 or less and clear cell carcinoma. Approximately 66% of participants had undergone prior nephrectomy. Interim and final analyses were presented.\n\nIn the temsirolimus study, there were statistically significant differences in median overall survival with temsirolimus (10.9 months) compared with IFN-α (7.3 months), in both the interim (HR 0.73, 95% CI 0.58 to 0.92; p = 0.008) and final analyses (HR 0.78, 95% CI 0.63 to 0.97; p = 0.0252). Some participants had not undergone prior nephrectomy and some had non-clear cell carcinoma. Subgroup analyses suggested that temsirolimus compared with IFN-α significantly improved overall survival for those who had not undergone prior nephrectomy (HR 0.61, 95% CI 0.41 to 0.91) and for those with non-clear-cell carcinoma (HR 0.55, 95% CI 0.33 to 0.90). No significant improvements in overall survival were observed for those who had undergone prior nephrectomy (HR 0.84, 95% CI 0.63 to 1.11) and those who had clear cell carcinoma (HR 0.85, 95% CI 0.64 to 1.08).\n\nIn the interim analyses, median progression-free survival was assessed by both site investigators and blinded independent assessment. For those receiving temsirolimus, the median progression-free survival was 3.8 months and 5.5 months as assessed by site investigators and blinded independent assessment, respectively. For those receiving IFN-α, the median progression-free survival was 1.9 months and 3.1 months, respectively. No statistical analysis was reported for the interim analyses. In the final analyses, the median progression-free survival was 3.8 months and 5.6 months as assessed by site investigators and blinded independent assessment, respectively. For those receiving IFN-α, median progression-free survival was 1.9 months and 3.2 months, respectively. There was a statistically significant difference in median progression-free survival with temsirolimus compared with IFN-α according to the independent assessment (HR 0.74, 95% CI 0.60 to 0.91; p = 0.0042) and the investigators' assessment (HR 0.74, 95% CI 0.60 to 0.90; p = 0.0028). Compared with IFN-α, temsirolimus improved progression-free survival for those who had not undergone prior nephrectomy (HR 0.62, 95% CI 0.43 to 0.88) and for those who had undergone prior nephrectomy (HR 0.72, 95% CI 0.55 to 0.93). Compared with IFN-α, temsirolimus improved progression-free survival for those who had non-clear-cell carcinoma (HR 0.36, 95% CI 0.22 to 0.59), and there was a non-statistically significant difference for those who had clear cell carcinoma (HR 0.84, 95% CI 0.67 to 1.05).\n\nThe temsirolimus study measured objective tumour response rate. The manufacturer of temsirolimus (Wyeth Pharmaceuticals) stated that no statistically significant differences were observed; the objective partial tumour response rate was 8.6% (18 participants) for those who received temsirolimus compared with 4.8% (10 participants) for those who received IFN-α. There was a statistically significant difference in the number of participants that achieved stable disease for at least 8 weeks with temsirolimus (131 participants, 62.7%) compared with IFN-α (80 participants, 38.6%).\n\nIn the temsirolimus study, time without symptoms and toxicity (TWiST) and quality-adjusted survival and toxicity (Q-TWiST) were reported as pre-defined endpoints. The reported results included some participants from the third treatment arm (temsirolimus plus IFN-α). Participants receiving temsirolimus had a significantly longer time in both TWiST and Q-TWiST health states (6.5 months and 7.0 months, respectively) compared with participants receiving IFN-α alone (4.7 months and 5.7 months, respectively). In the temsirolimus study, 67% of participants receiving temsirolimus and 78% of those receiving IFN-α alone reported a grade 3 or 4 adverse event (p = 0.02). Anaemia was the most commonly reported grade 3 or 4 adverse event in the temsirolimus arm (20%) and asthenia (loss of strength) in the IFN-α alone arm (26%). A total of 7% (n = 15) of participants in the temsirolimus arm discontinued treatment because of adverse events compared with 14% (n = 29) in the IFN-α alone arm. According to the Memorial Sloan-Kettering Cancer Center (MSKCC) risk classification, 31% of participants in the temsirolimus arm and 24% in the IFN-α alone arm had an intermediate rather than a poor prognosis.\n\nIn the bevacizumab study (see section 4.1.2), 9% of participants receiving bevacizumab plus IFN-α and 8% of those receiving IFN-α plus placebo were defined as having a poor prognosis. Only progression-free survival was reported according to this subgroup. There was no statistically significant difference in median progression-free survival between bevacizumab plus IFN-α (2.2 months) and IFN-α alone (2.1 months) for participants with at least three MSKCC risk factors for poor prognosis (HR 0.81, 95% CI 0.46 to 1.42).\n\n## First-line treatment for people unsuitable for immunotherapy\n\nThe Assessment Group did not identify any full reports of RCTs assessing sorafenib as first-line treatment for people with advanced and/or metastatic RCC who were unsuitable for immunotherapy. One RCT was identified with a small population subgroup (17% of the total number of participants) that was unsuitable for immunotherapy. However, these participants did not receive sorafenib as a first-line treatment because the RCT only included people who had received at least one prior systemic therapy. Further details of the sorafenib RCT are given in section 4.1.15. The manufacturer of sorafenib (Bayer) submitted data on first-line treatment of people unsuitable for immunotherapy from two expanded access programmes conducted in Europe (318 participants unsuitable for immunotherapy) and North America (224 participants unsuitable for immunotherapy). Both were in effect single-arm studies and the results were reported only in abstract form. The expanded access studies reported median progression-free survival of 6.0 months and 8.1 months, respectively.\n\n## First-line treatment for people with poor prognosis unsuitable for immunotherapy\n\nThe Assessment Group did not identify any data on the clinical effectiveness of sorafenib or temsirolimus as first-line treatment for people with advanced and/or metastatic RCC who had a poor prognosis and were unsuitable for immunotherapy. In order to inform a cost-effectiveness estimate for this population, the manufacturer of temsirolimus (Wyeth Pharmaceuticals) performed an indirect comparison of temsirolimus with best supportive care. Data were taken from the temsirolimus RCT and an RCT that compared IFN-α with medroxyprogresterone (MPA). No further details on clinical effectiveness were presented.\n\n## Second-line treatment for people in whom immunotherapy has failed\n\nOne RCT with 903 participants investigated the effectiveness of sorafenib (n = 451) compared with placebo, which was considered equivalent to best supportive care (n = 452). The RCT included people who had experienced disease progression after one systemic treatment within the previous 8 months. All participants in the RCT had clear cell carcinoma with an ECOG performance status of 0 or 1 and a favourable or intermediate MSKCC prognostic score. A total of 83% of participants had received previous immunotherapy and the remaining 17% of participants were unsuitable for immunotherapy so had received other first-line therapies. The primary outcome of the RCT was overall survival. The RCT was terminated early, on ethical grounds, after an independent review decided that sorafenib should be offered to participants who were receiving placebo.\n\nFor the whole trial population, at the time of the first interim analyses, the median overall survival in the sorafenib RCT had not been reached in the sorafenib arm, and was 14.7 months in the placebo arm (HR 0.72, 95% CI 0.54 to 0.94; p = 0.02). The difference was not considered statistically significant because it did not reach the pre-specified O'Brien–Fleming threshold of less than or equal to 0.0005.\n\nFrom the whole trial population of the sorafenib RCT, results were reported of a pre-planned interim analysis and an unplanned updated analysis (at the point of crossover) for progression-free survival. For the pre-planned analyses, both the independent and investigator assessments resulted in statistically significant differences in median progression-free survival. The independent assessment of median progression-free survival was 5.5 months in the sorafenib arm compared with 2.8 months in the placebo arm (HR 0.44, 95% CI 0.35 to 0.55). The investigator assessment of median progression-free survival was 5.9 months in the sorafenib arm compared with 2.8 months in the placebo arm (p < 0.001). The unplanned investigator assessment of median progression-free survival at the time of crossover was 5.5 months in the sorafenib arm compared with 2.8 months in the placebo arm (HR 0.51, 95% CI 0.43 to 0.60).\n\nThe sorafenib RCT measured tumour response rate. Out of the whole trial population, one participant who received sorafenib achieved a complete tumour response compared with none who received placebo. A total of 43 (10%) participants receiving sorafenib and 8 (2%) receiving placebo achieved a partial response, and 333 (74%) participants receiving sorafenib and 239 (53%) receiving placebo achieved stable disease. This difference was statistically significant (p < 0.001).\n\nHealth-related quality of life was measured in the whole trial population of the sorafenib RCT using the FACT-G and FKSI indices. There was no significant difference between the placebo and sorafenib groups in mean FACT-G physical well-being score nor was there any statistically significant difference in mean FKSI-10 total score between groups over the first 32 weeks of treatment (p = 0.83 and p = 0.98, respectively). However, median time to health status deterioration, as defined by a four-point or more drop in FKSI-10 total score, was significantly greater for those receiving sorafenib compared with those receiving placebo (p < 0.0001). On the following items of the FKSI-15 index, those people who had received sorafenib scored significantly better than those who had received placebo: coughing (p < 0.0001); fever (p = 0.0015); worry about their disease (p = 0.0004); ability to enjoy life (p = 0.0119). However, a significantly greater number of people receiving sorafenib reported 'bothersome side effects of treatment' than those receiving placebo (p < 0.0001). Skin rashes, hypertension, diarrhoea and hand–foot syndrome were more common in the sorafenib arm.\n\nOne randomised discontinuation trial was also identified that compared sorafenib with best supportive care. The randomised discontinuation trial included 65 people with advanced and/or metastatic RCC. In most participants immunotherapy had failed. Most participants in this trial had an ECOG performance status of 0 or 1 and had undergone prior nephrectomy. The median progression-free survival in the sorafenib randomised discontinuation trial was significantly longer for participants receiving sorafenib (24 weeks) compared with those receiving placebo (6 weeks); p = 0.0087. At 24 weeks, a greater proportion of participants who had received sorafenib had no evidence of disease progression compared with those who had received placebo (50% and 18%, respectively; p = 0.0077). Overall survival, health-related quality of life and adverse events were not assessed in the randomised discontinuation trial.\n\nTwo single-arm phase II studies, of 63 and 106 participants, investigated the effectiveness of sunitinib as second-line treatment following prior nephrectomy and at least one course of cytokine-based therapy. A total of 57% of the pooled population had an ECOG performance status of 0. In both studies, sunitinib was given until disease progression, and dose reductions were allowed if adverse effects were observed. In both studies, the primary outcome was objective tumour response.\n\nThe median overall survival in the smaller sunitinib study was 16.4 months (95% CI 10.8 to 'not reached') and 23.9 months (95% CI 14.1 to 30.7) in the larger sunitinib study. The median progression-free survival in the smaller sunitinib study was 8.7 months (95% CI 5.5 to 10.7) and 8.8 months (95% CI 7.8 to 13.5) in the larger sunitinib study. No participants achieved a complete tumour response in either of the sunitinib studies. A total of 40% in the smaller sunitinib study and 33% in the larger sunitinib study achieved partial tumour responses. Approximately equal proportions of the remaining participants in both studies experienced stable disease or progressive disease. Informal analysis comparing the pooled sunitinib studies with the best supportive care arm of the sorafenib RCT suggests that sunitinib may be clinically effective compared with best supportive care.\n\n## Second-line treatment for people unsuitable for immunotherapy\n\nThe Assessment Group did not identify any full reports of RCTs assessing sorafenib as a second-line treatment for people with advanced and/or metastatic RCC who were unsuitable for immunotherapy. The manufacturer of sorafenib (Bayer) submitted data from an RCT with a small population subgroup (17% of the total number of participants) who were unsuitable for immunotherapy but had received other first-line treatments. This was a trial of sorafenib compared with placebo, which was assumed to be equivalent to best supportive care. Further details of the sorafenib RCT are given in section 4.1.15. The Assessment Group did not consider the results from this subgroup because it was unclear whether the subgroups were defined at the start of the study and the size of the subgroup was small. The results of the trial for this subgroup were marked as academic in confidence. Therefore they are not presented in this document.\n\n## Summary of clinical effectiveness\n\nThe Assessment Group concluded from a summary of the data on the clinical effectiveness of first-line treatments for people who are suitable for immunotherapy, that bevacizumab plus IFN-α appears to have significant benefits compared with IFN-α alone in terms of progression-free survival and tumour response. For people with poor prognosis, temsirolimus appears to have significant benefits compared with IFN-α in terms of overall survival, progression-free survival and tumour response rate. There is some evidence to suggest that temsirolimus may have a differential effect on people who have non-clear-cell carcinoma and who have not undergone nephrectomy. The frequency of adverse events associated with bevacizumab and temsirolimus is comparable to that associated with IFN-α monotherapy, but the adverse event profiles differ between treatments.\n\nThe Assessment Group concluded that for second-line treatment for people in whom immunotherapy had failed, sorafenib demonstrated clinically and statistically significant benefits compared with best supportive care in terms of progression-free survival and tumour response rate. Sorafenib was associated with more adverse events than best supportive care, particularly hand–foot skin reactions and hypertension. The Assessment Group also stated that although an informal comparison suggests that sunitinib may be beneficial compared with best supportive care, no definitive conclusions could be drawn because of the absence of any comparator in the studies.\n\n# Cost effectiveness\n\nNo published studies of the cost effectiveness of bevacizumab, sorafenib, sunitinib or temsirolimus were identified. The manufacturers of each of the drugs submitted cost-effectiveness models and the Assessment Group developed a model for each treatment question.\n\n## Manufacturers' models\n\nThe manufacturer of bevacizumab (Roche Products) submitted a simple state-transition model with three health states: progression-free survival, progressive disease and death. The model compared bevacizumab plus IFN-α with IFN-α plus placebo as a first-line treatment for people suitable for immunotherapy. Patient-level data were taken from the bevacizumab trial (see section 4.1.2) and IFN-α use was limited to 1 year in both treatment arms as in the trial. Gompertz survival curves were fitted to the overall and progression-free survival data from the IFN-α plus placebo arm in the trial and the progression-free survival curve for the bevacizumab plus IFN-α arm. Because median overall survival was not reached in the bevacizumab plus IFN-α arm, the hazard ratio from the stratified 'safety population' was applied to the baseline IFN-α plus placebo overall survival Gompertz curve. The treatment-specific (that is, different utility scores calculated for the different trial arms) utility data from an RCT of sunitinib compared with IFN-α were averaged and the following values assigned: progression-free survival = 0.78 and progressive disease = 0.705. Drug costs were adjusted according to RCT data on dose intensity (that is, the amount of drug administered in a clinical trial as a proportion of the amount that would have been administered if there had been no withdrawals of participants or dose reductions). The cost adjustment of bevacizumab was estimated as 62%; that of IFN-α was estimated as 80% and 63% when used with bevacizumab and as monotherapy, respectively. A 'dose cap' pricing strategy was applied with bevacizumab being free to the NHS once 10 g has been purchased for a patient within a year of initiation of treatment.\n\nWith discounting at 3.5% per annum, the comparison of bevacizumab plus IFN-α with IFN-α plus placebo produced a base-case incremental cost-effectiveness ratio (ICER) of £74,999 per quality-adjusted life year (QALY) gained. One-way sensitivity analyses consisted only of exploring the effects of using an alternative log–logistic survival curve in the extrapolation of trial results. The use of this model reduced the ICER to £39,978 per QALY gained. The manufacturer of bevacizumab acknowledged that this sensitivity analysis may be implausible because the use of a log–logistic model resulted in a longer life expectancy (20 years) than would be expected for people with advanced and/or metastatic RCC.\n\nThe manufacturer of temsirolimus (Wyeth Pharmaceuticals) submitted a state-transition model with three health states: progression-free survival, post-progression and death. The progression-free survival state was then subdivided into stable disease, complete/partial response and progressive disease. The model compared temsirolimus with IFN-α as a first-line treatment for people with at least three of six risk factors for poor prognosis, who were suitable for immunotherapy. Patient-level data were taken from the temsirolimus trial described in section 4.1.7. Weibull regression models were applied to progression-free survival and overall survival data to calculate the time-dependent state transition probabilities. The following health-state utility values, derived from the temsirolimus trial, were applied: 0.658 for complete/partial response, 0.600 for stable disease and 0.446 for progressive disease and post-progression. Drug costs were adjusted according to RCT data on dose intensity and estimated as 92% for temsirolimus and 56% for IFN-α. At the time of the original submission, the manufacturer used a price of £515 (excluding VAT) for a 30-mg vial of temsirolimus (see section 4.2.18) and no wastage was assumed.\n\nWith discounting at 3.5% per annum, the comparison of temsirolimus with IFN-α produced an ICER of £55,814 per QALY gained in the base case. The one-way sensitivity analyses demonstrated that the ICER was most sensitive to the drug-related treatment costs and when these were explored the ICERs ranged from £39,977 to £65,542 per QALY gained. In subgroup analyses, the ICER for the subgroup with clear cell carcinoma was £57,731 per QALY gained, £51,159 per QALY gained for the subgroup with non-clear-cell carcinoma, £60,575 per QALY gained for those with prior nephrectomy and £49,690 per QALY gained for those without prior nephrectomy.\n\nThe manufacturer of temsirolimus (Wyeth Pharmaceuticals) submitted an indirect comparison of temsirolimus with best supportive care. The model described in section 4.2.4 was used. Data were taken from the temsirolimus RCT and an RCT that compared IFN-α with medroxyprogresterone (MPA). With discounting at 3.5% per annum, the indirect comparison of temsirolimus with best supportive care produced an ICER of £81,201 per QALY gained. No sensitivity analyses were conducted.\n\nThe manufacturer of sorafenib (Bayer) submitted a simple state-transition model with three health states: progression-free survival, progressed disease and death. The model compared sorafenib with best supportive care for people in whom immunotherapy had failed or who were unsuitable for immunotherapy. Patient-level data were taken from the sorafenib RCT (see section 4.1.15). For progression-free survival, the trial data were used directly for both the sorafenib and placebo arms. However, because of a short follow-up period, the data for overall survival were immature and were extrapolated over time by using an exponential function. Analysis was presented according to the following subgroups: people receiving sorafenib as second-line treatment after failure of immunotherapy; people receiving sorafenib as a second-line treatment who were unsuitable for immunotherapy and in whom a non-immunotherapy-based first-line treatment had failed; and a combination of the two subgroups. An exploratory analysis comparing sorafenib with sunitinib as second-line treatments was also presented. However, because the subgroup data and indirect comparison were marked as academic in confidence, only the data for the whole population are presented in this document. The following health-state utility values, taken from an unpublished survey of physicians, were applied: 0.737 for progression-free survival and 0.548 for progressed disease. The model assumed a sorafenib dose intensity of 100%. The manufacturer used a price of £2504.60 (excluding VAT) for a pack of 200-mg tablets (112 per pack).\n\nWith discounting at 3.5% per annum, the comparison of sorafenib with best supportive care produced an ICER of £90,630 per QALY gained for the combined group in the base case. The one-way sensitivity analyses did not produce an ICER lower than £60,000 per QALY gained as demonstrated by Tornado diagrams reported in the manufacturer's submission. The ICERs were most sensitive to health utility values for progression-free survival and progressed disease, and the resource associated with the number of inpatient days required when receiving sorafenib and best supportive care.\n\nThe manufacturer of sorafenib submitted revised cost-effectiveness analyses for the whole trial population and for the 83% of the trial participants in whom immunotherapy had failed. The revised cost-effectiveness estimates also incorporated a patient access scheme in which the first pack of sorafenib is free to the NHS. The Department of Health considered that this patient access scheme does not constitute an excessive administrative burden on the NHS. Details of the new price of sorafenib of £2980.47 for a pack of 112 200-mg tablets, which was agreed in the context of the Pharmaceutical Price Regulation Scheme (PPRS), were also provided. In the revised analyses, the progression-free and overall survival curves for both sorafenib and best supportive care were modelled by fitting independent Weibull distributions to each separate curve (rather than exponential extrapolation as in the original submission). The manufacturer stated that this approach was justified because it was more consistent with the distributions used in the Assessment Group's economic model. The manufacturer also made further amendments to the cost and utility assumptions to more closely reflect the original model developed by the Assessment Group. The revised ICER (taking into account the patient access scheme and new price) for the whole trial population was £72,546 per QALY gained. The revised ICER (taking into account the patient access scheme and new price) for the subgroup of participants in whom immunotherapy had failed was £62,256 per QALY gained. No sensitivity analyses of the revised cost-effectiveness estimates were presented by the manufacturer of sorafenib.\n\nIn the original submission, the manufacturer of sorafenib (Bayer) also submitted a cost-effectiveness estimate of sorafenib as second-line treatment for people who were unsuitable for immunotherapy compared with best supportive care. Patient-level data were taken from a small population subgroup of 17% of participants in the sorafenib RCT (described in section 4.1.15). The cost-effectiveness estimates for this subgroup were marked as academic in confidence. Therefore they are not presented in this document.\n\nThe manufacturer of sunitinib (Pfizer) submitted a simple state-transition model with three health states: progression-free survival, progressed disease and death. The model compared sunitinib with best supportive care as second-line therapies. Patient-level data on the effectiveness of sunitinib were taken from the smaller of the two single-arm phase II trials (see section 4.1.21). Data for best supportive care were taken from a pooled analysis of a review and Medicare data. Survival analysis was used to model disease progression, survival and treatment effect, with Weibull survival curves used to extrapolate independent data from different sources. The health-state utilities used were taken from EQ-5D data collected in the single-arm phase II trial with different utility values assigned according to treatment and health state: sunitinib/progression-free survival = 0.803; best supportive care/progression-free survival = 0.758; sunitinib/progressed disease and best supportive care/progressed disease = 0.683. The cost-effectiveness estimates also incorporated a patient access scheme in which the first pack of sunitinib is free to the NHS. The Department of Health considered that this patient access scheme does not constitute an excessive administrative burden on the NHS.\n\nWith discounting at 3.5% per annum, the comparison of sunitinib with best supportive care produced an ICER of £37,519 per QALY gained in the base case. The one-way sensitivity analyses demonstrated that the ICER was most sensitive to time spent in progression and the data source for best supportive care. The ICERs ranged from £27,935 to £206,962 per QALY gained when these parameters were explored.\n\n## Assessment Group model\n\nThe Assessment Group model was developed to estimate the cost effectiveness of bevacizumab plus IFN-α, sorafenib, sunitinib and temsirolimus against relevant comparators within the licensed indications for each drug, and according to the appraisal scope. The Markov model considered three treatment strategy questions: first-line treatment (bevacizumab plus IFN-α compared with IFN-α); first-line treatment of people with a poor prognosis (temsirolimus compared with IFN-α) and second-line treatment (sorafenib compared with best supportive care) using similar model structures but with different model parameter data for each question. The model used three distinct health states: progression-free survival, progressive disease and death.\n\nFor first-line treatment of people suitable for immunotherapy, baseline disease progression (IFN-α alone) was taken from the bevacizumab study (see section 4.1.2). Data for progression-free survival and overall survival for people receiving IFN-α were read directly from reported Kaplan–Meier curves, and Weibull curves were then fitted for use in the model. The disease progression for bevacizumab plus IFN-α was estimated using the ITT hazard ratios from the bevacizumab trial.\n\nFor first-line treatment of people with at least three of six factors indicating poor prognosis and who are suitable for immunotherapy, baseline disease progression (IFN-α alone) for progression-free survival and overall survival were estimated by fitting Weibull curves to empirical data from the temsirolimus study (see section 4.1.7). The disease progression for temsirolimus was estimated by applying the hazard ratios for progression-free and overall survival from the temsirolimus study. The following subgroup analyses were also performed: clear cell and non-clear-cell carcinoma; prior nephrectomy and no prior nephrectomy; a poor prognosis according to the MSKCC score (approximately 75% of participants in the temsirolimus study). The cost effectiveness of bevacizumab plus IFN-α for people with a poor prognosis was not estimated because of the small number of participants with a poor prognosis in the bevacizumab study.\n\nFor second-line treatment, baseline disease progression was modelled by fitting Weibull curves to the empirical progression-free survival and overall survival curves from the best supportive care arm of the sorafenib RCT. Disease progression for participants receiving sorafenib was estimated by applying the hazard ratios from the sorafenib RCT. No subgroup analyses were presented in the Assessment Group model as it was not clear whether the subgroups were defined a priori and the sample size calculations were based on the entire trial population. The cost effectiveness of sunitinib as a second-line treatment compared with best supportive care was not evaluated in the Assessment Group model because the data came from two single-arm trials and were considered inadequate by the Assessment Group.\n\nThe health-state utilities used in the Assessment Group model were derived from trial data in the manufacturer submissions and UK EQ-5D tariffs. Participants were assumed to be similar at baseline in terms of health-state value. Therefore treatment-specific health-state values were not applied. People who receive first-line treatments were assumed to have a utility of 0.78 when in the PFS state and 0.70 when in the PD state; these assumptions came from the data submitted by the manufacturer of sunitinib and used in the appraisal of sunitinib as a first-line treatment for advanced and/or metastatic RCC. People with a poor prognosis who can receive first-line treatments were assumed to have a utility of 0.60 when in the PFS state and 0.45 when in the PD state; these assumptions came from the Wyeth submission. People who were receiving second-line treatments were assumed to have a utility of 0.76 when in the PFS state and 0.68 when in the PD state; these assumptions came from the Pfizer submission.\n\nIn the Assessment Group model, drug acquisition costs (except for sorafenib) were modified according to dose intensities reported in the relevant RCTs. Current list prices were taken from the BNF (edition 55), and the agreed patient access scheme of the first pack of sorafenib being free to the NHS was applied. All other costs were inflated to 2007–8 values. Because temsirolimus had no BNF list price at the time of the submission, the price of a 30-mg vial was inferred from the price of a 25-mg dose of temsirolimus as submitted by the manufacturer, and calculated as £618. However, the price stated by the manufacturer in their original submission of £515 was included in the sensitivity analyses. The patient access scheme for bevacizumab, which was described by the manufacturer, was included in sensitivity analyses only. It was assumed that 100% of IFN-α monotherapy was administered at home, with 75% being self-administered. Additional resource uses associated with outpatient monitoring, scans and tests were used in the model for people in the PFS health state on drug treatment. In the PFS state, the medical management cost per cycle was £81 for best supportive care and £223 for all other drug treatments. In the PD state, the cost for each cycle was £435 for all treatments.\n\nA number of one-way and multi-way sensitivity analyses were performed to test the sensitivity of the cost-effectiveness analyses. The key sensitivity analyses investigated the assumptions that were made on clinical effectiveness, drug acquisition and administration costs, best supportive care and management costs and health-state utility values. In particular, the Assessment Group highlighted a paucity of data surrounding accurate health-state utility values and best supportive care costs. The Assessment Group performed sensitivity analyses on their own model by varying their own assumptions and also by incorporating the manufacturers' parameters. The Assessment Group also performed sensitivity analyses on the manufacturers' models by incorporating the Assessment Group's parameters and assumptions.\n\nWith discounting at 3.5% per annum, the comparison of bevacizumab plus IFN-α with IFN-α alone produced an ICER of £171,301 per QALY gained. The deterministic sensitivity analyses demonstrated that estimates of treatment effectiveness, drug pricing (including dose intensity data) and health-state utility input parameters were the key drivers affecting the ICERs. The ICERs were particularly sensitive to variations in estimates of the hazard ratio for overall survival, with ICERs ranging from £90,693 (HR for overall survival = 0.58) to £868,881 (HR for overall survival = 0.97) per QALY gained for bevacizumab plus IFN-α compared with IFN-α alone.\n\nWith discounting at 3.5% per annum and using a vial price of £618, the comparison of temsirolimus with IFN-α produced an ICER of £94,385 per QALY gained. In the subgroup analyses for temsirolimus (clear cell, non-clear-cell carcinoma; nephrectomy, no nephrectomy; and only participants with a poor prognosis according to the Motzer criteria), the ICERs ranged from £74,184 to £154,334 per QALY gained. The only subgroup that demonstrated a lower ICER than the base-case analysis was the subgroup with no prior nephrectomy, at £74,184 per QALY gained. The deterministic sensitivity analyses demonstrated that estimates of treatment effectiveness, cost of acquisition and administration of temsirolimus, and health-state utility input parameters were the key drivers affecting the ICERs. The ICER was particularly sensitive to variations in estimates of the hazard ratio for overall survival, with ICERs ranging from £56,452 (HR for overall survival = 0.58) to £253,443 (HR for overall survival = 0.92) per QALY gained in the Assessment Group's initial analyses.\n\nWith discounting at 3.5% per annum and using the original price of £2504.60, the comparison of sorafenib with best supportive care produced an ICER of £102,498 per QALY gained for all patients. The deterministic sensitivity analyses demonstrated that estimates of treatment effectiveness and cost of sorafenib (dose intensity assumption) were the key drivers affecting the ICERs. The health-state utility parameters affected the ICER marginally. The ICER was particularly sensitive to variations in estimates of the hazard ratio for overall survival, with ICERs ranging from £55,585 (HR for overall survival = 0.54) to £368,830 (HR for overall survival = 0.94) per QALY gained.\n\nAll ICERs were higher when using the Assessment Group model than the manufacturers' models. In general, the model structures used by the Assessment Group and the manufacturers were similar. However, there were some differences in assumptions and data inputs that have been highlighted by the Assessment Group.\n\nIn relation to the economic model submitted by Roche Products (bevacizumab plus IFN-α compared with IFN-α plus placebo), the Assessment Group stated that it was essentially the assumptions about costs (especially drug-related costs) that were associated with different cost-effectiveness estimates. If the original 'dose cap' patient access scheme detailed by the manufacturer was applied in the Assessment Group model, the ICER in the Assessment Group model was reduced from £171,301 to £90,584 per QALY gained. Similarly, if the original 'dose cap' patient access scheme was removed from the manufacturer's model, the ICER increased from £74,999 to £108,329 per QALY gained. Another important difference between the manufacturer's and Assessment Group models is the use of data on dose intensity. Incorporating the Assessment Group's higher dose intensity estimates into the manufacturer economic model further increased the ICER from £74,999 to £117,000 per QALY gained.\n\nIn relation to the economic model submitted by Wyeth Pharmaceuticals (temsirolimus compared with IFN-α), the Assessment Group stated that the key differences were the assumptions made on resource use and costs, particularly costs associated with the acquisition of temsirolimus and the administration of IFN-α. If the Assessment Group's assumptions of lower costs of administration of IFN-α were incorporated into the Wyeth model (which used a vial price of £515), the Wyeth base case ICER increased from £55,814 to £102,000 per QALY gained. The ICERs for the different subgroups also increased: from £51,159 to £63,100 per QALY gained for the subgroup with non-clear-cell carcinoma; from £57,731 to £121,300 per QALY gained for the subgroup with clear cell carcinoma; from £49,690 to £84,000 per QALY gained for the subgroup with no prior nephrectomy; and from £60,575 to £117,000 per QALY gained for the subgroup with prior nephrectomy.\n\nFollowing consultation on the draft guidance, the Assessment Group and the Decision Support Unit (DSU) were requested to explore the issues raised during the consultation.\n\nThe manufacturer of bevacizumab (Roche Products) requested that the following parameters were altered in the Assessment Group's economic model:\n\nThe hazard ratio for overall survival should be reduced from 0.75 to 0.613. This is because 28% of the participants in the bevacizumab plus IFN-α arm and 18% of the participants in the IFN-α plus placebo arm of the trial received second-line treatments. The hazard ratio of 0.613 represents the effect of bevacizumab plus IFN-α compared with IFN-α plus placebo on overall survival when the participants who received any second-line treatments were censored from the analysis.\n\nThe average cumulative dose of bevacizumab per participant should be based on the empirical trial data; that is, an average dose of 756.7 mg of bevacizumab per administration (the Assessment Group's base case assumed an average bevacizumab dose intensity of 88% over 12 months, which was based on the dosage implied by the trial protocol).\n\nThe average number of bevacizumab administrations per participant should be based on empirical trial data; that is, an average duration of bevacizumab treatment of 7.36 months (the Assessment Group's base case assumed a treatment duration of 12 months, based on the interpretation of the trial protocol).\n\nThe cost of bevacizumab administration should be reduced from £197 to £98 because of the reduced time needed to administer intravenous bevacizumab.\n\nApplying these parameter changes to the Assessment Group's base case reduced the cost-effectiveness estimate of bevacizumab plus IFN-α compared with IFN-α plus placebo. Applying the revised hazard ratio for overall survival reduced the ICER from £171,301 per QALY gained to £101,340 per QALY gained. Using the empirical trial data on dosage of bevacizumab and number of administrations reduced the base-case ICER from £171,301 to £114,624 per QALY gained and reduced the revised ICER (with a hazard ratio for overall survival of 0.613) from £101,340 to £68,561 per QALY gained. Reducing the cost of bevacizumab administration further reduced the base-case ICER from £114,624 to £108,835 per QALY gained and the revised ICER (with a hazard ratio for overall survival of 0.613) from £68,561 to £65,213 per QALY gained.\n\nThe DSU highlighted concerns that the revised hazard ratio for overall survival as presented by Roche (0.613) was now lower than the hazard ratio for progression-free survival (0.63). The DSU performed additional analysis of the parameter changes that set the hazard ratio for overall survival equal to that of progression-free survival (that is, hazard ratios of 0.63 for both). This reduced the original Assessment Group base-case ICER from £171,301 to £107,489 per QALY gained.\n\nFollowing consultation on the parameter changes made to the Assessment Group model by the DSU, the manufacturer of bevacizumab responded stating that the dose intensity should be revised to 92%. A revised cost of bevacizumab administration of £170 per dose was also suggested by the manufacturer of bevacizumab. The DSU was requested to calculate an updated cost-effectiveness estimate for bevacizumab plus IFN-α compared with IFN-α in the Assessment Group's model. The DSU was asked to use the following parameters: a corrected bevacizumab dose intensity of 92%; a bevacizumab administration cost of £170; and a hazard ratio for overall survival of 0.63 (equal to that of progression-free survival). Using these parameters in the Assessment Group's model resulted in an ICER of £82,732 per QALY gained for bevacizumab plus IFN-α compared with IFN-α.\n\nFollowing further consultation, the manufacturer of bevacizumab (Roche) included details of an updated patient access scheme which had been agreed with the Department of Health. The patient access scheme includes a rebate of the costs of bevacizumab after 10 g has been given to a patient in a 12-month period and a rebate of all costs of IFN-α when it is given with bevacizumab. The Department of Health considered that this patient access scheme does not constitute an excessive administrative burden to the NHS. The DSU was asked to provide a revised cost-effectiveness estimate using the Assessment Group model, incorporating the parameter changes requested by the manufacturer of bevacizumab (see section 4.2.27) and the costs with the patient access scheme. Applying the parameter changes and including the costs from the patient access scheme reduced the cost-effectiveness estimate of bevacizumab plus IFN-α compared with IFN-α plus placebo from £82,732 to £53,820 per QALY gained.\n\nThe manufacturer of sorafenib (Bayer) provided a late submission, which revised their original analysis of the whole trial population and the 83% of participants in whom first-line immunotherapy had failed. No revised analyses were provided of the 17% in whom other first-line (non-immunotherapy) treatments had failed. The revised analyses also included details of a patient access scheme in which the first pack of sorafenib is free to the NHS. The manufacturer also presented information about the new price of sorafenib in the context of the PPRS. The DSU was asked to appraise the approach used by the manufacturer and provide cost-effectiveness estimates using the Assessment Group model, incorporating costs with the scheme and the new increased price. In relation to the approach used by the manufacturer. The DSU acknowledged that the alternative modelling approach, utility values and costs had been changed by the manufacturer to reflect those used in the Assessment Group model and that a more complete dataset for the people in whom immunotherapy had failed was used in the revised analyses. The DSU also agreed with the manufacturer that the assumption of proportional hazards was not valid and this resulted in a large reduction in the ICERs. However, the DSU noted that the revised analysis resulted in ICERs for people in whom immunotherapy had failed which were lower than the total group ICERs and this was markedly different from the original (confidential) analyses presented by the manufacturer of sorafenib, where the subgroup ICER was higher than the total group ICER. The DSU also highlighted that the follow-up of the participants randomised to receive sorafenib was much longer than that of the participants randomised to receive best supportive care. This was because participants were allowed to crossover from best supportive care to sorafenib treatment after the study was terminated early on ethical grounds. There were also no details about whether participants randomised to receive sorafenib received any subsequent treatments. Therefore the DSU stated that a more appropriate approach would have been to censor both arms at the same point. The DSU noted that this approach was presented in the main publication of the trial.\n\nThe DSU then calculated the respective cost-effectiveness estimates using the Assessment Group's economic model. The DSU accepted arguments presented by the manufacturer of sorafenib that the proportional hazards assumption did not hold and that independent curve modelling should be used. In order to address the concerns surrounding the censoring approach used by the manufacturer, the DSU censored both arms at the same point (that is, at the point of trial termination). The DSU then modelled the progression-free and overall survival curves for sorafenib and best supportive care using independent Weibull curves. The revised ICER for the whole trial population (including costs with the patient access scheme and new price) was £74,915 per QALY gained. The revised ICER (including costs with the patient access scheme and new price) for the subgroup of participants in whom immunotherapy had failed was £65,929 per QALY gained.\n\n# Consideration of the evidence\n\nThe Appraisal Committee reviewed the data available on the clinical and cost effectiveness of bevacizumab (first-line), sorafenib (first- and second-line), sunitinib (second-line) and temsirolimus (first-line), having considered evidence on the nature of the condition and the value placed on the benefits of bevacizumab (first-line), sorafenib (first- and second-line), sunitinib (second-line) and temsirolimus (first-line) by people with advanced and/or metastatic RCC, those who represent them, and clinical specialists. It was also mindful of the need to take account of the effective use of NHS resources.\n\nThe Committee heard from clinical specialists and patient experts that there are limited treatment options for people with advanced and/or metastatic RCC. The Committee noted that the only current standard first-line treatment is immunotherapy and there are no current treatment options for people in whom immunotherapy has failed or who are considered unsuitable for immunotherapy. Moreover, there are no current standard second-line treatment options. The Committee heard from people with RCC and patient experts that immunotherapy is associated with limited effectiveness and high toxicity. The Committee also heard that RCC does not respond well to conventional chemotherapies and that bevacizumab (first-line), sorafenib (first- and second-line), sunitinib (second-line) and temsirolimus (first-line) represent improvements in the treatment of advanced and/or metastatic RCC.\n\nThe Committee heard from people with RCC and patient experts that advanced and/or metastatic RCC is a relatively rare cancer and noted the views of both patient and clinical experts concerning the severity of the disease. The Committee also heard from clinical experts, the Assessment Group and manufacturers that there is a paucity of data on the utility values associated with living with advanced and/or metastatic RCC. The Committee noted that it may be difficult to fully capture the effects of bevacizumab (first-line), sorafenib (first- and second-line), sunitinib (second-line) and temsirolimus (first-line) on health-related quality of life. The Committee acknowledged the comments that were received from people with RCC and the public, stating that some people with RCC had experienced significant improvements in their quality of life as a result of using the drugs.\n\nThe Committee was aware of the supplementary advice from NICE that should be taken into account when appraising treatments which may extend the life of people with a short life expectancy and which are licensed for indications that affect small numbers of people with incurable illnesses. For this advice to be applied, all the following criteria must be met:\n\nThe treatment is indicated for patients with a short life expectancy, normally less than 24 months.\n\nThere is sufficient evidence to indicate that the treatment offers an extension to life, normally of at least an additional 3 months, compared with current NHS treatment.\n\nNo alternative treatment with comparable benefits is available through the NHS.\n\nThe treatment is licensed or otherwise indicated for a small patient population.In addition, when taking these into account the Committee must be persuaded that the estimates of the extension to life are robust and the assumptions used in the reference case economic modelling are plausible, objective and robust.\n\n## First-line treatment for people suitable for immunotherapy\n\nThe Committee reviewed the evidence of clinical effectiveness from the bevacizumab study. The Committee noted that bevacizumab plus IFN-α demonstrated a statistically significant gain in terms of progression-free survival compared with IFN-α plus placebo. The Committee was aware that the data presented on overall survival were immature because median overall survival had not been reached. The Committee was persuaded that bevacizumab plus IFN-α is a clinically effective first-line treatment. However, the Committee heard testimony from clinical specialists and people with RCC that IFN-α is associated with high toxicity, is poorly tolerated and is administered by subcutaneous injection. Therefore the Committee was mindful of the concerns highlighted by patient experts and clinical specialists associated with the combination of bevacizumab and IFN-α.\n\nThe Committee considered the estimates of cost effectiveness of bevacizumab plus IFN-α. It noted that the models from the manufacturer and the Assessment Group were similar in terms of structure and data sources; the models differed chiefly in the drug acquisition costs. These differences resulted in different estimates of cost effectiveness between the manufacturer and the Assessment Group of £75,000 and £171,000 per QALY gained, respectively. The Committee noted that when the original patient access scheme was applied to the Assessment Group cost-effectiveness estimate, the Assessment Group base-case ICER was reduced from £171,000 to £90,500 per QALY gained. The Committee noted that the original patient access scheme was not agreed by the Department of Health and that the final agreed patient access scheme had an additional component which would further reduce these ICERs.\n\nThe Committee considered the parameter changes suggested by the manufacturer of bevacizumab for insertion into the Assessment Group's model (see section 4.2.27). Although the first suggestion to censor participants once second-line treatments were received was appropriate in principle, the Committee noted that its application produced some anomalous findings: there were more participants in the bevacizumab arm than the IFN-α arm that were censored. Although the Committee noted that, on average, the participants in the bevacizumab plus IFN-α arm had received treatment for almost twice as long as those in the IFN-α plus placebo arm, the Committee considered that the cause of the greater censoring was likely to be the withdrawal of more participants from bevacizumab plus IFN-α treatment than IFN-α plus placebo treatment because of the adverse effects of bevacizumab plus IFN-α. It also noted that the revised hazard ratio for overall survival was now lower than the original hazard ratio for progression-free survival. The Committee considered that a reduced hazard ratio for overall survival was plausible, but that it would not be expected to be lower than the hazard ratio for progression-free survival. The Committee then reviewed the bevacizumab dosages and quantity and cost of bevacizumab administrations applied in the economic model. The Committee accepted that it was plausible that in the trial participants may have stopped treatment before 12 months, but considered that the trial protocol and exact interpretation of treatment duration was unclear. The Committee also considered that lower costs of bevacizumab administration were plausible, although noted that the costs of administration were unlikely to be halved. The Committee noted and accepted the revised dose intensity estimate of 92% and bevacizumab administration cost of £170 as provided by the manufacturer of bevacizumab.\n\nThe Committee then discussed the fact that bevacizumab was licensed to be given to people with advanced and/or metastatic RCC in combination with IFN-α. It noted that the health-state utilities used in calculating the cost-effectiveness estimate of bevacizumab plus IFN-α compared with IFN-α plus placebo were obtained from an RCT of sunitinib compared with IFN-α (see section 4.2.2), and that the health-state utilities were not treatment specific. The Committee was aware that the costs of adverse effects had been included in the economic model, although these were negligible. It considered that there would be disutility associated with the high toxicity, poor tolerance and issues with the administration of bevacizumab plus IFN-α, that had been highlighted by clinical specialists and patient experts, and that this disutility had not been incorporated into the cost-effectiveness estimate of bevacizumab plus IFN-α compared with IFN-α. Taking these concerns that had been highlighted into account the Committee agreed that the ICER was likely to be an underestimate and therefore the Committee concluded that the lowest plausible ICER estimate was £53,800 per QALY gained.\n\nThe Committee next discussed whether bevacizumab plus IFN-α for the treatment of advanced and/or metastatic RCC fulfilled the criteria for a life-extending, end-of-life treatment. The Committee noted from the clinical trials that life expectancy with IFN-α treatment alone was unlikely to be greater than 24 months and was potentially as low as 12 months. The Committee agreed that it was likely that bevacizumab plus IFN-α would increase overall survival by more than 3 months in comparison with IFN-α alone. It had heard that RCC does not respond well to IFN-α alone, but considered that bevacizumab plus IFN-α does represent a marked change in the treatment of advanced and/or metastatic RCC. The Committee was aware that the total number of people with advanced and/or metastatic RCC in England and Wales was approximately 4000. However, the Committee understood that it should take into account the cumulative population for each product in considering the strength of any case, for justifying decisions which employ, in whole or part, the supplementary criteria for appraising life-extending, end-of-life treatments. It noted that bevacizumab was licensed for a number of other indications involving much larger patient groups. The Committee noted that the manufacturer argued that the use of bevacizumab was restricted in the UK and that, in effect, the valid patient population for bevacizumab is small. However the Committee considered that this point did not override its view that bevacizumab is licensed for a relatively large population across its range of indications. In summary, the Committee was not persuaded that bevacizumab plus IFN-α meets all the criteria for a life-extending end-of-life treatment, given the size of the patient populations (in RCC and other cancers) for whom it is licensed.\n\nThe Committee considered the lowest plausible cost-effectiveness estimate of bevacizumab plus IFN-α of £53,800 per QALY gained and concluded that bevacizumab plus IFN-α as a first-line treatment for people with advanced and/or metastatic RCC would not be a cost-effective use of NHS resources.\n\n## First-line treatment for people suitable for immunotherapy with three of six factors indicating poor prognosis\n\nThe Committee reviewed the evidence of clinical effectiveness from the temsirolimus study. The Committee was mindful that the criteria used for defining poor prognosis in the temsirolimus trial were different from those commonly used in clinical practice. It noted that temsirolimus demonstrated a statistically significant gain in terms of overall survival, progression-free survival and tumour response rate compared with IFN-α. The Committee discussed the available subgroup data, but had concerns as to whether the data were robust enough to distinguish particular subgroup responses. Some of the subgroups were very small, in particular one of the subgroups highlighted by the manufacturer, non-clear-cell carcinoma, was based on less than 20% (n=73) of the trial population. This subgroup was also defined imprecisely as 'non-clear-cell carcinoma and 'indeterminate histologies' in the trial. It was also unclear whether all of the subgroup analyses had been defined a priori. However, the Committee was persuaded that in general temsirolimus is a clinically effective first-line treatment for people with a poor prognosis, and was minded to consider the cost-effectiveness evidence, including the subgroups who might gain greater benefit.\n\nTherefore the Committee considered the estimates of cost effectiveness of temsirolimus. It noted that the original models from the manufacturer and the Assessment Group were similar in terms of structure and data sources; the models differed chiefly in the acquisition cost of temsirolimus and costs associated with the administration of IFN-α. However, the Committee heard from clinical specialists that most people would be able to self-administer IFN-α at home and that the proportion needing help with administration assumed by the Assessment Group was considered reasonable. The Committee acknowledged consultation responses from the manufacturer that highlighted that the duration of temsirolimus treatment had been overestimated in the Assessment Group economic model by the use of hazard ratios for deriving survival curves. Therefore the Committee considered that the most appropriate ICERs were those calculated by the manufacturer, but with the Assessment Group's costs for IFN-α administration incorporated and the manufacturer's initial cost for the acquisition of temsirolimus. These resulted in a base-case ICER of £102,000 per QALY gained and subgroup ICERs ranging from £63,100 ('non-clear-cell carcinoma and indeterminate histologies') to £121,300 (clear-cell carcinoma) per QALY gained. However, The Committee noted the recently published price of £620 for a vial of temsirolimus and was aware that these ICER estimates were derived using an underestimate of the price of a vial of temsirolimus of £515. Therefore it concluded that the ICERs were underestimates and would all increase if the recently published price of temsirolimus was incorporated into the cost-effectiveness analyses.\n\nThe Committee next discussed whether temsirolimus for the treatment of advanced and/or metastatic RCC fulfilled the criteria for a life-extending, end-of-life treatment. The Committee noted from the clinical trials that life expectancy with IFN-α treatment alone was unlikely to be greater than 24 months and was potentially as low as 7 months for patients with a poor prognosis. The Committee considered that evidence from the temsirolimus trial suggested that temsirolimus increased survival by more than 3 months compared with IFN-α alone and it considered temsirolimus to be an improvement in treatment for advanced and/or metastatic RCC. It was aware that the total number of people with advanced and/or metastatic RCC in England and Wales was approximately 4000 and that temsirolimus was licensed for people with a poor prognosis and so had a very small patient population. The Committee agreed that the criterion for the robustness of evidence was convincing for the overall trial data, but not for the subgroup data. In summary, the Committee was satisfied that temsirolimus met the criteria for being a life-extending, end-of-life treatment for the whole trial population.\n\nThe Committee then considered the cost-effectiveness estimate of temsirolimus of £102,000 per QALY gained (noting that this was an underestimate because of the underestimated price of temsirolimus), in light of the appraisal of a life-extending, end-of-life treatment. The Committee was aware that the patient population eligible for temsirolimus treatment was very small, but noted that NICE had not received direction from the Department of Health that 'ultra-orphan' conditions should be appraised differently from any other appraisal; including those that meet the end-of-life criteria. The Committee considered that the additional weight that would need to be assigned to the original QALY benefits in this patient group for the cost effectiveness of temsirolimus to fall within the current threshold range would be too great. The subgroup data were not considered to be robust enough to apply a consideration of additional weight that would need to be assigned to the original QALY benefits in these subgroups. Therefore the Committee concluded that temsirolimus as a first-line treatment for people with advanced RCC and a poor prognosis would not be a cost-effective use of NHS resources.\n\nVery few data were presented to the Committee on the clinical effectiveness of bevacizumab plus IFN-α compared with IFN-α plus placebo as a first-line treatment for people with a poor prognosis, suitable for immunotherapy. The Committee noted that only a small subgroup of the bevacizumab RCT (see section 4.1.2) had a poor prognosis and the data available confirmed no benefit in terms of progression-free survival. The Committee concluded that with such limited evidence, it could not consider bevacizumab plus IFN-α as a clinically effective first-line treatment for people with poor prognosis, suitable for immunotherapy with advanced and/or metastatic RCC.\n\n## First-line treatment for people unsuitable for immunotherapy\n\nThe only data presented to the Committee for the first-line treatment of people unsuitable for immunotherapy came from two single-arm studies of sorafenib which were presented in abstract form only. The Committee concluded that, with such weak evidence, it could not consider sorafenib as a clinically effective first-line treatment for people with advanced RCC who were unsuitable for immunotherapy.\n\n## First-line treatment for people unsuitable for immunotherapy with three of six factors indicating poor prognosis\n\nThe Committee reviewed the evidence of clinical and cost effectiveness for temsirolimus compared with best supportive care as presented by the manufacturer (Wyeth Pharmaceuticals). The Committee was aware that the data informing the comparisons came from an indirect comparison. Limited information on the trial used in the comparison was presented and the Committee heard that the best supportive care in the trial was unlikely to be offered as current clinical practice. The Committee concluded that temsirolimus had not been shown to be a clinically effective first-line treatment for people with advanced RCC and a poor prognosis and who were unsuitable for immunotherapy.\n\nNo data were presented to the Committee on the clinical or cost effectiveness of sorafenib compared with best supportive care as a first-line treatment for people with a poor prognosis who were unsuitable for immunotherapy. The Committee noted that the sorafenib RCT included only people with an ECOG performance status of 0 or 1 and therefore did not include people with a poor performance. The Committee concluded that, in the absence of evidence, sorafenib had not been shown to be a clinically effective first-line treatment for people with advanced RCC and a poor prognosis and who were unsuitable for immunotherapy.\n\n## Second-line treatment for people in whom immunotherapy has failed\n\nThe Committee reviewed the clinical effectiveness of sorafenib for people in whom immunotherapy has failed. The Committee noted that sorafenib demonstrated a clinically relevant and statistically significant advantage over best supportive care in terms of progression-free survival and tumour response for the 83% of the trial participants in whom immunotherapy had failed. The Committee was persuaded that sorafenib is a clinically effective therapy for second-line treatment of RCC for people in whom immunotherapy has failed.\n\nThe Committee then reviewed the cost-effectiveness estimates for the subgroup in whom immunotherapy had failed. The Committee noted that the trial was not stratified according to prior treatments, but acknowledged responses from consultation that the subgroup was pre-specified, and considered that the subgroup represented most of the trial participants and was relatively large. The Committee noted comments from the DSU that the reduced ICERs, presented by the manufacturer of sorafenib in the revised analyses, were derived using appropriate modelling techniques, similar to that used by the Assessment Group. However, the Committee agreed that due to the concerns raised by the DSU about the change in direction of the subgroup ICER as presented by the manufacturer of sorafenib that the most reasonable subgroup estimate came from the DSU revised analysis using the Assessment Group's economic model. The Committee, noting instructions from the Department of Health that all of the cost-effectiveness estimates should include the first pack of sorafenib as free to the NHS and the new increased price of sorafenib, accepted that the most plausible ICER for sorafenib compared with best supportive care for people in whom immunotherapy had failed was £65,900 per QALY gained.\n\nThe Committee next discussed whether sorafenib for the treatment of advanced RCC fulfilled the criteria for consideration as a life-extending, end-of-life treatment. The Committee noted from the clinical trials that life expectancy with best supportive care alone was unlikely to be greater than 24 months and was potentially as low as 6 months. The Committee considered that even though the sorafenib trial was terminated early, this was done after a report of increased progression-free survival in the sorafenib arm. The Committee considered that it was likely that sorafenib would increase overall survival by more than 3 months in comparison with best supportive care. It also agreed that sorafenib provided an improvement in the treatment of advanced RCC. It was aware that the total number of people with advanced and/or metastatic RCC in England and Wales was approximately 4000. Therefore the Committee was satisfied that sorafenib meets the criteria for being a life-extending, end-of-life treatment and that the trial evidence presented for this consideration was robust.\n\nThe Committee then considered the most plausible cost effectiveness of sorafenib for people in whom immunotherapy had failed, of £65,900 per QALY gained, in light of the appraisal of a life-extending, end-of-life treatment. It considered that the magnitude of additional weight that would need to be assigned to the original QALY benefits in this patient group for the cost effectiveness of the drug to fall within the current threshold range would be too great. Therefore the Committee concluded that sorafenib as a second-line treatment for people with advanced RCC in whom immunotherapy has failed would not be a cost-effective use of NHS resources.\n\nThe Committee then reviewed the clinical and cost effectiveness for sunitinib as a second-line treatment compared with best supportive care for people in whom immunotherapy had failed. The Committee was concerned that the data informing the comparisons came from two small single-arm trials. The Committee acknowledged that the comparison with best supportive care suggested that sunitinib may be clinically effective compared with best supportive care. However, in the absence of further robust data, the Committee concluded that sunitinib could not be considered a clinically effective second-line treatment for people with advanced and/or metastatic RCC in whom immunotherapy had failed.\n\n## Second-line treatment for people in whom non-immunotherapy first-line treatment has failed and who are unsuitable for immunotherapy\n\nThe Committee reviewed the academic-in-confidence evidence on the clinical effectiveness of sorafenib compared with best supportive care for people unsuitable for immunotherapy as presented by the manufacturer (Bayer). The Committee noted that the subgroup constituted a small proportion (17%) of the sorafenib RCT, but that the overall trial population was relatively large. Following consultation, the Committee heard that the data informing the comparison came from a pre-planned subgroup from the sorafenib RCT, although it was unclear what prior therapies the subgroup had received. The Committee concluded that, although the data were limited, sorafenib could be considered as a clinically effective second-line treatment for those unsuitable for immunotherapy with advanced RCC.\n\nThe Committee then reviewed the estimates of cost effectiveness of sorafenib as a second-line treatment for people unsuitable for immunotherapy. The Committee noted that the manufacturer of sorafenib (Bayer) had not provided revised ICERs for this subgroup. The Committee noted that, overall, the revised models submitted by the manufacturer and the Assessment Group were generally similar in terms of structure, data sources and assumptions. The resulting estimates of cost effectiveness were broadly similar with a revised manufacturer base-case ICER for the whole trial population of £72,500, per QALY gained and a DSU revised Assessment Group base-case ICER of £74,900 per QALY gained. The Committee noted that the subgroup ICER for the 83% of trial participants in whom immunotherapy had failed was lower than these ICERs for the whole trial population. The Committee therefore agreed that the most plausible subgroup ICER for the 17% of trial participants who were unsuitable for immunotherapy must be higher than the ICER for the whole trial population of £72,500 or £74,900 per QALY gained.\n\nThe Committee agreed that the criterion for the robustness of evidence for this subgroup was not convincing therefore the Committee did not discuss whether sorafenib for the second-line treatment of people with advanced RCC who are unsuitable for immunotherapy fulfilled the criteria for consideration as a life-extending, end-of-life treatment. This was because it was not clear what prior therapies the people in the subgroup had received and no cost-effectiveness estimates were provided. The Committee considered the most plausible ICERs that were higher than £72,500 and £74,900 per QALY gained and concluded that sorafenib as second-line treatment for people in whom non-immunotherapy first-line treatment has failed and who are unsuitable for immunotherapy with advanced RCC would not be a cost-effective use of NHS resources.\n\n## Second-line treatment for people in whom sunitinib has failed\n\nThe Committee noted the suggestion made by the manufacturer of sorafenib that consideration should be given to the sequencing of treatments (particularly sunitinib as a first-line treatment followed by sorafenib as second-line treatment). It also noted that the marketing authorisation of sorafenib was for people in whom immunotherapy had failed or who were unsuitable for immunotherapy. Therefore the Committee considered that the use of sorafenib after sunitinib would be relevant only for people who had received sunitinib as a first-line treatment and were unsuitable for immunotherapy. The Committee noted that the evidence base for this treatment pathway was absent, because participants were excluded from the sorafenib RCT if they had received sunitinib as a first-line treatment and the sunitinib RCT only included people who were suitable for immunotherapy. In the absence of robust data, the Committee could not reach any conclusions on whether sorafenib could be considered a clinically effective second-line treatment for people with advanced RCC who had received sunitinib as a first-line treatment.\n\n## The Institute's duties under the equalities legislation\n\nIn carrying out its consideration of the evidence and reaching its conclusions, the Committee was aware of the Institute's duties under the equalities legislation and considered whether those duties required the Committee to alter or to add to its recommendations in any way. However, the Committee did not identify any way in which its guidance would have a particular impact on any of the groups whose interests are protected by the equalities legislation. It noted that in relation to first-line treatment for people who are unsuitable for immunotherapy and second-line treatment for people who are unsuitable for immunotherapy its recommendations are based on the view that there is limited or no evidence of clinical effectiveness for any patient group. For the other patient populations the Committee's conclusions are based on the view that the treatments are not cost effective for any patient group. The guidance does not recommend the availability of the treatments to some patients and not to others. The recommendations apply to all patients with renal cell carcinomas and all such patients are affected by the guidance in the same way.", 'Recommendations for further research': 'There are a number of ongoing trials which are actively recruiting participants and which are relevant to this appraisal. Some of these trials are investigating the optimum sequences of treatment. Full details of ongoing research can be found at the National Institute for Health Research Clinical Research Network, ClinicalTrials.gov and Current Controlled Trials.\n\nThe Assessment Group considered that the following well-conducted RCTs reporting health-related utility values in accordance with the NICE methods guide could be of value:\n\nRCTs to investigate the effectiveness of temsirolimus and sorafenib as first-line treatments (both as monotherapy) compared with best supportive care in people who are unsuitable or have contraindications for immunotherapy and who have a poor or intermediate prognosis.\n\nRCTs of sunitinib as a second-line treatment in people in whom immunotherapy has failed.\n\nRCTs of sorafenib as a second-line treatment in whom first-line non-immunotherapy treatment (including sunitinib) has failed and who are unsuitable or have contraindications to immunotherapy.', 'Related NICE guidance': 'Sunitinib for the first-line treatment of advanced and/or metastatic renal cell carcinoma. NICE technology appraisal guidance 169 (2009).\n\nPercutaneous radiofrequency ablation of renal cancer. NICE interventional procedure guidance 91 (2004). [Replaced by NICE interventional procedure guidance 353 (2010)]\n\nImproving outcomes in urological cancers. NICE cancer service guidance (2002).', 'Review of guidance': 'The review date for a technology appraisal refers to the month and year in which the Guidance Executive will consider whether the technology should be reviewed. This decision will be taken in the light of information gathered by the Institute, and in consultation with consultees and commentators.\n\nThe guidance on this technology will be considered for review by June 2011.\n\nAndrew DillonChief ExecutiveAugust 2009', 'Changes after publication': 'February 2014: minor maintenance\n\nMarch 2012: minor maintenance', 'About this guidance': 'NICE technology appraisal guidance is about the use of new and existing medicines and treatments in the NHS in England and Wales.\n\nThis guidance was developed using the NICE multiple technology appraisal process.\n\nWe have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available.\n\nYour responsibility\n\nThis guidance represents the views of NICE and was arrived at after careful consideration of the evidence available. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. However, the guidance does not override the individual responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.\n\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.\n\nCopyright\n\n© National Institute for Health and Clinical Excellence 2009. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.'}	https://www.nice.org.uk/guidance/ta178	Evidence-based recommendations on bevacizumab (Avastin), sorafenib (Nexavar), sunitinib (Sutent) and temsirolimus (Torisel) for treating advanced or metastatic renal cell carcinoma in adults.
f555929df02f255c145cefd55e82868e848bd7f1	nice	Extracorporeal shockwave therapy for refractory plantar fasciitis	Extracorporeal shockwave therapy for refractory plantar fasciitis # Guidance The evidence on extracorporeal shockwave therapy (ESWT) for refractory plantar fasciitis raises no major safety concerns; however, current evidence on its efficacy is inconsistent. Therefore, this procedure should only be used with special arrangements for clinical governance, consent and audit or research. Clinicians wishing to undertake ESWT for refractory plantar fasciitis should take the following actions. Inform the clinical governance leads in their Trusts. Ensure that patients understand the uncertainty about the procedure's efficacy and provide them with clear written information. In addition, the use of NICE's information for patients ('Understanding NICE guidance') is recommended. Audit and review clinical outcomes of all patients having ESWT for refractory plantar fasciitis (see section 3.1). NICE encourages further research into ESWT for refractory plantar fasciitis. Future research should take the form of clinical studies with clearly described patient selection and treatment protocols, including a description of local anaesthesia use and the type of energy applied (see section 2.5). The studies should include validated outcome measures and be based on a minimum of 1-year follow-up. NICE may review the procedure on publication of further evidence.# The procedure # Indications and current treatments Plantar fasciitis is characterised by chronic degeneration of the plantar fascia, which causes pain on the underside of the heel. It is usually caused by injury or biomechanical abnormalities and may be associated with microtears, inflammation or fibrosis. Conservative treatments include rest, application of ice, analgesic medication, non-steroidal anti-inflammatory drugs, orthotic devices, physiotherapy, eccentric training/stretching and corticosteroid injection. # Outline of the procedure Extracorporeal shockwave therapy is a non-invasive treatment in which a device is used to pass acoustic shockwaves through the skin to the affected area. Ultrasound guidance can be used to assist with positioning of the device. Extracorporeal shockwave therapy may be applied in one or several sessions. Local anaesthesia may be used because high-energy ESWT can be painful. Different energies can be used and there is evidence that local anaesthesia may influence the outcome of ESWT. The mechanism by which this therapy might have an effect on tendinopathy is unknown. Sections 2.3 and 2.4 describe efficacy and safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview. # Efficacy A randomised controlled trial (RCT) of 293 patients treated by ESWT or sham ESWT reported that 47% (67/144) and 30% (42/141) of patients, respectively, had 'successful' outcomes at 3-month follow-up (defined as at least 50% reduction in pressure-induced pain and pain during walking, at least a 1-point reduction in pain score on a 5-point visual analogue scale and no requirement for pain medication 10–12 weeks after treatment) (p = 0.008). In an RCT of 172 patients treated by ESWT or sham ESWT, the mean reduction in pain score (assessed by a 5-point VAS) from baseline to 3-month follow-up was 3.4 in the ESWT group (n = 112) compared with 1.8 in the sham ESWT group (n = 56) (p < 0.001). An RCT of 149 patients treated by ESWT or conservative management reported that 69% of ESWT patients and no patients treated conservatively had an 'excellent' result (no heel pain) and 14% and 55% of each group, respectively, had a 'good' result (50% or greater reduction in baseline pain) at a mean follow-up of 64 months. The Specialist Advisers stated that the key efficacy outcome was relief of symptoms. # Safety The RCTs of 272 and 166 patients reported pain during treatment in 5% (7/135) and 1% (1/81) of ESWT patients, and 1% (2/136) and 1% (1/85) of sham patients, respectively. The RCT of 125 patients reported throbbing pain and erythema requiring ice in 10% (6/61) of ESWT patients, compared with pain requiring analgesia or ice for a mean duration of 7 days in 13% (8/64) of patients who had a single corticosteroid injection. The RCT of 272 patients reported that 12% (16/135) of ESWT patients and 4% (5/136) of sham ESWT patients had skin reddening. In the RCTs of 272 and 172 patients, 2% (3/135) of ESWT patients and 1 ESWT patient, respectively, had local swelling. The Specialist Advisers listed adverse events as bruising, pain and local skin damage. They considered theoretical adverse events to include exacerbation of the condition because of rupture of the plantar fascia or local soft tissue damage. # Other comments The Committee found interpretation of the data difficult because of the diversity of treatment protocols and comparators used, varying reported end points, and inconsistencies in terms of the use of local anaesthesia and energy type. The results of studies conflicted and there was evidence of a substantial placebo response. Previous guidance on this procedure published in 2005 had found the evidence on efficacy inadequate, and new evidence has not been published to alter that view. Plantar fasciitis is a common condition and many patients who have it are refractory to other treatments. If the procedure is efficacious in selected patients, it has the potential for a high impact. This makes provision of robust data particularly important.# Further information This guidance requires that clinicians undertaking the procedure make special arrangements for audit. NICE has identified relevant audit criteria and developed an audit tool (which is for use at local discretion). For related NICE guidance see our website. # Information for patients NICE has produced information on this procedure for patients and carers ('Understanding NICE guidance'). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.# Other NICE recommendations on extracorporeal shockwave therapy Guidance has also been issued on Extracorporeal shockwave therapy for refractory Achilles tendinopathy and Extracorporeal shockwave therapy for refractory tennis elbow. It replaces the previous guidance on Extracorporeal shockwave therapy for refractory tendinopathies (plantar fasciitis and tennis elbow) (IPG139, November 2005).# About this guidance NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland. This guidance was developed using the NICE interventional procedure guidance process. We have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available. Changes since publication January 2012: minor maintenance. Your responsibility This guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer. Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties. Copyright © National Institute for Health and Clinical Excellence 2009. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE. Contact NICE National Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT www.nice.org.uk nice@nice.org.uk	{'Guidance ': "The evidence on extracorporeal shockwave therapy (ESWT) for refractory plantar fasciitis raises no major safety concerns; however, current evidence on its efficacy is inconsistent. Therefore, this procedure should only be used with special arrangements for clinical governance, consent and audit or research.\n\nClinicians wishing to undertake ESWT for refractory plantar fasciitis should take the following actions.\n\nInform the clinical governance leads in their Trusts.\n\nEnsure that patients understand the uncertainty about the procedure's efficacy and provide them with clear written information. In addition, the use of NICE's information for patients ('Understanding NICE guidance') is recommended.\n\nAudit and review clinical outcomes of all patients having ESWT for refractory plantar fasciitis (see section 3.1).\n\nNICE encourages further research into ESWT for refractory plantar fasciitis. Future research should take the form of clinical studies with clearly described patient selection and treatment protocols, including a description of local anaesthesia use and the type of energy applied (see section 2.5). The studies should include validated outcome measures and be based on a minimum of 1-year follow-up. NICE may review the procedure on publication of further evidence.", 'The procedure': "# Indications and current treatments\n\nPlantar fasciitis is characterised by chronic degeneration of the plantar fascia, which causes pain on the underside of the heel. It is usually caused by injury or biomechanical abnormalities and may be associated with microtears, inflammation or fibrosis.\n\nConservative treatments include rest, application of ice, analgesic medication, non-steroidal anti-inflammatory drugs, orthotic devices, physiotherapy, eccentric training/stretching and corticosteroid injection.\n\n# Outline of the procedure\n\nExtracorporeal shockwave therapy is a non-invasive treatment in which a device is used to pass acoustic shockwaves through the skin to the affected area. Ultrasound guidance can be used to assist with positioning of the device.\n\nExtracorporeal shockwave therapy may be applied in one or several sessions. Local anaesthesia may be used because high-energy ESWT can be painful. Different energies can be used and there is evidence that local anaesthesia may influence the outcome of ESWT.\n\nThe mechanism by which this therapy might have an effect on tendinopathy is unknown.\n\nSections 2.3 and 2.4 describe efficacy and safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview.\n\n# Efficacy\n\nA randomised controlled trial (RCT) of 293 patients treated by ESWT or sham ESWT reported that 47% (67/144) and 30% (42/141) of patients, respectively, had 'successful' outcomes at 3-month follow-up (defined as at least 50% reduction in pressure-induced pain and pain during walking, at least a 1-point reduction in pain score on a 5-point visual analogue scale [VAS] [higher scores indicate greater pain] and no requirement for pain medication 10–12 weeks after treatment) (p = 0.008).\n\nIn an RCT of 172 patients treated by ESWT or sham ESWT, the mean reduction in pain score (assessed by a 5-point VAS) from baseline to 3-month follow-up was 3.4 in the ESWT group (n = 112) compared with 1.8 in the sham ESWT group (n = 56) (p < 0.001).\n\nAn RCT of 149 patients treated by ESWT or conservative management reported that 69% of ESWT patients and no patients treated conservatively had an 'excellent' result (no heel pain) and 14% and 55% of each group, respectively, had a 'good' result (50% or greater reduction in baseline pain) at a mean follow-up of 64 months.\n\nThe Specialist Advisers stated that the key efficacy outcome was relief of symptoms.\n\n# Safety\n\nThe RCTs of 272 and 166 patients reported pain during treatment in 5% (7/135) and 1% (1/81) of ESWT patients, and 1% (2/136) and 1% (1/85) of sham patients, respectively. The RCT of 125 patients reported throbbing pain and erythema requiring ice in 10% (6/61) of ESWT patients, compared with pain requiring analgesia or ice for a mean duration of 7 days in 13% (8/64) of patients who had a single corticosteroid injection.\n\nThe RCT of 272 patients reported that 12% (16/135) of ESWT patients and 4% (5/136) of sham ESWT patients had skin reddening. In the RCTs of 272 and 172 patients, 2% (3/135) of ESWT patients and 1 ESWT patient, respectively, had local swelling.\n\nThe Specialist Advisers listed adverse events as bruising, pain and local skin damage. They considered theoretical adverse events to include exacerbation of the condition because of rupture of the plantar fascia or local soft tissue damage.\n\n# Other comments\n\nThe Committee found interpretation of the data difficult because of the diversity of treatment protocols and comparators used, varying reported end points, and inconsistencies in terms of the use of local anaesthesia and energy type. The results of studies conflicted and there was evidence of a substantial placebo response. Previous guidance on this procedure published in 2005 had found the evidence on efficacy inadequate, and new evidence has not been published to alter that view.\n\nPlantar fasciitis is a common condition and many patients who have it are refractory to other treatments. If the procedure is efficacious in selected patients, it has the potential for a high impact. This makes provision of robust data particularly important.", 'Further information': "This guidance requires that clinicians undertaking the procedure make special arrangements for audit. NICE has identified relevant audit criteria and developed an audit tool (which is for use at local discretion).\n\nFor related NICE guidance see our website.\n\n# Information for patients\n\nNICE has produced information on this procedure for patients and carers ('Understanding NICE guidance'). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.", 'Other NICE recommendations on extracorporeal shockwave therapy': 'Guidance has also been issued on Extracorporeal shockwave therapy for refractory Achilles tendinopathy and Extracorporeal shockwave therapy for refractory tennis elbow. It replaces the previous guidance on Extracorporeal shockwave therapy for refractory tendinopathies (plantar fasciitis and tennis elbow) (IPG139, November 2005).', 'About this guidance': 'NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland.\n\nThis guidance was developed using the NICE interventional procedure guidance process.\n\nWe have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available.\n\nChanges since publication\n\nJanuary 2012: minor maintenance.\n\nYour responsibility\n\nThis guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.\n\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.\n\nCopyright\n\n© National Institute for Health and Clinical Excellence 2009. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.\n\nContact NICE\n\nNational Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT\n\nwww.nice.org.uk\n \n nice@nice.org.uk\n 0845 033 7780'}	https://www.nice.org.uk/guidance/ipg311
d19748fe36b2276c14ac3bf6d0c9fc01cdd45247	nice	Extracorporeal shockwave therapy for refractory tennis elbow	Extracorporeal shockwave therapy for refractory tennis elbow # Guidance The evidence on extracorporeal shockwave therapy (ESWT) for refractory tennis elbow raises no major safety concerns; however, current evidence on its efficacy is inconsistent. Therefore, this procedure should only be used with special arrangements for clinical governance, consent and audit or research. Clinicians wishing to undertake ESWT for refractory tennis elbow should take the following actions. Inform the clinical governance leads in their Trusts. Ensure that patients understand the uncertainty about the procedure's efficacy and provide them with clear written information. In addition, the use of NICE's information for patients ('Understanding NICE guidance') is recommended. Audit and review clinical outcomes of all patients having ESWT for refractory tennis elbow (see section 3.1). NICE encourages further research into ESWT for refractory tennis elbow. Future research should take the form of clinical studies with clearly described patient selection and treatment protocols, including a description of local anaesthesia use and the type of energy applied (see section 2.5). The studies should include validated outcome measures and be based on a minimum of 1-year follow-up. NICE may review the procedure on publication of further evidence.# The procedure # Indications and current treatments Tennis elbow (also known as lateral epicondylitis) is characterised by chronic degeneration at the origin of the extensor carpi radialis brevis muscle on the lateral epicondyle of the humerus. It is usually caused by injury or overuse. Symptoms include pain, weakness and stiffness of the outer elbow. Conservative treatments include rest, application of ice, analgesic medication, non-steroidal anti-inflammatory drugs, orthotic devices, physiotherapy, eccentric training/stretching and corticosteroid injection. # Outline of the procedure Extracorporeal shockwave therapy is a non-invasive treatment in which a device is used to pass acoustic shockwaves through the skin to the affected area. Ultrasound guidance can be used to assist with positioning of the device. Extracorporeal shockwave therapy may be applied in one or several sessions. Local anaesthesia may be used because high-energy ESWT can be painful. Different energies can be used and there is evidence that local anaesthesia may influence the outcome of ESWT. The mechanism by which this therapy might have an effect on tendinopathy is unknown. Sections 2.3 and 2.4 describe efficacy and safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview. # Efficacy In a randomised controlled trial (RCT) comparing 272 patients treated by ESWT or sham ESWT, success was reported in 26% (32/124) and 25% (31/122) of patients, respectively, at 3-month follow-up (success defined as a Roles and Maudsley score of 1 or 2 out of 4 and no requirement for additional treatment). An RCT of 93 patients treated by ESWT or steroid injection reported treatment success (at least 50% improvement in Visual Analogue Scale score) in 60% (29/48) and 84% (21/25) of patients, respectively, at 3-month follow-up (p < 0.05). An RCT of 75 patients treated by ESWT or sham ESWT reported that at 3 months, 35% (14/40) and 37% (13/35) of patients, respectively, had at least a 50% improvement in VAS score for pain during the day (p < 0.01 in both treatment groups); and 30% (12/40) and 43% (15/35) of patients, respectively, had at least a 50% improvement in VAS score for pain at night (p value stated as 'non-significant' and p < 0.05, respectively). The Specialist Advisers listed key efficacy outcomes as relief of symptoms and functional improvement. # Safety Two RCTs of 272 and 114 patients reported pain in 11% (15/134) and 50% (28/56) of ESWT patients, and 4% (6/136) and 22% (13/58) of sham ESWT patients, respectively. In the RCT of 272 patients, transient skin reddening occurred in 31% (42/134) of ESWT patients and 8% (11/136) of sham ESWT patients, and transient swelling occurred in 7% (9/134) and 6% (8/136) of patients, respectively. The RCT of 114 patients treated by ESWT or sham ESWT reported a local reaction (not otherwise described) in 11% (6/56) and 9% (5/58) of patients, respectively. In this study 18% (10/56) of patients in the ESWT group experienced nausea compared with none in the sham ESWT group. In the RCT of 75 patients, 2 patients in the ESWT group had worsened symptoms after 2 treatment sessions and withdrew from the study. The Specialist Advisers listed adverse events as bruising, transient skin reddening and local skin damage. Theoretical adverse events include rupture of the common extensor tendon. # Other comments The Committee found interpretation of the data difficult because of the diversity of treatment protocols and comparators used, varying reported end points and inconsistencies in terms of the use of local anaesthesia and energy type. The results of studies conflicted and there was evidence of a substantial placebo response. Previous guidance on this procedure published in 2005 had found the evidence on efficacy inadequate, and new evidence has not been published to alter that view. Tennis elbow is a common condition and many patients who have it are refractory to other treatments. If the procedure is efficacious in selected patients, it has the potential for a high impact. This makes provision of robust data particularly important.# Further information This guidance requires that clinicians undertaking the procedure make special arrangements for audit. NICE has identified relevant audit criteria and developed an audit tool (which is for use at local discretion). For related NICE guidance see our website. # Information for patients NICE has produced information on this procedure for patients and carers ('Understanding NICE guidance'). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.# Other NICE recommendations on extracorporeal shockwave therapy Guidance has also been issued on Extracorporeal shockwave therapy for refractory Achilles tendinopathy and Extracorporeal shockwave therapy for refractory plantar fasciitis. It replaces the previous guidance on Extracorporeal shockwave therapy for refractory tendinopathies (plantar fasciitis and tennis elbow) (IPG139, November 2005).# About this guidance NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland. This guidance was developed using the NICE interventional procedure guidance process. We have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available. Changes since publication January 2012: minor maintenance. Your responsibility This guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer. Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties. Copyright © National Institute for Health and Clinical Excellence 2009. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE. Contact NICE National Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT www.nice.org.uk nice@nice.org.uk	{'Guidance': "The evidence on extracorporeal shockwave therapy (ESWT) for refractory tennis elbow raises no major safety concerns; however, current evidence on its efficacy is inconsistent. Therefore, this procedure should only be used with special arrangements for clinical governance, consent and audit or research.\n\nClinicians wishing to undertake ESWT for refractory tennis elbow should take the following actions.\n\nInform the clinical governance leads in their Trusts.\n\nEnsure that patients understand the uncertainty about the procedure's efficacy and provide them with clear written information. In addition, the use of NICE's information for patients ('Understanding NICE guidance') is recommended.\n\nAudit and review clinical outcomes of all patients having ESWT for refractory tennis elbow (see section 3.1).\n\nNICE encourages further research into ESWT for refractory tennis elbow. Future research should take the form of clinical studies with clearly described patient selection and treatment protocols, including a description of local anaesthesia use and the type of energy applied (see section 2.5). The studies should include validated outcome measures and be based on a minimum of 1-year follow-up. NICE may review the procedure on publication of further evidence.", 'The procedure': "# Indications and current treatments\n\nTennis elbow (also known as lateral epicondylitis) is characterised by chronic degeneration at the origin of the extensor carpi radialis brevis muscle on the lateral epicondyle of the humerus. It is usually caused by injury or overuse. Symptoms include pain, weakness and stiffness of the outer elbow.\n\nConservative treatments include rest, application of ice, analgesic medication, non-steroidal anti-inflammatory drugs, orthotic devices, physiotherapy, eccentric training/stretching and corticosteroid injection.\n\n# Outline of the procedure\n\nExtracorporeal shockwave therapy is a non-invasive treatment in which a device is used to pass acoustic shockwaves through the skin to the affected area. Ultrasound guidance can be used to assist with positioning of the device.\n\nExtracorporeal shockwave therapy may be applied in one or several sessions. Local anaesthesia may be used because high-energy ESWT can be painful. Different energies can be used and there is evidence that local anaesthesia may influence the outcome of ESWT.\n\nThe mechanism by which this therapy might have an effect on tendinopathy is unknown.\n\nSections 2.3 and 2.4 describe efficacy and safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview.\n\n# Efficacy\n\nIn a randomised controlled trial (RCT) comparing 272 patients treated by ESWT or sham ESWT, success was reported in 26% (32/124) and 25% (31/122) of patients, respectively, at 3-month follow-up (success defined as a Roles and Maudsley score of 1 or 2 out of 4 and no requirement for additional treatment). An RCT of 93 patients treated by ESWT or steroid injection reported treatment success (at least 50% improvement in Visual Analogue Scale [VAS] score) in 60% (29/48) and 84% (21/25) of patients, respectively, at 3-month follow-up (p < 0.05).\n\nAn RCT of 75 patients treated by ESWT or sham ESWT reported that at 3 months, 35% (14/40) and 37% (13/35) of patients, respectively, had at least a 50% improvement in VAS score for pain during the day (p < 0.01 in both treatment groups); and 30% (12/40) and 43% (15/35) of patients, respectively, had at least a 50% improvement in VAS score for pain at night (p value stated as 'non-significant' and p < 0.05, respectively).\n\nThe Specialist Advisers listed key efficacy outcomes as relief of symptoms and functional improvement.\n\n# Safety\n\nTwo RCTs of 272 and 114 patients reported pain in 11% (15/134) and 50% (28/56) of ESWT patients, and 4% (6/136) and 22% (13/58) of sham ESWT patients, respectively.\n\nIn the RCT of 272 patients, transient skin reddening occurred in 31% (42/134) of ESWT patients and 8% (11/136) of sham ESWT patients, and transient swelling occurred in 7% (9/134) and 6% (8/136) of patients, respectively.\n\nThe RCT of 114 patients treated by ESWT or sham ESWT reported a local reaction (not otherwise described) in 11% (6/56) and 9% (5/58) of patients, respectively. In this study 18% (10/56) of patients in the ESWT group experienced nausea compared with none in the sham ESWT group.\n\nIn the RCT of 75 patients, 2 patients in the ESWT group had worsened symptoms after 2 treatment sessions and withdrew from the study.\n\nThe Specialist Advisers listed adverse events as bruising, transient skin reddening and local skin damage. Theoretical adverse events include rupture of the common extensor tendon.\n\n# Other comments\n\nThe Committee found interpretation of the data difficult because of the diversity of treatment protocols and comparators used, varying reported end points and inconsistencies in terms of the use of local anaesthesia and energy type. The results of studies conflicted and there was evidence of a substantial placebo response. Previous guidance on this procedure published in 2005 had found the evidence on efficacy inadequate, and new evidence has not been published to alter that view.\n\nTennis elbow is a common condition and many patients who have it are refractory to other treatments. If the procedure is efficacious in selected patients, it has the potential for a high impact. This makes provision of robust data particularly important.", 'Further information': "This guidance requires that clinicians undertaking the procedure make special arrangements for audit. NICE has identified relevant audit criteria and developed an audit tool (which is for use at local discretion).\n\nFor related NICE guidance see our website.\n\n# Information for patients\n\nNICE has produced information on this procedure for patients and carers ('Understanding NICE guidance'). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.", 'Other NICE recommendations on extracorporeal shockwave therapy': 'Guidance has also been issued on Extracorporeal shockwave therapy for refractory Achilles tendinopathy and Extracorporeal shockwave therapy for refractory plantar fasciitis. It replaces the previous guidance on Extracorporeal shockwave therapy for refractory tendinopathies (plantar fasciitis and tennis elbow) (IPG139, November 2005).', 'About this guidance': 'NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland.\n\nThis guidance was developed using the NICE interventional procedure guidance process.\n\nWe have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available.\n\nChanges since publication\n\nJanuary 2012: minor maintenance.\n\nYour responsibility\n\nThis guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.\n\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.\n\nCopyright\n\n© National Institute for Health and Clinical Excellence 2009. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.\n\nContact NICE\n\nNational Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT\n\nwww.nice.org.uk\n \n nice@nice.org.uk\n 0845 033 7780'}	https://www.nice.org.uk/guidance/ipg313
f719cc7639a8e7645049e95a2b6b727d370522ab	nice	Placement of pectus bar for pectus excavatum (also known as MIRPE or the Nuss procedure)	Placement of pectus bar for pectus excavatum (also known as MIRPE or the Nuss procedure) # Guidance This document replaces previous guidance on minimally invasive placement of pectus bar (interventional procedure guidance 3). Current evidence on the safety and efficacy of placement of pectus bar for pectus excavatum (also known as MIRPE or the Nuss procedure) is adequate to support its use provided that normal arrangements are in place for clinical governance, consent and audit. Placement of pectus bar for pectus excavatum should be carried out only by surgeons with cardiac and thoracic training and experience, who are capable of managing cardiac or liver injury, and where there are facilities for this. This procedure should be carried out only by surgeons with specific training in inserting the device, and they should perform their initial procedures with an experienced mentor.# The procedure # Indications and current treatments Pectus excavatum is the most common congenital deformity of the sternum and anterior chest wall. The cosmetic disfigurement of pectus excavatum may sometimes be accompanied by impaired cardiac or respiratory function. Surgery may be carried out in mid-to-late childhood, and includes open surgical repair involving subperichondrial resection of abnormal costal cartilages, transverse osteotomy and internal fixation of the sternum (the Ravitch procedure). # Outline of the procedure Placement of pectus bar for pectus excavatum is carried out with the patient under general anaesthesia. The procedure is performed through several small incisions on either side of the chest, and is usually carried out under visualisation by thoracoscopy. After subcutaneous tunnelling, a curved steel (pectus) bar is inserted behind the ribs and sternum with its concavity facing anteriorly. The bar is then rotated through 180° using a 'flipper' device, so that its convexity faces anteriorly, pushing out the sternum and correcting the deformity. Sometimes two bars are used. Various fixation techniques are used to keep the bars in place, including lateral stabilisers attached to the bars and ribs using wires and/or sutures. Sections 2.3 and 2.4 describe efficacy and safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview. # Efficacy Data from a UK register for 260 patients recorded cosmetic appearance scores preoperatively (on a scale from 1 to 10 ) and postoperatively (from 1 to 10 ). Of 109 patients with preoperative scores and 119 patients with postoperative scores, the mean scores were 3.1 and 8.4, respectively (mean follow-up 369 days). A case series of 947 patients reported that of 521 patients who had the bar removed and had a follow-up of 2 years, 83% had an 'excellent' cosmetic result, 12% had a 'good' result, 2% had a 'fair' result (method of assessment not stated) and 2% had recurrence of pectus excavatum (absolute figures not stated) (follow-up 1–15 years). In a survey of 45 patients, the mean patient satisfaction score for postoperative appearance was 4.1 (±0.8) (on a scale from 1 to 5 ) at 54-month follow-up. The patients rated their self-esteem preoperatively as 6.3 (±1.2). This score improved to 7.9 (±0.8) after the procedure (on a scale from 1 to 10 ) (mean follow-up 54 months). When asked if they would have the operation again, the mean patient score was 9.1 (on a scale from 0 to 10 ). In a survey of 43 patients who had either the Nuss procedure or the Ravitch procedure, there were no reported differences in health-related quality of life (assessed using the Child Health Questionnaire) or in physical and psychosocial quality of life (assessed using the Pectus Excavatum Evaluation Questionnaire) between the groups (mean follow-up 16 months). The Specialist Advisers listed the key efficacy outcomes as cosmetic appearance and patient satisfaction. # Safety In 2 case series of 167 and 172 patients, each reported 1 case of intraoperative liver perforation. In 2 case series of 167 and 322 patients, each reported 1 case of intraoperative cardiac perforation. A case report described cardiac injury during surgery in all 4 patients resulting in 1 death. The case series of 167 patients reported 15 cases of intraoperative rupture of the intercostal muscles (in older patients), 10 cases of haemothorax or haematopneumothorax and 7 cases of minor pericardial tears (follow-up not stated). Data from the UK register reported perioperative adverse events in 9% (24/260) of patients and postoperative adverse events in 19% (49/260) of patients (follow-up 4–2477 days). In 3 case series, bar displacements required surgical revision in 7% (50/668), 3% (11/322) and 2% (3/167) of patients, respectively (follow-up not stated). In 4 case series and the UK register, pneumothorax occurred in 55% (369/668), 7% (24/322), 3% (5/172), 9% (15/167) and 2% (6/260) of patients, respectively. The studies of 668, 322 and 172 patients reported pneumonia in 7, 3 and 3 patients; and pleural effusion in 5, 8 and 3 patients, respectively (follow-up not stated). The studies of 322 and 172 patients and the UK register data for 260 patients reported pericardial effusion in 8, 1 and 1 patients, respectively (timing of events not stated). In the study of 668 patients pericarditis was reported in 6 patients (timing of event not stated). The UK register reported 1 case of perioperative lower lobe collapse and 1 case of persistent air leak. The retrospective case series of 863 patients reported metal allergies in 2% (19/863) of patients. The Specialist Advisers listed adverse events as injury to the lungs, heart, mammary artery and liver; pericarditis; pericardial effusion; bar migration; pleural effusion; pneumothorax; haemothorax; infection; osteochondrodystrophy; pain; metal allergy; and anaesthetic complications.# Further information # Information for patients NICE has produced information on this procedure for patients and carers ('Understanding NICE guidance'). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.# About this guidance NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland. This guidance was developed using the NICE interventional procedure guidance process. It updates and replaces NICE interventional procedure guidance 3. We have produced a summary of this guidance for patients and carers. Information about the evidence it is based on is also available. Changes since publication January 2012: minor maintenance. Your responsibility This guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer. Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties. Copyright © National Institute for Health and Clinical Excellence 2009. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE. Contact NICE National Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT www.nice.org.uk nice@nice.org.uk	{'Guidance': 'This document replaces previous guidance on minimally invasive placement of pectus bar (interventional procedure guidance 3).\n\nCurrent evidence on the safety and efficacy of placement of pectus bar for pectus excavatum (also known as MIRPE [minimally invasive repair of pectus excavatum] or the Nuss procedure) is adequate to support its use provided that normal arrangements are in place for clinical governance, consent and audit.\n\nPlacement of pectus bar for pectus excavatum should be carried out only by surgeons with cardiac and thoracic training and experience, who are capable of managing cardiac or liver injury, and where there are facilities for this.\n\nThis procedure should be carried out only by surgeons with specific training in inserting the device, and they should perform their initial procedures with an experienced mentor.', 'The procedure': "# Indications and current treatments\n\nPectus excavatum is the most common congenital deformity of the sternum and anterior chest wall. The cosmetic disfigurement of pectus excavatum may sometimes be accompanied by impaired cardiac or respiratory function.\n\nSurgery may be carried out in mid-to-late childhood, and includes open surgical repair involving subperichondrial resection of abnormal costal cartilages, transverse osteotomy and internal fixation of the sternum (the Ravitch procedure).\n\n# Outline of the procedure\n\nPlacement of pectus bar for pectus excavatum is carried out with the patient under general anaesthesia. The procedure is performed through several small incisions on either side of the chest, and is usually carried out under visualisation by thoracoscopy.\n\nAfter subcutaneous tunnelling, a curved steel (pectus) bar is inserted behind the ribs and sternum with its concavity facing anteriorly. The bar is then rotated through 180° using a 'flipper' device, so that its convexity faces anteriorly, pushing out the sternum and correcting the deformity. Sometimes two bars are used.\n\nVarious fixation techniques are used to keep the bars in place, including lateral stabilisers attached to the bars and ribs using wires and/or sutures.\n\nSections 2.3 and 2.4 describe efficacy and safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview.\n\n# Efficacy\n\nData from a UK register for 260 patients recorded cosmetic appearance scores preoperatively (on a scale from 1 [dislike] to 10 [like]) and postoperatively (from 1 [no change] to 10 [perfect]). Of 109 patients with preoperative scores and 119 patients with postoperative scores, the mean scores were 3.1 and 8.4, respectively (mean follow-up 369 days). A case series of 947 patients reported that of 521 patients who had the bar removed and had a follow-up of 2 years, 83% had an 'excellent' cosmetic result, 12% had a 'good' result, 2% had a 'fair' result (method of assessment not stated) and 2% had recurrence of pectus excavatum (absolute figures not stated) (follow-up 1–15 years).\n\nIn a survey of 45 patients, the mean patient satisfaction score for postoperative appearance was 4.1 (±0.8) (on a scale from 1 [very dissatisfied] to 5 [extremely satisfied]) at 54-month follow-up. The patients rated their self-esteem preoperatively as 6.3 (±1.2). This score improved to 7.9 (±0.8) after the procedure (on a scale from 1 [very dissatisfied] to 10 [extremely satisfied]) (mean follow-up 54 months). When asked if they would have the operation again, the mean patient score was 9.1 (on a scale from 0 [no] to 10 [yes]).\n\nIn a survey of 43 patients who had either the Nuss procedure or the Ravitch procedure, there were no reported differences in health-related quality of life (assessed using the Child Health Questionnaire) or in physical and psychosocial quality of life (assessed using the Pectus Excavatum Evaluation Questionnaire) between the groups (mean follow-up 16 months).\n\nThe Specialist Advisers listed the key efficacy outcomes as cosmetic appearance and patient satisfaction.\n\n# Safety\n\nIn 2 case series of 167 and 172 patients, each reported 1 case of intraoperative liver perforation. In 2 case series of 167 and 322 patients, each reported 1 case of intraoperative cardiac perforation. A case report described cardiac injury during surgery in all 4 patients resulting in 1 death.\n\nThe case series of 167 patients reported 15 cases of intraoperative rupture of the intercostal muscles (in older patients), 10 cases of haemothorax or haematopneumothorax and 7 cases of minor pericardial tears (follow-up not stated).\n\nData from the UK register reported perioperative adverse events in 9% (24/260) of patients and postoperative adverse events in 19% (49/260) of patients (follow-up 4–2477 days).\n\nIn 3 case series, bar displacements required surgical revision in 7% (50/668), 3% (11/322) and 2% (3/167) of patients, respectively (follow-up not stated).\n\nIn 4 case series and the UK register, pneumothorax occurred in 55% (369/668), 7% (24/322), 3% (5/172), 9% (15/167) and 2% (6/260) of patients, respectively.\n\nThe studies of 668, 322 and 172 patients reported pneumonia in 7, 3 and 3 patients; and pleural effusion in 5, 8 and 3 patients, respectively (follow-up not stated). The studies of 322 and 172 patients and the UK register data for 260 patients reported pericardial effusion in 8, 1 and 1 patients, respectively (timing of events not stated). In the study of 668 patients pericarditis was reported in 6 patients (timing of event not stated). The UK register reported 1 case of perioperative lower lobe collapse and 1 case of persistent air leak.\n\nThe retrospective case series of 863 patients reported metal allergies in 2% (19/863) of patients.\n\nThe Specialist Advisers listed adverse events as injury to the lungs, heart, mammary artery and liver; pericarditis; pericardial effusion; bar migration; pleural effusion; pneumothorax; haemothorax; infection; osteochondrodystrophy; pain; metal allergy; and anaesthetic complications.", 'Further information': "# Information for patients\n\nNICE has produced information on this procedure for patients and carers ('Understanding NICE guidance'). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.", 'About this guidance': 'NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland.\n\nThis guidance was developed using the NICE interventional procedure guidance process.\n\nIt updates and replaces NICE interventional procedure guidance 3.\n\nWe have produced a summary of this guidance for patients and carers. Information about the evidence it is based on is also available.\n\nChanges since publication\n\nJanuary 2012: minor maintenance.\n\nYour responsibility\n\nThis guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.\n\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.\n\nCopyright\n\n© National Institute for Health and Clinical Excellence 2009. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.\n\nContact NICE\n\nNational Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT\n\nwww.nice.org.uk\n \n nice@nice.org.uk\n 0845 033 7780'}	https://www.nice.org.uk/guidance/ipg310
3e903523512d4c1b13be1e7729499e60335b82e9	nice	Tenofovir disoproxil for the treatment of chronic hepatitis B	Tenofovir disoproxil for the treatment of chronic hepatitis B Evidence-based recommendations on tenofovir disoproxil for treating chronic hepatitis B. # Guidance This guidance does not apply to people with chronic hepatitis B who also have hepatitis C, hepatitis D or HIV. Tenofovir disoproxil, within its marketing authorisation, is recommended as an option for the treatment of people with chronic HBeAg-positive or HBeAg-negative hepatitis B in whom antiviral treatment is indicated.# The technology Tenofovir disoproxil (Viread, Gilead) is a nucleotide analogue. It works by blocking the enzyme reverse transcriptase, which is responsible for hepatitis B virus (HBV) replication. Tenofovir disoproxil has a marketing authorisation in the UK for the treatment of chronic hepatitis B in adults with compensated liver disease, with evidence of active viral replication, persistently elevated serum alanine aminotransferase (ALT) levels and histological evidence of active inflammation and/or fibrosis. Adverse events associated with the use of nucleotide analogues include lactic acidosis and progression of hepatomegaly. Additional adverse events reported for tenofovir disoproxil include headache, fatigue and gastrointestinal disorders. For full details of side effects and contraindications, see the summary of product characteristics. The acquisition cost of tenofovir disoproxil (excluding VAT; 'British national formulary' edition 56) is £255.00 for a 30-tablet pack. Costs may vary in different settings because of negotiated procurement discounts. Tenofovir disoproxil is licensed for use in adults over 18 years. The dosage is a once-daily tablet of 245 mg. The optimal treatment duration is currently unknown. Costs may vary in different settings because of negotiated procurement discounts.# The manufacturer's submission The Appraisal Committee (appendix A) considered evidence submitted by the manufacturer of tenofovir disoproxil and a review of this submission by the Evidence Review Group (ERG; appendix B). The manufacturer approached the decision problem by comparing tenofovir disoproxil monotherapy with lamivudine, adefovir dipivoxil and entecavir in adults with compensated liver disease and active chronic hepatitis B (that is, evidence of viral replication and active liver inflammation). The manufacturer did not compare tenofovir disoproxil with any of the interferons. The primary outcome measures outlined in the decision problem were virological response (hepatitis B virus DNA), histological improvement (inflammation and fibrosis), biochemical response (for example, ALT levels), and hepatitis B surface antigen (HBsAg) and hepatitis B 'e' antigen (HBeAg) seroconversion rate. The manufacturer's submission presented evidence on the clinical effectiveness of tenofovir disoproxil from two randomised controlled trials (RCTs) that compared tenofovir disoproxil with adefovir dipivoxil. The protocol for both studies specified that the populations would be people who had not previously received nucleotide analogue therapy, although prior experience of the nucleoside analogues lamivudine or emtricitabine was allowed in the study of people with HBeAg-negative chronic hepatitis B. One trial compared tenofovir disoproxil with adefovir dipivoxil in people with HBeAg-positive hepatitis B (176 participants received tenofovir disoproxil and 90 adefovir dipivoxil); the other made the same comparison in people with HBeAg-negative disease (250 participants received tenofovir disoproxil and 125 adefovir dipivoxil). The results of the two RCTs showed that at 48 weeks tenofovir disoproxil gave a greater proportion of complete responses (that is, histological response and HBV DNA below 400 copies/ml) than adefovir dipivoxil in people with HBeAg-positive and HBeAg-negative disease. The difference was statistically significant (p 0.001, in both trials). A similar proportion of people with HBeAg-positive disease had seroconversion or HBeAg loss with tenofovir disoproxil and adefovir dipivoxil, but significantly more people treated with tenofovir disoproxil had hepatitis B surface antigen (HBsAg) loss at 48 weeks (3.2% versus 0.0%, p = 0.018). No people with HBeAg-negative disease in either treatment group had experienced HBsAg loss or seroconverted to anti-HBs at 48 weeks. Both RCTs reported a smaller proportion of people with HBV mutation-conserved site changes (suggestive of a potential for future resistance) with tenofovir disoproxil than with adefovir dipivoxil at 48 weeks. There were no cases of substitution in the HBV polymerase/reverse transcriptase associated with resistance to tenofovir disoproxil in either study. There were no cases of viral resistance. The incidence of severe, life-threatening or disabling adverse events was similar between treatment groups, with no deaths reported in either study. However, more participants had at least one treatment-related adverse event in the tenofovir disoproxil treatment group in one study (30.7% versus 16.7%, p = 0.018); the manufacturer attributed this to a higher incidence of 'mild nausea'. The incidence of arthralgia was higher for the group receiving tenofovir disoproxil in the other study (6.0% versus 0.0%, p = 0.003). The manufacturer pointed out that there were no trials that included all treatment options in any of the patient populations and therefore a series of mixed-treatment comparison meta-analyses were carried out to assess the relative efficacy of adefovir dipivoxil, entecavir, lamivudine, tenofovir disoproxil and placebo in nucleoside-naive and lamivudine-refractory patients. For HBeAg-positive disease, the included outcomes were the probability of achieving HBV DNA suppression (< 300 copies/ml), and the probability of HBeAg seroconversion over 1 year of treatment. All analyses were conducted using random-effects models unless the between-studies standard deviation was close to zero. For HBeAg-positive nucleoside- and nucleotide-naive participants, the mixed-treatment comparison showed that tenofovir disoproxil had a statistically significantly higher predicted probability of HBV DNA suppression than all comparators. There was no statistically significant difference between the antiviral drugs for the probability of seroconversion. For HBeAg-negative disease, the manufacturer explained that no meaningful analysis could be undertaken because of the small number of trials identified. The manufacturer undertook an additional analysis combining trials investigating patients with HbeAg-positive disease and those with HbeAg-negative disease. In this additional analysis, the proportion of participants who were HBeAg positive was considered as a covariate. The results for HbeAg-negative participants were similar to those seen in the HBeAg-positive subgroup in terms of the probability of achieving HBV DNA suppression (< 300 copies/ml). The manufacturer pooled data from the RCTs and the observational studies identified while undertaking the systematic review in order to obtain and compare estimates of resistance for available treatments for HBeAg-positive treatment-naive and lamivudine-refractory patients. The results suggested a low risk of viral resistance with tenofovir disoproxil in both treatment-naive and lamivudine-refractory patients and there were no cases of resistance with up to 2 years of use. The manufacturer submitted a cost-effectiveness analysis using a Markov model that could be applied either to a cohort of people with HBeAg-positive or HBeAg-negative disease at the start of treatment. The model had 11 main states defined as: active chronic hepatitis B (HBV DNA ≥ 300 copies/ml), viral suppression (HBV DNA < 300 copies/ml), HBeAg seroconverted (not applicable to HBeAg-negative disease), HBsAg seroconverted, compensated cirrhosis with detectable HBV DNA, compensated cirrhosis with undetectable HBV DNA, decompensated cirrhosis, hepatocellular carcinoma, liver transplantation (year in which transplantation occurs), post liver transplantation and death. These were based on health states used in previous economic evaluations. The model was designed to compare tenofovir disoproxil, adefovir dipivoxil, lamivudine and entecavir. It incorporated sequences of first-, second- and third-line treatments and people were assumed to move on to the next treatment regimen if they developed resistance to their current treatment. For people with HBeAg-positive disease and those with HBeAg-negative disease the model has a lifetime horizon, a cycle length of 1 year, and patients are assumed to continue to receive an antiviral regimen until they die, undergo HBeAg seroconversion, undergo HBsAg seroconversion, or develop resistance, at which stage they would switch to an alternative regimen. In the base-case manufacturer's economic analysis, after treatment sequences that were dominated or extendedly dominated were excluded, the incremental cost-effectiveness ratios (ICERs) of interest in HBeAg-positive chronic hepatitis B were as follows: lamivudine as first-line treatment followed by tenofovir disoproxil had an ICER of £6014 per quality-adjusted life year (QALY) relative to lamivudine followed by best supportive care tenofovir disoproxil as first-line treatment followed by lamivudine had an ICER of £9940 per QALY relative to lamivudine followed by tenofovir disoproxil tenofovir disoproxil as first-line treatment followed by the combination of tenofovir disoproxil and lamivudine had an ICER of £13,619 per QALY relative to tenofovir disoproxil followed by lamivudine tenofovir disoproxil as first-line treatment followed by the combination of tenofovir and lamivudine followed by entecavir had an ICER of £36,583 per QALY relative to tenofovir disoproxil followed by tenofovir disoproxil plus lamivudine. In the base-case manufacturer's economic analysis, after treatment sequences that were dominated or extendedly dominated were excluded, ICERs of interest in HBeAg-negative chronic hepatitis B were as follows: tenofovir disoproxil as first-line treatment followed by lamivudine had an ICER of £9811 per QALY relative to best supportive care tenofovir disoproxil as first-line treatment followed by the combination of tenofovir and lamivudine had an ICER of £13,854 per QALY relative to tenofovir disoproxil followed by lamivudine alone tenofovir disoproxil as first-line treatment followed by the combination of tenofovir and lamivudine followed by entecavir had an ICER of £20,781 per QALY relative to tenofovir disoproxil followed by tenofovir disoproxil plus lamivudine. The manufacturer also presented results for an analysis in a cohort in which lamivudine resistance had developed: tenofovir disoproxil alone as treatment for lamivudine-refractory HBeAg-positive disease had an ICER of £7707 per QALY relative to best supportive care tenofovir disoproxil alone as treatment for lamivudine-refractory HBeAg-negative disease had an ICER of £11,078 per QALY relative to best supportive care. The ERG viewed the mixed-treatment comparison methodology to be generally sound, but pointed out that it was weakened by the small number of studies (as low as 1 in some networks), a lack of quality assessment of included studies, no discussion of potential clinical heterogeneity and limited discussion of statistical heterogeneity. Therefore the ERG concluded that the results should be treated with caution. The ERG viewed the pooled analysis of resistance in the manufacturer's submission as appropriate, but pointed out that data for long-term resistance (more than 2 years) are currently unavailable. The ERG pointed out that there were a number of analytical errors in the manufacturer's electronic model and therefore re-ran the model with discount factors for future health effects applied to all of the model cycles, amendments to transition matrices and a once-only application of a reduction of excess mortality for patients with compensated cirrhosis achieving viral suppression. The results for people with HBeAg-positive disease gave an ICER for first-line tenofovir disoproxil followed by lamivudine relative to lamivudine followed by tenofovir disoproxil of £17,590. The ICER for tenofovir disoproxil followed by lamivudine plus tenofovir disoproxil relative to first-line tenofovir disoproxil followed by lamivudine was £27,479. The results for people with HBeAg-negative disease gave an ICER for first-line tenofovir disoproxil followed by lamivudine relative to lamivudine followed by tenofovir disoproxil of £17,640. The ICER for tenofovir disoproxil followed by lamivudine plus tenofovir disoproxil relative to first-line tenofovir disoproxil followed by lamivudine was £28,324. Full details of all the evidence are in the manufacturer's submission and the ERG report.# Consideration of the evidence The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of tenofovir disoproxil, having considered evidence on the nature of the condition and the value placed on the benefits of tenofovir disoproxil by people with chronic hepatitis B, those who represent them, and clinical specialists. It was also mindful of the need to take account of the effective use of NHS resources. The Committee was advised by the clinical experts of the importance of having a variety of treatments available in order to combat the problem of viral resistance. The Committee heard from the patient experts that tenofovir disoproxil was well tolerated with few adverse effects. The patient experts also explained that treatments which are associated with a low risk of viral resistance would increase peace of mind and hence quality of life. The Committee was also mindful of the long-term risk of progression to cirrhosis or hepatocellular carcinoma associated with chronic hepatitis B infection, and the impact of this in terms of costs, mortality and health-related quality of life. The Committee considered the treatment options available for patients with chronic hepatitis B in the UK. The Committee discussed the relevance of previous NICE guidance on chronic hepatitis B and where in the treatment pathway tenofovir disoproxil should be considered. The Committee understood that tenofovir disoproxil could be considered an alternative to other antiviral drugs as primary first-line therapy if an interferon is considered inappropriate (because of a contraindication or intolerance) or as second-line therapy when either a course of an interferon has not brought about seroconversion, or resistance has developed to another antiviral drug. The Committee discussed the clinical effectiveness of tenofovir disoproxil in treating chronic hepatitis B and considered all of the available evidence. It acknowledged that in the RCTs tenofovir disoproxil was more effective than adefovir dipivoxil in terms of surrogate endpoints. The Committee then considered the indirect mixed-treatment comparison undertaken by the manufacturer to compare tenofovir disoproxil with entecavir, lamivudine and adefovir dipivoxil in people with HBeAg-positive and HBeAg-negative disease. The Committee noted discrepancies between the results from the mixed-treatment comparison and those from the individual RCTs. The Committee also took into account the ERG's remarks on the quality of the analysis of the mixed-treatment comparison. However, the Committee agreed that the identified weaknesses in the analysis were not sufficiently serious to prevent it making a decision on the use of tenofovir disoproxil in chronic hepatitis B in the light of the evidence available from the individual RCTs. The Committee discussed the limitations and the degree of uncertainty in the economic models presented. The Committee noted that both the manufacturer's and ERG's estimates of the ICERs for tenofovir disoproxil as first-line monotherapy in both HBeAg-positive and -negative disease were below £20,000 per additional QALY gained. The Committee also noted that the results of the probabilistic sensitivity analysis showed a 60% and 58% probability that first-line therapy with tenofovir disoproxil is the most cost-effective antiviral strategy for treatment of HBeAg-positive and HBeAg-negative disease at a willingness to pay threshold of £20,000 per QALY. The Committee noted that the effectiveness estimates used in the economic model were taken from the mixed-treatment comparison and that concern had been expressed about this comparison. However, the Committee was satisfied that the effectiveness of tenofovir disoproxil was at least comparable to that of other currently recommended options, notably entecavir, and that the acquisition cost of tenofovir disoproxil was lower. Therefore the Committee concluded that tenofovir disoproxil is a cost-effective option for the treatment of HBeAg-positive and HBeAg-negative chronic hepatitis B. The Committee understood the high-degree of mutability of the hepatitis B virus and noted that tenofovir disoproxil appeared to have a low potential for inducing viral resistance. The Committee also noted that the estimates of resistance rates for tenofovir disoproxil and other antiviral drugs used in the cost-effectiveness analysis were based on a pooled analysis of resistance data undertaken by the manufacturer. Taking into account the ERG's comments and the clinical expert views on the biological plausibility of the findings, the Committee agreed that tenofovir disoproxil had a similar or more favourable resistance profile at 1 year compared with other available treatments for chronic hepatitis B. However, the Committee agreed that given the data available it could not be assumed that this low rate of resistance would be maintained in the long term. The Committee discussed the possibility that tenofovir disoproxil might be used as combination therapy with another antiviral agent as a strategy to reduce resistance. They heard from the clinical experts that this strategy would be based on experience gained in treating HIV, and that there was little evidence to support such a strategy in chronic hepatitis B at present. Furthermore, the experts noted that current European guidelines recommended entecavir or tenofovir disoproxil monotherapy as first-line therapy. The Committee heard that there was a lack of data from RCTs to allow an evaluation of the effectiveness of tenofovir disoproxil in combination with other agents as first-line or subsequent therapy. The Committee also heard that data on long-term resistance would be needed to guide decisions on whether combination therapy should be given, and these data are presently unavailable. However, the Committee noted comments from the consultees that there may be circumstances in which combination therapy might be appropriate (for example, tenofovir disoproxil could be added to another drug as rescue therapy when resistance to the first drug has developed). Although acknowledging that evidence on the long-term clinical effectiveness and cost-effectiveness of combination therapy was lacking, the Committee agreed that using tenofovir disoproxil in combination regimens might be acceptable when evidence supporting its clinical effectiveness becomes available. The Committee concluded that the available evidence only supported the use of tenofovir disoproxil as monotherapy, but it accepted that there may be exceptional circumstances in which tenofovir disoproxil might be used in combination with other antiviral agents. Therefore in recommending tenofovir disoproxil as an option for the treatment of chronic hepatitis B, the Committee did not specify that the treatment should be restricted absolutely to use as monotherapy, but noted that this was the approach that was supported by the evidence.# Recommendations for further research A phase III trial of entecavir plus tenofovir disoproxil combination therapy versus entecavir monotherapy in treatment-naive people with chronic hepatitis B is currently recruiting participants. Research on the long-term risk of resistance with tenofovir disoproxil monotherapy and tenofovir disoproxil in combination with other antiviral agents is needed because few RCTs are currently available.# Related NICE guidance Entecavir for the treatment of chronic hepatitis B. NICE technology appraisal guidance 153 (2008). Telbivudine for the treatment of chronic hepatitis B. NICE technology appraisal guidance 154 (2008). Adefovir dipivoxil and peginterferon alfa-2a for the treatment of chronic hepatitis B. NICE technology appraisal guidance 96 (2006).# Review of guidance The review date for a technology appraisal refers to the month and year in which the Guidance Executive will consider whether the technology should be reviewed. This decision will be taken in the light of information gathered by the Institute, and in consultation with consultees and commentators. The guidance on this technology will be considered for review in March 2012, at the same time as NICE technology appraisal guidance 96, 153, and 154. Andrew DillonChief ExecutiveJuly 2009# Changes after publication February 2014: implementation section updated to clarify that tenofovir disoproxil is recommended as an option for treating chronic hepatitis B. Additional minor maintenance update also carried out. March 2012: minor maintenance# About this guidance NICE technology appraisal guidance is about the use of new and existing medicines and treatments in the NHS in England and Wales. This guidance was developed using the NICE single technology appraisal process. We have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available. Your responsibility This guidance represents the views of NICE and was arrived at after careful consideration of the evidence available. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. However, the guidance does not override the individual responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or guardian or carer. Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties. Copyright © National Institute for Health and Clinical Excellence 2009. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.	{'Guidance': 'This guidance does not apply to people with chronic hepatitis B who also have hepatitis C, hepatitis D or HIV.\n\nTenofovir disoproxil, within its marketing authorisation, is recommended as an option for the treatment of people with chronic HBeAg-positive or HBeAg-negative hepatitis B in whom antiviral treatment is indicated.', 'The technology ': "Tenofovir disoproxil (Viread, Gilead) is a nucleotide analogue. It works by blocking the enzyme reverse transcriptase, which is responsible for hepatitis B virus (HBV) replication. Tenofovir disoproxil has a marketing authorisation in the UK for the treatment of chronic hepatitis B in adults with compensated liver disease, with evidence of active viral replication, persistently elevated serum alanine aminotransferase (ALT) levels and histological evidence of active inflammation and/or fibrosis.\n\nAdverse events associated with the use of nucleotide analogues include lactic acidosis and progression of hepatomegaly. Additional adverse events reported for tenofovir disoproxil include headache, fatigue and gastrointestinal disorders. For full details of side effects and contraindications, see the summary of product characteristics.\n\nThe acquisition cost of tenofovir disoproxil (excluding VAT; 'British national formulary' [BNF] edition 56) is £255.00 for a 30-tablet pack. Costs may vary in different settings because of negotiated procurement discounts. Tenofovir disoproxil is licensed for use in adults over 18\xa0years. The dosage is a once-daily tablet of 245\xa0mg. The optimal treatment duration is currently unknown. Costs may vary in different settings because of negotiated procurement discounts.", "The manufacturer's submission": "The Appraisal Committee (appendix A) considered evidence submitted by the manufacturer of tenofovir disoproxil and a review of this submission by the Evidence Review Group (ERG; appendix\xa0B).\n\nThe manufacturer approached the decision problem by comparing tenofovir disoproxil monotherapy with lamivudine, adefovir dipivoxil and entecavir in adults with compensated liver disease and active chronic hepatitis B (that is, evidence of viral replication and active liver inflammation). The manufacturer did not compare tenofovir disoproxil with any of the interferons. The primary outcome measures outlined in the decision problem were virological response (hepatitis B virus [HBV] DNA), histological improvement (inflammation and fibrosis), biochemical response (for example, ALT levels), and hepatitis B surface antigen (HBsAg) and hepatitis B 'e' antigen (HBeAg) seroconversion rate.\n\nThe manufacturer's submission presented evidence on the clinical effectiveness of tenofovir disoproxil from two randomised controlled trials (RCTs) that compared tenofovir disoproxil with adefovir dipivoxil. The protocol for both studies specified that the populations would be people who had not previously received nucleotide analogue therapy, although prior experience of the nucleoside analogues lamivudine or emtricitabine was allowed in the study of people with HBeAg-negative chronic hepatitis B. One trial compared tenofovir disoproxil with adefovir dipivoxil in people with HBeAg-positive hepatitis B (176 participants received tenofovir disoproxil and 90 adefovir dipivoxil); the other made the same comparison in people with HBeAg-negative disease (250 participants received tenofovir disoproxil and 125 adefovir dipivoxil).\n\nThe results of the two RCTs showed that at 48\xa0weeks tenofovir disoproxil gave a greater proportion of complete responses (that is, histological response and HBV DNA below 400 copies/ml) than adefovir dipivoxil in people with HBeAg-positive and HBeAg-negative disease. The difference was statistically significant (p\xa0\xa00.001, in both trials). A similar proportion of people with HBeAg-positive disease had seroconversion or HBeAg loss with tenofovir disoproxil and adefovir dipivoxil, but significantly more people treated with tenofovir disoproxil had hepatitis B surface antigen (HBsAg) loss at 48\xa0weeks (3.2% versus 0.0%, p\xa0=\xa00.018). No people with HBeAg-negative disease in either treatment group had experienced HBsAg loss or seroconverted to anti-HBs at 48\xa0weeks.\n\nBoth RCTs reported a smaller proportion of people with HBV mutation-conserved site changes (suggestive of a potential for future resistance) with tenofovir disoproxil than with adefovir dipivoxil at 48\xa0weeks. There were no cases of substitution in the HBV polymerase/reverse transcriptase associated with resistance to tenofovir disoproxil in either study. There were no cases of viral resistance.\n\nThe incidence of severe, life-threatening or disabling adverse events was similar between treatment groups, with no deaths reported in either study. However, more participants had at least one treatment-related adverse event in the tenofovir disoproxil treatment group in one study (30.7% versus 16.7%, p\xa0=\xa00.018); the manufacturer attributed this to a higher incidence of 'mild nausea'. The incidence of arthralgia was higher for the group receiving tenofovir disoproxil in the other study (6.0% versus 0.0%, p\xa0=\xa00.003).\n\nThe manufacturer pointed out that there were no trials that included all treatment options in any of the patient populations and therefore a series of mixed-treatment comparison meta-analyses were carried out to assess the relative efficacy of adefovir dipivoxil, entecavir, lamivudine, tenofovir disoproxil and placebo in nucleoside-naive and lamivudine-refractory patients. For HBeAg-positive disease, the included outcomes were the probability of achieving HBV DNA suppression (<\xa0300 copies/ml), and the probability of HBeAg seroconversion over 1 year of treatment. All analyses were conducted using random-effects models unless the between-studies standard deviation was close to zero. For HBeAg-positive nucleoside- and nucleotide-naive participants, the mixed-treatment comparison showed that tenofovir disoproxil had a statistically significantly higher predicted probability of HBV DNA suppression than all comparators. There was no statistically significant difference between the antiviral drugs for the probability of seroconversion.\n\nFor HBeAg-negative disease, the manufacturer explained that no meaningful analysis could be undertaken because of the small number of trials identified. The manufacturer undertook an additional analysis combining trials investigating patients with HbeAg-positive disease and those with HbeAg-negative disease. In this additional analysis, the proportion of participants who were HBeAg positive was considered as a covariate. The results for HbeAg-negative participants were similar to those seen in the HBeAg-positive subgroup in terms of the probability of achieving HBV DNA suppression (<\xa0300 copies/ml). The manufacturer pooled data from the RCTs and the observational studies identified while undertaking the systematic review in order to obtain and compare estimates of resistance for available treatments for HBeAg-positive treatment-naive and lamivudine-refractory patients. The results suggested a low risk of viral resistance with tenofovir disoproxil in both treatment-naive and lamivudine-refractory patients and there were no cases of resistance with up to 2\xa0years of use.\n\nThe manufacturer submitted a cost-effectiveness analysis using a Markov model that could be applied either to a cohort of people with HBeAg-positive or HBeAg-negative disease at the start of treatment. The model had 11 main states defined as: active chronic hepatitis B (HBV DNA ≥\xa0300 copies/ml), viral suppression (HBV DNA < 300 copies/ml), HBeAg seroconverted (not applicable to HBeAg-negative disease), HBsAg seroconverted, compensated cirrhosis with detectable HBV DNA, compensated cirrhosis with undetectable HBV DNA, decompensated cirrhosis, hepatocellular carcinoma, liver transplantation (year in which transplantation occurs), post liver transplantation and death. These were based on health states used in previous economic evaluations. The model was designed to compare tenofovir disoproxil, adefovir dipivoxil, lamivudine and entecavir. It incorporated sequences of first-, second- and third-line treatments and people were assumed to move on to the next treatment regimen if they developed resistance to their current treatment. For people with HBeAg-positive disease and those with HBeAg-negative disease the model has a lifetime horizon, a cycle length of 1\xa0year, and patients are assumed to continue to receive an antiviral regimen until they die, undergo HBeAg seroconversion, undergo HBsAg seroconversion, or develop resistance, at which stage they would switch to an alternative regimen.\n\nIn the base-case manufacturer's economic analysis, after treatment sequences that were dominated or extendedly dominated were excluded, the incremental cost-effectiveness ratios (ICERs) of interest in HBeAg-positive chronic hepatitis B were as follows:\n\nlamivudine as first-line treatment followed by tenofovir disoproxil had an ICER of £6014 per quality-adjusted life year (QALY) relative to lamivudine followed by best supportive care\n\ntenofovir disoproxil as first-line treatment followed by lamivudine had an ICER of £9940 per QALY relative to lamivudine followed by tenofovir disoproxil\n\ntenofovir disoproxil as first-line treatment followed by the combination of tenofovir disoproxil and lamivudine had an ICER of £13,619 per QALY relative to tenofovir disoproxil followed by lamivudine\n\ntenofovir disoproxil as first-line treatment followed by the combination of tenofovir and lamivudine followed by entecavir had an ICER of £36,583 per QALY relative to tenofovir disoproxil followed by tenofovir disoproxil plus lamivudine.\n\nIn the base-case manufacturer's economic analysis, after treatment sequences that were dominated or extendedly dominated were excluded, ICERs of interest in HBeAg-negative chronic hepatitis B were as follows:\n\ntenofovir disoproxil as first-line treatment followed by lamivudine had an ICER of £9811 per QALY relative to best supportive care\n\ntenofovir disoproxil as first-line treatment followed by the combination of tenofovir and lamivudine had an ICER of £13,854 per QALY relative to tenofovir disoproxil followed by lamivudine alone\n\ntenofovir disoproxil as first-line treatment followed by the combination of tenofovir and lamivudine followed by entecavir had an ICER of £20,781 per QALY relative to tenofovir disoproxil followed by tenofovir disoproxil plus lamivudine.\n\nThe manufacturer also presented results for an analysis in a cohort in which lamivudine resistance had developed:\n\ntenofovir disoproxil alone as treatment for lamivudine-refractory HBeAg-positive disease had an ICER of £7707 per QALY relative to best supportive care\n\ntenofovir disoproxil alone as treatment for lamivudine-refractory HBeAg-negative disease had an ICER of £11,078 per QALY relative to best supportive care.\n\nThe ERG viewed the mixed-treatment comparison methodology to be generally sound, but pointed out that it was weakened by the small number of studies (as low as 1 in some networks), a lack of quality assessment of included studies, no discussion of potential clinical heterogeneity and limited discussion of statistical heterogeneity. Therefore the ERG concluded that the results should be treated with caution.\n\nThe ERG viewed the pooled analysis of resistance in the manufacturer's submission as appropriate, but pointed out that data for long-term resistance (more than 2\xa0years) are currently unavailable.\n\nThe ERG pointed out that there were a number of analytical errors in the manufacturer's electronic model and therefore re-ran the model with discount factors for future health effects applied to all of the model cycles, amendments to transition matrices and a once-only application of a reduction of excess mortality for patients with compensated cirrhosis achieving viral suppression. The results for people with HBeAg-positive disease gave an ICER for first-line tenofovir disoproxil followed by lamivudine relative to lamivudine followed by tenofovir disoproxil of £17,590. The ICER for tenofovir disoproxil followed by lamivudine plus tenofovir disoproxil relative to first-line tenofovir disoproxil followed by lamivudine was £27,479. The results for people with HBeAg-negative disease gave an ICER for first-line tenofovir disoproxil followed by lamivudine relative to lamivudine followed by tenofovir disoproxil of £17,640. The ICER for tenofovir disoproxil followed by lamivudine plus tenofovir disoproxil relative to first-line tenofovir disoproxil followed by lamivudine was £28,324.\n\nFull details of all the evidence are in the manufacturer's submission and the ERG report.", 'Consideration of the evidence': "The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of tenofovir disoproxil, having considered evidence on the nature of the condition and the value placed on the benefits of tenofovir disoproxil by people with chronic hepatitis B, those who represent them, and clinical specialists. It was also mindful of the need to take account of the effective use of NHS resources.\n\nThe Committee was advised by the clinical experts of the importance of having a variety of treatments available in order to combat the problem of viral resistance. The Committee heard from the patient experts that tenofovir disoproxil was well tolerated with few adverse effects. The patient experts also explained that treatments which are associated with a low risk of viral resistance would increase peace of mind and hence quality of life. The Committee was also mindful of the long-term risk of progression to cirrhosis or hepatocellular carcinoma associated with chronic hepatitis B infection, and the impact of this in terms of costs, mortality and health-related quality of life.\n\nThe Committee considered the treatment options available for patients with chronic hepatitis B in the UK. The Committee discussed the relevance of previous NICE guidance on chronic hepatitis B and where in the treatment pathway tenofovir disoproxil should be considered. The Committee understood that tenofovir disoproxil could be considered an alternative to other antiviral drugs as primary first-line therapy if an interferon is considered inappropriate (because of a contraindication or intolerance) or as second-line therapy when either a course of an interferon has not brought about seroconversion, or resistance has developed to another antiviral drug.\n\nThe Committee discussed the clinical effectiveness of tenofovir disoproxil in treating chronic hepatitis B and considered all of the available evidence. It acknowledged that in the RCTs tenofovir disoproxil was more effective than adefovir dipivoxil in terms of surrogate endpoints. The Committee then considered the indirect mixed-treatment comparison undertaken by the manufacturer to compare tenofovir disoproxil with entecavir, lamivudine and adefovir dipivoxil in people with HBeAg-positive and HBeAg-negative disease. The Committee noted discrepancies between the results from the mixed-treatment comparison and those from the individual RCTs. The Committee also took into account the ERG's remarks on the quality of the analysis of the mixed-treatment comparison. However, the Committee agreed that the identified weaknesses in the analysis were not sufficiently serious to prevent it making a decision on the use of tenofovir disoproxil in chronic hepatitis B in the light of the evidence available from the individual RCTs.\n\nThe Committee discussed the limitations and the degree of uncertainty in the economic models presented. The Committee noted that both the manufacturer's and ERG's estimates of the ICERs for tenofovir disoproxil as first-line monotherapy in both HBeAg-positive and -negative disease were below £20,000 per additional QALY gained. The Committee also noted that the results of the probabilistic sensitivity analysis showed a 60% and 58% probability that first-line therapy with tenofovir disoproxil is the most cost-effective antiviral strategy for treatment of HBeAg-positive and HBeAg-negative disease at a willingness to pay threshold of £20,000 per QALY. The Committee noted that the effectiveness estimates used in the economic model were taken from the mixed-treatment comparison and that concern had been expressed about this comparison. However, the Committee was satisfied that the effectiveness of tenofovir disoproxil was at least comparable to that of other currently recommended options, notably entecavir, and that the acquisition cost of tenofovir disoproxil was lower. Therefore the Committee concluded that tenofovir disoproxil is a cost-effective option for the treatment of HBeAg-positive and HBeAg-negative chronic hepatitis B.\n\nThe Committee understood the high-degree of mutability of the hepatitis B virus and noted that tenofovir disoproxil appeared to have a low potential for inducing viral resistance. The Committee also noted that the estimates of resistance rates for tenofovir disoproxil and other antiviral drugs used in the cost-effectiveness analysis were based on a pooled analysis of resistance data undertaken by the manufacturer. Taking into account the ERG's comments and the clinical expert views on the biological plausibility of the findings, the Committee agreed that tenofovir disoproxil had a similar or more favourable resistance profile at 1\xa0year compared with other available treatments for chronic hepatitis B. However, the Committee agreed that given the data available it could not be assumed that this low rate of resistance would be maintained in the long term.\n\nThe Committee discussed the possibility that tenofovir disoproxil might be used as combination therapy with another antiviral agent as a strategy to reduce resistance. They heard from the clinical experts that this strategy would be based on experience gained in treating HIV, and that there was little evidence to support such a strategy in chronic hepatitis B at present. Furthermore, the experts noted that current European guidelines recommended entecavir or tenofovir disoproxil monotherapy as first-line therapy. The Committee heard that there was a lack of data from RCTs to allow an evaluation of the effectiveness of tenofovir disoproxil in combination with other agents as first-line or subsequent therapy. The Committee also heard that data on long-term resistance would be needed to guide decisions on whether combination therapy should be given, and these data are presently unavailable. However, the Committee noted comments from the consultees that there may be circumstances in which combination therapy might be appropriate (for example, tenofovir disoproxil could be added to another drug as rescue therapy when resistance to the first drug has developed). Although acknowledging that evidence on the long-term clinical effectiveness and cost-effectiveness of combination therapy was lacking, the Committee agreed that using tenofovir disoproxil in combination regimens might be acceptable when evidence supporting its clinical effectiveness becomes available. The Committee concluded that the available evidence only supported the use of tenofovir disoproxil as monotherapy, but it accepted that there may be exceptional circumstances in which tenofovir disoproxil might be used in combination with other antiviral agents. Therefore in recommending tenofovir disoproxil as an option for the treatment of chronic hepatitis B, the Committee did not specify that the treatment should be restricted absolutely to use as monotherapy, but noted that this was the approach that was supported by the evidence.", 'Recommendations for further research': 'A phase III trial of entecavir plus tenofovir disoproxil combination therapy versus entecavir monotherapy in treatment-naive people with chronic hepatitis B is currently recruiting participants.\n\nResearch on the long-term risk of resistance with tenofovir disoproxil monotherapy and tenofovir disoproxil in combination with other antiviral agents is needed because few RCTs are currently available.', 'Related NICE guidance': 'Entecavir for the treatment of chronic hepatitis B. NICE technology appraisal guidance 153 (2008).\n\nTelbivudine for the treatment of chronic hepatitis B. NICE technology appraisal guidance 154 (2008).\n\nAdefovir dipivoxil and peginterferon alfa-2a for the treatment of chronic hepatitis B. NICE technology appraisal guidance 96 (2006).', 'Review of guidance': 'The review date for a technology appraisal refers to the month and year in which the Guidance Executive will consider whether the technology should be reviewed. This decision will be taken in the light of information gathered by the Institute, and in consultation with consultees and commentators.\n\nThe guidance on this technology will be considered for review in March 2012, at the same time as NICE technology appraisal guidance 96, 153, and 154.\n\nAndrew DillonChief ExecutiveJuly 2009', 'Changes after publication': 'February 2014: implementation section updated to clarify that tenofovir disoproxil is recommended as an option for treating chronic hepatitis B. Additional minor maintenance update also carried out.\n\nMarch 2012: minor maintenance', 'About this guidance': 'NICE technology appraisal guidance is about the use of new and existing medicines and treatments in the NHS in England and Wales.\n\nThis guidance was developed using the NICE single technology appraisal process.\n\nWe have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available.\n\nYour responsibility\n\nThis guidance represents the views of NICE and was arrived at after careful consideration of the evidence available. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. However, the guidance does not override the individual responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.\n\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.\n\nCopyright\n\n© National Institute for Health and Clinical Excellence 2009. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.'}	https://www.nice.org.uk/guidance/ta173	Evidence-based recommendations on tenofovir disoproxil for treating chronic hepatitis B.
41a5f7f0fde299bbf820a40e9fb8d952bb18b894	nice	Rituximab for the first-line treatment of chronic lymphocytic leukaemia	Rituximab for the first-line treatment of chronic lymphocytic leukaemia Evidence-based recommendations on rituximab for untreated chronic lymphocytic leukaemia in adults. # Guidance Rituximab in combination with fludarabine and cyclophosphamide is recommended as an option for the first-line treatment of chronic lymphocytic leukaemia in people for whom fludarabine in combination with cyclophosphamide is considered appropriate. Rituximab in combination with chemotherapy agents other than fludarabine and cyclophosphamide is not recommended for the first-line treatment of chronic lymphocytic leukaemia.# The technology Rituximab (MabThera, Roche) is a chimeric monoclonal antibody that binds selectively to the CD20 antigen expressed on the surface of mature B lymphocytes and tumour cells that express CD20. Rituximab is licensed for the first-line treatment of people with chronic lymphocytic leukaemia in combination with chemotherapy. Rituximab is administered intravenously, once every 4 weeks for a total of six cycles; a complete course of treatment with rituximab lasts 24 weeks. Dosing is calculated according to body surface area, with an initial dose of 375 mg/m² followed by 500 mg/m² for all subsequent doses. Six cycles of rituximab equate to a total dose of 2875 mg/m². The summary of product characteristics states that rituximab should be administered under the close supervision of an experienced physician, and in an environment where full resuscitation facilities are immediately available. The most frequently observed adverse events in people receiving rituximab are infusion-related reactions, including cytokine release syndrome. The majority of these reactions occur during the first infusion. Serious but rare adverse events associated with rituximab include neutropenia and leucopenia (including febrile neutropenia), infections (predominantly bacterial and viral) and cardiovascular events (hypotension, hypertension, arrhythmias and angina). Very rare serious adverse events include hepatitis B reactivation and progressive multifocal leucoencephalopathy. For full details of side effects and contraindications, see the summary of product characteristics. Rituximab is available in 100 mg (10 ml) and 500 mg (50 ml) vials. The cost of a 100 mg vial is £174.63, and of a 500 mg vial is £873.15 (excluding VAT; 'British national formulary' edition 57). For a person with a body surface area of 1.93 m², the cost of rituximab for the first dose is £1397 and for subsequent doses £1746 including wastage of excess rituximab. The total cost of rituximab is £10,128 per course. Costs may vary in different settings because of negotiated procurement discounts.# The manufacturer's submission The Appraisal Committee (appendix A) considered evidence submitted by the manufacturer of rituximab for the first-line treatment of chronic lymphocytic leukaemia and a review of this submission by the Evidence Review Group (ERG; appendix B). The manufacturer's submission compared rituximab in combination with fludarabine and cyclophosphamide with fludarabine and cyclophosphamide combination therapy. This comparison was based on the CLL-8 trial, a phase III randomised controlled trial. The CLL-8 trial was a multicentre, open-label, parallel-group study in people with previously untreated chronic lymphocytic leukaemia. In the CLL-8 trial a total of 817 people were randomised to receive either fludarabine and cyclophosphamide or rituximab in combination with fludarabine and cyclophosphamide; data were reported on 810 people. The median age of trial participants was 61 years and 74% of participants were men. Participants had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and 95% of participants had Binet stage B or C disease. People with Binet stage A disease (n = 40) were enrolled into the trial until a protocol amendment stopped further enrolment. Trial participants were randomised to six cycles of treatment, with an interim staging after three cycles. People with progressive or stable disease at interim staging were offered alternative treatments by their clinicians outside the trial. People in the control group whose disease did not respond to treatment did not cross over to the treatment group, but could be offered rituximab-containing regimens. People whose disease showed a partial or complete response at the interim staging received all six cycles of treatment. Each cycle of 28 days consisted of fludarabine and cyclophosphamide chemotherapy (fludarabine and cyclophosphamide on days 1, 2 and 3) with or without rituximab (375 mg/m² on day 0 of cycle 1, 500 mg/m² on day 1 of cycles 2-6). All trial treatments were administered intravenously. The primary outcome of the trial was progression-free survival, defined as the time between randomisation and the date of the first documented disease progression, relapse or death by any cause. Secondary outcomes were event-free survival, overall survival, disease-free survival, duration of response, time to new chronic lymphocytic leukaemia treatment and response rates. Quality-of-life data were collected in the trial using the Spitzer Quality of Life Index and the European Organisation for Research and Treatment of Cancer-Quality of Life Questionnaire Core 30 (EORTC-QLQC30). Demographic characteristics and disease characteristics, including Binet stage B symptoms and prognostic markers such as cytogenetic abnormalities, were well balanced between the trial groups. Of all trial participants, 64% had Binet stage B disease, 31% had Binet stage C disease, and 5% had Binet stage A disease. The trial also enrolled 46 people (8%) with p53 deletion, a chromosome abnormality associated with a poorer prognosis. A pre-planned interim analysis of the trial data after a median follow-up of 20.7 months showed a statistically significant difference in progression-free survival between the treatment groups. At this point the trial was halted and the interim analysis became the main analysis. The reported median progression-free survival was 39.8 months in the rituximab in combination with fludarabine and cyclophosphamide group and 32.2 months in the fludarabine and cyclophosphamide group, with a hazard ratio of 0.56 (95% confidence interval 0.43 to 0.72, p < 0.0001). The trial also reported an overall response rate of 86.1% in the rituximab in combination with fludarabine and cyclophosphamide group and 72.7% in the fludarabine and cyclophosphamide group. At this point median overall survival had not been reached and the trial reported a hazard ratio of 0.64 (95% CI 0.41 to 1.00, p = 0.05). The manufacturer also submitted analyses of data from the CLL-8 trial collected from three follow-up points of a longer duration. After a median duration of follow-up of 25.4 months, the reported median progression-free survival was 42.8 months in the rituximab in combination with fludarabine and cyclophosphamide group and 32.5 months in the fludarabine and cyclophosphamide group, with a hazard ratio of 0.60 (95% CI 0.48 to 0.76, p < 0.001). At the end of this follow-up period the statistically significant difference in overall survival was not maintained (hazard ratio 0.72, 95% CI 0.48 to 1.09, p = 0.13). However, the data remained highly censored, because the majority of people were still alive. A further analysis after a median follow-up of 25.5 months reported a rate of progression-free survival of 76.6% in the rituximab in combination with fludarabine and cyclophosphamide group and 62.3% in the fludarabine and cyclophosphamide group (p < 0.001). At this follow-up point, the CLL-8 trial reported an overall response rate of 95% in the rituximab in combination with fludarabine and cyclophosphamide group and 88% in the fludarabine and cyclophosphamide group (p = 0.001). The overall survival rate was 91% in the rituximab in combination with fludarabine and cyclophosphamide group and 88% in the fludarabine and cyclophosphamide group (p = 0.18). In a further analysis after a median follow-up of 26.4 months the reported mean progression-free survival was 37.1 months in the rituximab in combination with fludarabine and cyclophosphamide group and 30.8 months in the fludarabine and cyclophosphamide group (p < 0.001). The hazard ratio for progression-free survival was 0.6 (95% CI 0.47 to 0.75, p < 0.0001). Mean overall survival was 47.7 months in the rituximab in combination with fludarabine and cyclophosphamide group and 48.2 months in the fludarabine and cyclophosphamide group (p = 0.18). The manufacturer presented a number of subgroup analyses. For the people with the p53 mutation the hazard ratio for progression-free survival was 0.6 (95% CI 0.31 to 1.19). The hazard ratio for progression-free survival for people with Binet stage A disease was 0.13 (95% CI 0.03 to 0.61, p = 0.01), Binet stage B disease was 0.46 (95% CI 0.32 to 0.63, p < 0.0001) and Binet stage C disease was 0.88 (95% CI 0.58 to 1.33, p = 0.54). The CLL-8 trial was not powered to detect differences in treatment effect for any of these subgroups. In the CLL-8 trial, 77% of people in the rituximab in combination with fludarabine and cyclophosphamide group experienced a grade 3 or 4 adverse event compared with 62% in the fludarabine and cyclophosphamide group. In the rituximab in combination with fludarabine and cyclophosphamide group 46% of people experienced a serious adverse event; this figure was 41% of people in the fludarabine and cyclophosphamide group. The main adverse events were haematological toxicities, with neutropenia, leucopenia, febrile neutropenia and pancytopenia having a higher incidence (at least 2% difference) in the rituximab in combination with fludarabine and cyclophosphamide group, and thrombocytopenia, anaemia and pyrexia having a higher incidence (at least 2% difference) in the fludarabine and cyclophosphamide group. There were no differences in the rate of other adverse events between the trial groups. The manufacturer provided data from four uncontrolled phase II trials on the efficacy and tolerability of combining rituximab with different chemotherapy regimens. The combination chemotherapies included fludarabine, pentostatin, cyclophosphamide and mitoxantrone for the first-line treatment of chronic lymphocytic leukaemia. One of the studies (n = 300) compared a group of people treated with rituximab in combination with fludarabine and cyclophosphamide with a group of people who had been treated with fludarabine-based regimens in the past and provided data with a median follow-up of 6 years. For the group receiving rituximab the rate of overall survival after 6 years was 77% with a 95% overall response rate. Median time to progression was 80 months. In comparison with the historical control group, rituximab in combination with fludarabine and cyclophosphamide was associated with statistically significant overall survival and was the strongest independent predictor of survival (hazard ratio 0.48, p < 0.001). In their submission, the manufacturer also compared rituximab in combination with fludarabine and cyclophosphamide with chlorambucil using a mixed treatment comparison. A mixed treatment comparison was conducted because there were no head-to-head studies comparing rituximab with comparators other than fludarabine and cyclophosphamide. As well as chlorambucil, this analysis also included alemtuzumab, fludarabine alone and bendamustine. In addition to CLL-8, a further seven trials were identified and used to create a network of evidence to make indirect comparisons of rituximab in combination with fludarabine and cyclophosphamide with the other comparators. The studies were combined using a fixed effect model because there was no apparent gain in goodness of fit when a random effects model was used. The mixed treatment comparison showed that chlorambucil had the shortest progression-free survival and therefore this was used as the reference treatment. The mean hazard ratios for other treatments compared with chlorambucil were 0.24 for rituximab in combination with fludarabine and cyclophosphamide, 0.43 for fludarabine and cyclophosphamide, 0.59 for alemtuzumab and 0.86 for fludarabine alone. The mean hazard ratio for progression-free survival was 0.56 for rituximab in combination with fludarabine and cyclophosphamide compared with fludarabine and cyclophosphamide, 0.24 for rituximab in combination with fludarabine and cyclophosphamide compared with chlorambucil, 0.42 for rituximab in combination with fludarabine and cyclophosphamide compared with alemtuzumab and 0.28 for rituximab in combination with fludarabine and cyclophosphamide compared with fludarabine alone. The manufacturer's submission presented an economic analysis comparing rituximab in combination with fludarabine and cyclophosphamide with fludarabine and cyclophosphamide, and rituximab in combination with fludarabine and cyclophosphamide with chlorambucil. The manufacturer developed a three-state Markov model with a cycle length of 1 month and a 15-year time horizon (to represent a lifetime horizon). The health states in the model were 'progression-free survival', 'progressed', or 'death'. People entered the model in the progression-free survival health state. The probability of transition from the progression-free survival to the progressed health state was taken from the groups in CLL-8. For the transition from the progression-free survival to the death health state, trial data were used and supplemented with Office of National Statistics data to inform the background mortality rate. Transition from the progressed to the progression-free survival health state was not possible. For the transition from the progressed to the death health state, data for people from both groups of the trial were aggregated and a single probability from the trial applied as there was a non-significant difference in survival following progression between the groups in the trial. In the model the drug costs were calculated assuming a body surface area of 1.93 m², which reflects the average body surface area of the people in the CLL-8 trial. The CLL-8 trial used fludarabine and cyclophosphamide administered intravenously, but it is more common to use oral chemotherapy in the UK. In the model it was assumed that the efficacy of fludarabine and cyclophosphamide is the same regardless of the route of administration if the dosage is adjusted to ensure equivalent bioavailability. The costs of fludarabine and cyclophosphamide treatment in the model were adjusted to allow for the difference in the route of administration. The drug costs for rituximab were £1397 for the first cycle of treatment and £1746 for subsequent cycles. For six cycles of treatment the total drug cost of rituximab was £10,128. The total drug costs of fludarabine, cyclophosphamide and chlorambucil were calculated as £2790, £22 and £286, respectively. In the base case, all people received six cycles of therapy unless disease progression occurred before the end of the six cycles. The model included costs for supportive care that varied between the health states. This included costs for blood transfusions and bone marrow transplant in the progression-free survival health state taken from the CLL-8 trial and costs for second-line therapies for the progressed health state. In the model rituximab had a cost for intravenous administration of £430 per cycle of treatment and the cost for an appointment to prescribe oral fludarabine and cyclophosphamide chemotherapy was £280. It was assumed that oral chemotherapy could be prescribed in the same appointment as rituximab so no additional cost of prescribing oral chemotherapy was included for the rituximab treatment group. Costs were also added for the pharmacist's time to prepare the infusion. The utility values used in the manufacturer's submission were taken from a Health Technology Assessment report (Hancock et al. 2002) that assessed the cost effectiveness of fludarabine as a first-line treatment for chronic lymphocytic leukaemia. A utility of 0.8 was attached to the progression-free survival health state and 0.6 to the progressed health state. The estimates of utility were not preference based, and were estimated by the authors of the Health Technology Assessment report from condition-specific health-related quality-of-life data. No disutility for adverse events was included in the model. The manufacturer provided an interim analysis of 11 people from an observational study of utility in people with chronic lymphocytic leukaemia. The value for progression-free survival was consistent with that used in the manufacturer's submission. No conclusions could be drawn about the utility value appropriate for the progressed health state, as data for only two people were available. The manufacturer provided a base-case estimate of incremental cost effectiveness of rituximab in combination with fludarabine and cyclophosphamide in comparison with fludarabine and cyclophosphamide. The incremental quality-adjusted life year (QALY) gain was 0.88 at an incremental cost of £11,617, giving an incremental cost-effectiveness ratio (ICER) of £13,189 per QALY gained. The probabilistic sensitivity analysis presented suggested that rituximab in combination with fludarabine and cyclophosphamide had a 91.9% probability of being cost effective at £20,000 and 98.6% probability of being cost effective at £30,000 when compared with fludarabine and cyclophosphamide. The manufacturer also provided an estimate of the incremental cost effectiveness of rituximab in combination with fludarabine and cyclophosphamide in comparison with chlorambucil. The incremental QALY gain was 1.91 at an incremental cost of £12,250, giving an ICER of £6422 per QALY gained. Probabilistic sensitivity analysis suggested that the probability of rituximab in combination with fludarabine and cyclophosphamide being cost effective in comparison with chlorambucil was 100% at both £20,000 and £30,000 per QALY gained. A sensitivity analysis was presented in the manufacturer's submission using different parametric models for the progression-free survival extrapolation. Additional sensitivity analyses were completed as follows: including costs for adverse events including costs for febrile neutropenia episodes (as in CLL-8) increasing and decreasing supportive care costs for the health states by 50% assuming utility values for the health states such that the difference in the values between the health states was 0.4 and 0.1. The assumption of a similar rate of adverse events for chlorambucil and fludarabine and cyclophosphamide was tested by assuming no bone-marrow transplants, fewer transfusions and less febrile neutropenia for the chlorambucil arm. One-way sensitivity analyses suggested that the results were not sensitive to a variety of parameter assumptions including utility values, monthly supportive care costs and drug administration costs. The results were sensitive to the function used to extrapolate progression-free survival (exponential, Gompertz), and the highest ICER reported (using a Gompertz function) was £22,661 per QALY gained. The manufacturer's submission also included a scenario analysis to explore the impact on the ICER of using intravenous administration of fludarabine and cyclophosphamide chemotherapy instead of oral administration. This analysis demonstrated that the ICER was not sensitive to assumptions about the mechanism of administration. A further scenario analysis modelled the cost effectiveness of rituximab in combination with chemotherapy agents other than fludarabine and cyclophosphamide. The results of this analysis suggested that the QALY gain from combining rituximab with chemotherapy would need to decrease to about 40% of that in the base case, all else remaining the same, for the ICER for rituximab to increase to over £30,000 per QALY gained. At the request of the ERG, the manufacturer performed a further one-way sensitivity analysis to explore the impact on the ICER of using alternative assumptions about different mortality rates between the progression-free survival and progressed health states. The manufacturer increased the mortality rate in the rituximab in combination with fludarabine and cyclophosphamide group by 315% so that the life years gained in both treatment groups were the same (0.24 QALYs). In this scenario the incremental QALY gain was 0.24 at an incremental cost of £7226, giving an ICER of £30,336 per QALY gained. The ERG considered that all the relevant studies had been identified. The ERG noted that the manufacturer's submission was based on only one completed clinical trial, and that this was unpublished. However, it considered this study to be of good quality. In addition, it noted that this study used intravenous administration of fludarabine and cyclophosphamide rather than oral administration which is normally used in UK clinical practice. The ERG considered the study population was appropriate. It noted that the subgroup of people with chronic lymphocytic leukaemia and the p53 deletion was only considered in relation to progression-free survival and not assessed in the cost–utility model. The ERG considered that the main comparators used in the cost-effectiveness analysis (fludarabine and cyclophosphamide, and chlorambucil) were appropriate. It noted that the mixed treatment comparison provided estimates of clinical effectiveness comparing rituximab in combination with fludarabine and cyclophosphamide with additional comparators, including alemtuzumab, fludarabine monotherapy and bendamustine. The ERG considered that the mixed treatment comparison completed by the manufacturer was appropriate. The ERG considered the fact that in the manufacturer's economic model people in the progressed health state could not move back into the progression-free survival health state was unrealistic due to the natural history of chronic lymphocytic leukaemia. People with chronic lymphocytic leukaemia may receive further treatment at progression, which may then result in further periods of progression-free survival. The relapsing nature of chronic lymphocytic leukaemia means that subsequent relapses are less likely to respond to further treatment. This implies that subsequent relapses are likely to be associated with higher disease-related mortality. Therefore, the ERG considered that the manufacturer's assumption of a constant hazard of death after progression may not be appropriate. The ERG highlighted that the overall effect of the aggregated progressed health state and constant hazard of death from this health state was to imply a correlation between progression-free survival and overall survival which it did not consider had been empirically demonstrated in the manufacturer's submission. The ERG further considered that the sensitivity analyses presented by the manufacturer did not fully investigate the uncertainty associated with the extent to which gains in progression-free survival led to gains in overall survival. The ERG performed an exploratory analysis of the comparison of rituximab in combination with fludarabine and cyclophosphamide with fludarabine and cyclophosphamide. First, it conducted a component analysis to examine the relative contributions to utility gain from the gain in progression-free survival and the gain in overall survival. This analysis showed that progression-free survival contributed to 0.24 QALYs and overall survival to 0.64 QALYs (of a total gain of 0.88 QALYs). The ERG concluded that this demonstrated that in the model the majority of the benefit is derived from overall survival, making it sensitive to changes in assumptions about overall survival benefits from rituximab. The ERG noted that within the model, because a single transition probability is attached to all people in the progressed health state, the benefit in overall survival is derived almost entirely from the different rate of transfer from the progression-free health state to the progressed health state. The ERG repeated the analysis completed by the manufacturer (see section 3.18) that removed the differences in overall survival between the two groups in the model. This was done by decreasing the probability of death in the progressed health state for the fludarabine and cyclophosphamide group. A decrease in the probability of death in the fludarabine and cyclophosphamide group to 57% of the base-case level removed the difference in overall survival between the groups and resulted in a QALY gain of 0.24 at an incremental cost of £7228 and an ICER of £30,304 per QALY gained. When assuming no difference in overall survival between the two treatment groups in the analysis, the results suggested that the probability of rituximab in combination with fludarabine and cyclophosphamide being cost effective compared with fludarabine and cyclophosphamide at £20,000 per QALY gained was 29% and at £30,000 per QALY gained was 49%. The ERG identified that if it is assumed that there is no difference in overall survival between the rituximab in combination with fludarabine and cyclophosphamide and fludarabine and cyclophosphamide groups, the model outputs become sensitive to the assumed utility differences between the progression-free and the progressed health states. If the difference in utility between the health states is reduced by 0.1 (that is from 0.2 to 0.1), the ICER increases to £60,302 per QALY gained. The ERG completed another exploratory analysis that assumed that the actual overall survival benefit from treatment with rituximab was somewhere between the manufacturer's base case and the assumption of no overall survival benefit. The ERG incorporated this assumption into the probabilistic sensitivity analysis by adding an additional variable, in which the decrease in probability of death in the fludarabine and cyclophosphamide group was sampled as a uniform distribution between 1 and 0.574. The results suggested that rituximab in combination with fludarabine and cyclophosphamide had a 72% probability of being cost effective compared with fludarabine and cyclophosphamide at £20,000 per QALY gained and 88% probability of being cost effective at £30,000 per QALY gained. In response to consultation on the appraisal consultation document, the manufacturer submitted additional evidence in support of the combination of rituximab with chlorambucil compared with chlorambucil alone. The manufacturer presented data from four randomised controlled trials in follicular lymphoma, another low-grade B-cell cancer with a relapsing and remitting course. In these studies the addition of rituximab to a range of chemotherapy regimens showed a benefit in progression-free survival and response rates. A further phase II trial of rituximab in combination with chlorambucil in 29 people with a range of low-grade lymphoproliferative disorders showed an overall response rate of 89%, with a complete response rate of 63%. The manufacturer also provided additional economic analysis comparing rituximab in combination with chlorambucil with chlorambucil alone. This used the same model as the original submission, with a number of amendments. The age of the cohort was increased to 70 years to reflect the fact that people treated with chlorambucil in routine clinical practice are generally older than those treated with fludarabine and cyclophosphamide. The baseline risk for the chlorambucil group was taken from the mixed treatment comparison included in the original submission. It was assumed that the hazard ratio for the addition of rituximab to fludarabine and cyclophosphamide observed in the CLL-8 trial (0.595) could be applied to this baseline risk to estimate the effect of adding rituximab to chlorambucil. Drug and administrative costs for rituximab and chlorambucil were included and all other model inputs and assumptions remained the same. Assuming the same hazard ratio meant the relative effect of adding rituximab to chlorambucil was the same as adding rituximab to fludarabine and cyclophosphamide. However, the absolute treatment effect would be smaller because single agent chlorambucil is less effective than fludarabine and cyclophosphamide. The analysis suggested the incremental QALY gain was 0.51 at an incremental cost of £11,570, giving an ICER of £22,490 per QALY gained. A probabilistic sensitivity analysis using the 95% CIs around the assumed hazard ratios showed an 18.6% probability of the ICER being below £20,000 per QALY gained and a 99.7% probability of the ICER being below £30,000 per QALY gained. The manufacturer also noted that a single arm phase II trial is underway of rituximab in combination with chlorambucil in people with untreated chronic lymphocytic leukaemia who are not fit for fludarabine-based treatment. The primary objective of the study is a safety analysis of the combination of rituximab and chlorambucil. Secondary objectives include: response rate, progression-free survival, overall survival, disease-free survival and duration of response. An interim analysis of the data is to be presented in December 2009 and a full analysis is expected towards the end of 2010. Full details of all the evidence are in the manufacturer's submission and the ERG report.# Consideration of the evidence The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of rituximab for the first-line treatment of chronic lymphocytic leukaemia, having considered evidence on the nature of the condition and the value placed on the benefits of rituximab by people with chronic lymphocytic leukaemia, those who represent them, and clinical specialists. It also took into account the effective use of NHS resources. # Clinical effectiveness The Appraisal Committee discussed current standard clinical management of people with chronic lymphocytic leukaemia. The Committee heard from clinical specialists that approximately 90% of people with chronic lymphocytic leukaemia are asymptomatic and that diagnosis may be made as a chance finding on routine blood testing. People who are asymptomatic may not need immediate treatment, although some will need treatment later in life. The Committee heard that fludarabine in combination with cyclophosphamide is frequently used for people who need immediate treatment. However, chlorambucil alone is normally used for people with poor performance status or comorbidities, especially impaired renal function. The Committee heard from patient experts that people with chronic lymphocytic leukaemia who need treatment will often have a series of treatments following first-line treatment, with further lines of treatment used after each relapse. The Committee specifically considered the clinical management of people whose chronic lymphocytic leukaemia has the p53 mutation. The Committee heard from clinical specialists that these people have a poorer prognosis and are usually treated with alternative treatments (for example, alemtuzumab) rather than chemotherapy. The Committee noted that the evidence of clinical effectiveness was based mainly on a single unpublished randomised controlled trial (the CLL-8 trial), which compared rituximab in combination with fludarabine and cyclophosphamide with fludarabine and cyclophosphamide. The Committee accepted that the CLL-8 trial demonstrated a benefit in progression-free survival, and increased overall and complete response rates for rituximab. The Committee heard from clinical specialists that the CLL-8 trial population was younger and fitter than the population of people with chronic lymphocytic leukaemia seen in routine practice within the NHS in England and Wales. However, for the study population fludarabine in combination with cyclophosphamide was the appropriate comparator, and these people reflected the group who would receive fludarabine in combination with cyclophosphamide in clinical practice. The Committee noted that an interim analysis of the clinical trial results had demonstrated a statistically significant gain in overall survival but this gain had not been maintained during longer follow-up. The Committee accepted that crossover and subsequent lines of treatment in the trial made the overall survival benefit difficult to prove. The Committee heard expert opinion that the degree of response to treatment and the duration of progression-free survival were generally accepted as surrogates for overall survival. In addition, the Committee heard that cohort studies using historical controls had also shown survival benefits for people treated with rituximab-containing regimens, although results may have been influenced by changing clinical management, such as earlier identification of people with chronic lymphocytic leukaemia. On balance, the Committee was persuaded that the benefits observed in progression-free survival and response rate were likely to lead to a gain in overall survival, although currently this would be difficult to quantify. The Committee recognised that the manufacturer had also provided evidence from uncontrolled phase II trials that reported the benefits of adding rituximab to other chemotherapy regimens for the first-line treatment of people with chronic lymphocytic leukaemia. The Committee discussed the methodological limitations of obtaining an estimate of clinical effectiveness from uncontrolled and historical comparison studies. In addition, the Committee discussed the further evidence from comparative studies of follicular lymphoma provided by the manufacturer in response to consultation on the appraisal consultation document. The Committee was specifically mindful of comments from consultees about the addition of rituximab to chlorambucil for the treatment of people who are unable to tolerate fludarabine therapies. It accepted that it was reasonable to expect that rituximab would be of benefit when added to any chemotherapy regimen. However, the Committee considered that the additional comparative studies provided by the manufacturer involved the use of more toxic regimens than chlorambucil and were likely to have enrolled people who were on average younger and had a better performance status than people treated with chlorambucil in clinical practice. The Committee were not persuaded that the estimates of treatment effects from different studies were transferable. The Committee heard from clinical specialists that they considered that there was no evidence to support adding rituximab to chlorambucil, but that there was an ongoing trial investigating this. The Committee concluded that there was considerable uncertainty about the relative clinical benefit associated with adding rituximab to chemotherapy regimens other than fludarabine and cyclophosphamide in the treatment of chronic lymphocytic leukaemia. The Committee was aware that fludarabine and cyclophosphamide were administered intravenously in the CLL-8 trial. It heard from clinical specialists that these chemotherapy agents were routinely administered orally in the NHS. The Committee accepted that the efficacy of both methods of administration was equivalent as long as doses were adjusted to ensure equivalent bioavailability. The Committee heard from patient experts that progression-free survival was associated with a marked improvement in quality of life compared with the symptomatic progressed state. Patient experts commented that the first treatment-induced remission was likely to be the longest and associated with the most substantial improvements in quality of life. For this reason people with chronic lymphocytic leukaemia valued having a choice of first-line treatments. # Cost effectiveness The Committee discussed the economic model submitted by the manufacturer. It noted that the manufacturer had only presented estimates of cost effectiveness for rituximab in combination with fludarabine and cyclophosphamide, and that this was compared with fludarabine in combination with cyclophosphamide and chlorambucil monotherapy. The Committee heard from clinical specialists that for those people for whom chlorambucil was the most appropriate treatment (that is, people with poor performance status or comorbidities), rituximab in combination with fludarabine and cyclophosphamide would not be considered an appropriate treatment option. Therefore the Committee was not persuaded that the comparison of rituximab in combination with fludarabine and cyclophosphamide with chlorambucil was valid as the chemotherapy regimens were used in different populations and such a choice between the two treatments was not expected to be clinically meaningful. The Committee reviewed the manufacturer's economic model and the critique of it by the ERG. The Committee noted that the model was based on all people entering the model in the progression-free survival health state and moving to the progressed health state, and did not allow people to move from the progressed health state to the progression-free survival health state. The Committee was mindful that the economic model allowed for costs of subsequent lines of therapy to be included but noted that this did not allow any benefit from further therapy to be taken into account. More importantly a single transition probability from the progressed health state to death was applied to people from both trial groups in the progressed health state. The Committee recognised that although the manufacturer had not assumed any relative advantage in survival following progression, the use of a single transition probability from the progressed health state to death had the effect of associating improved progression-free survival with improved overall survival. The Committee considered that the assumed association between progression-free survival and overall survival in the model could overestimate the benefits of the clinical effectiveness of rituximab as taken from the CLL-8 trial, because this had not demonstrated a statistically significant difference in overall survival between treatment groups. The Committee discussed the analysis by the ERG that suggested that two-thirds of the QALY gain (0.64 out of 0.88) in the model was because of the modelled improvement in overall survival, which is driven by gain in progression-free survival being reflected in gain in overall survival. The Committee noted that when the overall survival benefit was removed from the model the ICER increased from £13,000 to £30,000 per QALY gained. The Committee recognised therefore that the assumption about the amount of gain in overall survival from treatment with rituximab was an important assumption in the economic model and the use of different assumptions could have a large impact on the estimates of cost effectiveness. The Committee noted that condition-specific quality-of-life data collected in the rituximab trial had not been fully reported in the manufacturer's submission and that the utility values used in the model were not consistent with the NICE reference case because they were not preference-based. The Committee considered that the manufacturer may have been able to map the health-related quality-of-life data from the rituximab trial to a preference-based measure to derive utilities and that this may have provided an alternative to the utility data used. The Committee noted that, if there was no difference in overall survival between the treatment groups in the model, the results became very sensitive to the difference between the utility values used for the progression-free survival health state and the progressed health state. The Committee considered the lack of appropriate utility data contributed to substantial uncertainty in the economic modelling. The Committee discussed the additional exploratory analysis done by the ERG using an assumption that the actual survival benefit from treatment with rituximab was somewhere between that presented in the base case and an assumption that there was no gain in survival (see section 3.23). The Committee noted that the probability, using the base-case utilities (that is, 0.80 for the progression-free survival health state and 0.60 for the progressed health state), of rituximab in combination with fludarabine and cyclophosphamide being cost effective at £20,000 per QALY gained was 71% and at £30,000 per QALY gained was 87%. On balance, the Committee was persuaded that even taking into account the additional uncertainty about the utility values, the economic analysis had demonstrated that rituximab in combination with fludarabine and cyclophosphamide for the first-line treatment of chronic lymphocytic leukaemia was a cost-effective use of NHS resources. The Committee considered the economic analysis provided by the manufacturer after consultation on the appraisal consultation document. It examined the assumptions used in the economic modelling for the comparison of rituximab and chlorambucil with chlorambucil alone. The Committee noted that the economic analysis assumed that the hazard ratio observed in the CLL-8 trial was exactly transferable to other chemotherapy regimens. However, the Committee noted that subgroup analyses of the CLL-8 trial demonstrated that there were differences in effect between different subgroups of patients based on age and staging. The Committee recognised that the marketing authorisation for rituximab allowed its use with any chemotherapy regimen. However, the Committee was not persuaded that the relative effects of the treatment or hazard ratio were transferable between various chemotherapies combined with rituximab and between different subgroups of people. The Committee was also mindful that the base-case ICER for rituximab in combination with chlorambucil from the manufacturer's additional analysis was £22,000 per QALY gained (section 3.25). The Committee considered that this estimate would be higher if benefits in progression-free survival did not lead to benefits in overall survival (section 4.9). The Committee noted that these uncertainties had increased the base-case ICER estimate for rituximab in combination with fludarabine and cyclophosphamide compared with fludarabine and cyclophosphamide in the main analysis from £13,000 to £30,000 per QALY gained. This estimate was also associated with uncertainty because no preference-based utility values were available (section 4.10). The Committee was also aware that the analysis did not allow for the possibility of increased costs and disutilities because of adverse events that a population with poorer performance status or comorbidities may experience. The Committee considered that these uncertainties could make the ICER for rituximab in combination with chlorambucil considerably less favourable. The Committee agreed that the uncertainty regarding the relative clinical effectiveness and the assumptions that had to be included in the additional economic analysis did not support the clinical and cost effectiveness of the use of rituximab in combination with chlorambucil. The Committee was therefore not persuaded that it could recommend rituximab in combination with chlorambucil as a cost-effective use of NHS resources. The Committee noted that the group of patients who are not suitable for a regimen of fludarabine in combination with cyclophosphamide, and who might therefore be treated with rituximab in combination with chlorambucil, would include a high proportion of people with poor performance status or comorbidities. The Committee considered whether the equalities legislation and the requirement for fairness meant that it should make a positive recommendation for rituximab in combination with chlorambucil for this group. However the Committee noted that a negative recommendation for rituximab in combination with chlorambucil did not appear to have an impact on any group protected by the equalities legislation. It is not obvious that there is a clear correlation between the comorbidity factors which rendered this patient group unsuitable for certain chemotherapies and 'disability' as defined in the Disability Discrimination Act 1995. The Committee could not be satisfied that a negative recommendation of rituximab in combination with chlorambucil represented less favourable treatment or loss of benefit, given the lack of clear evidence as to the relative clinical effectiveness of rituximab in combination with chlorambucil in this particular patient group. Given the lack of evidence for both the clinical and cost effectiveness of this combination, the Committee could not justify a positive recommendation of rituximab in combination with chlorambucil. The Committee was aware that new data on the combination of rituximab with chlorambucil in chronic lymphocytic leukaemia would soon be available. It considered that even though this was not a comparative trial, the data could potentially provide more certain estimates of cost effectiveness of rituximab in combination with chlorambucil. The Committee therefore agreed that the current guidance should be reviewed when all data from the ongoing trial become available.# Related NICE guidance Fludarabine monotherapy for the first-line treatment of chronic lymphocytic leukaemia. NICE technology appraisal guidance 119 (2007). Improving outcomes in haematological cancers. NICE cancer service guidance (2003). Rituximab for the treatment of relapsed or refractory chronic lymphocytic leukaemia. NICE technology appraisal guidance 193 (2010).# Review of guidance The guidance on this technology will be considered for review in 2012. The Guidance Executive will decide whether the technology should be reviewed based on information gathered by NICE, and in consultation with consultees and commentators. Andrew DillonChief ExecutiveJuly 2009# Changes after publication February 2014: implementation section updated to clarify that rituximab is recommended as an option for treating chronic lymphocytic leukaemia. Additional minor maintenance update also carried out. March 2012: minor maintenance# About this guidance NICE technology appraisal guidance is about the use of new and existing medicines and treatments in the NHS in England and Wales. This guidance was developed using the NICE single technology appraisal process We have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available. Your responsibility This guidance represents the views of NICE and was arrived at after careful consideration of the evidence available. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. However, the guidance does not override the individual responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or guardian or carer. Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties. Copyright © National Institute for Health and Clinical Excellence 2009. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.	{'Guidance': 'Rituximab in combination with fludarabine and cyclophosphamide is recommended as an option for the first-line treatment of chronic lymphocytic leukaemia in people for whom fludarabine in combination with cyclophosphamide is considered appropriate.\n\nRituximab in combination with chemotherapy agents other than fludarabine and cyclophosphamide is not recommended for the first-line treatment of chronic lymphocytic leukaemia.', 'The technology ': "Rituximab (MabThera, Roche) is a chimeric monoclonal antibody that binds selectively to the CD20 antigen expressed on the surface of mature B lymphocytes and tumour cells that express CD20. Rituximab is licensed for the first-line treatment of people with chronic lymphocytic leukaemia in combination with chemotherapy. Rituximab is administered intravenously, once every 4\xa0weeks for a total of six cycles; a complete course of treatment with rituximab lasts 24\xa0weeks. Dosing is calculated according to body surface area, with an initial dose of 375\xa0mg/m² followed by 500\xa0mg/m² for all subsequent doses. Six cycles of rituximab equate to a total dose of 2875\xa0mg/m². The summary of product characteristics states that rituximab should be administered under the close supervision of an experienced physician, and in an environment where full resuscitation facilities are immediately available.\n\nThe most frequently observed adverse events in people receiving rituximab are infusion-related reactions, including cytokine release syndrome. The majority of these reactions occur during the first infusion. Serious but rare adverse events associated with rituximab include neutropenia and leucopenia (including febrile neutropenia), infections (predominantly bacterial and viral) and cardiovascular events (hypotension, hypertension, arrhythmias and angina). Very rare serious adverse events include hepatitis B reactivation and progressive multifocal leucoencephalopathy. For full details of side effects and contraindications, see the summary of product characteristics.\n\nRituximab is available in 100\xa0mg (10\xa0ml) and 500\xa0mg (50\xa0ml) vials. The cost of a 100\xa0mg vial is £174.63, and of a 500\xa0mg vial is £873.15 (excluding VAT; 'British national formulary' [BNF] edition 57). For a person with a body surface area of 1.93\xa0m², the cost of rituximab for the first dose is £1397 and for subsequent doses £1746 including wastage of excess rituximab. The total cost of rituximab is £10,128 per course. Costs may vary in different settings because of negotiated procurement discounts.", "The manufacturer's submission": "The Appraisal Committee (appendix A) considered evidence submitted by the manufacturer of rituximab for the first-line treatment of chronic lymphocytic leukaemia and a review of this submission by the Evidence Review Group (ERG; appendix B).\n\nThe manufacturer's submission compared rituximab in combination with fludarabine and cyclophosphamide with fludarabine and cyclophosphamide combination therapy. This comparison was based on the CLL-8 trial, a phase III randomised controlled trial. The CLL-8 trial was a multicentre, open-label, parallel-group study in people with previously untreated chronic lymphocytic leukaemia. In the CLL-8 trial a total of 817 people were randomised to receive either fludarabine and cyclophosphamide or rituximab in combination with fludarabine and cyclophosphamide; data were reported on 810 people. The median age of trial participants was 61\xa0years and 74% of participants were men. Participants had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and 95% of participants had Binet stage\xa0B or C disease. People with Binet stage\xa0A disease (n\xa0=\xa040) were enrolled into the trial until a protocol amendment stopped further enrolment.\n\nTrial participants were randomised to six cycles of treatment, with an interim staging after three cycles. People with progressive or stable disease at interim staging were offered alternative treatments by their clinicians outside the trial. People in the control group whose disease did not respond to treatment did not cross over to the treatment group, but could be offered rituximab-containing regimens. People whose disease showed a partial or complete response at the interim staging received all six cycles of treatment. Each cycle of 28\xa0days consisted of fludarabine and cyclophosphamide chemotherapy (fludarabine [25\xa0mg/m²] and cyclophosphamide [250\xa0mg/m²] on days\xa01, 2 and 3) with or without rituximab (375\xa0mg/m² on day\xa00 of cycle\xa01, 500\xa0mg/m² on day\xa01 of cycles\xa02-6). All trial treatments were administered intravenously.\n\nThe primary outcome of the trial was progression-free survival, defined as the time between randomisation and the date of the first documented disease progression, relapse or death by any cause. Secondary outcomes were event-free survival, overall survival, disease-free survival, duration of response, time to new chronic lymphocytic leukaemia treatment and response rates. Quality-of-life data were collected in the trial using the Spitzer Quality of Life Index and the European Organisation for Research and Treatment of Cancer-Quality of Life Questionnaire Core 30 (EORTC-QLQC30).\n\nDemographic characteristics and disease characteristics, including Binet stage\xa0B symptoms and prognostic markers such as cytogenetic abnormalities, were well balanced between the trial groups. Of all trial participants, 64% had Binet stage\xa0B disease, 31% had Binet stage\xa0C disease, and 5% had Binet stage\xa0A disease. The trial also enrolled 46 people (8%) with p53 deletion, a chromosome abnormality associated with a poorer prognosis.\n\nA pre-planned interim analysis of the trial data after a median follow-up of 20.7\xa0months showed a statistically significant difference in progression-free survival between the treatment groups. At this point the trial was halted and the interim analysis became the main analysis. The reported median progression-free survival was 39.8\xa0months in the rituximab in combination with fludarabine and cyclophosphamide group and 32.2\xa0months in the fludarabine and cyclophosphamide group, with a hazard ratio of 0.56 (95% confidence interval [CI] 0.43 to 0.72, p\xa0<\xa00.0001). The trial also reported an overall response rate of 86.1% in the rituximab in combination with fludarabine and cyclophosphamide group and 72.7% in the fludarabine and cyclophosphamide group. At this point median overall survival had not been reached and the trial reported a hazard ratio of 0.64 (95% CI 0.41 to 1.00, p\xa0=\xa00.05).\n\nThe manufacturer also submitted analyses of data from the CLL-8 trial collected from three follow-up points of a longer duration. After a median duration of follow-up of 25.4\xa0months, the reported median progression-free survival was 42.8\xa0months in the rituximab in combination with fludarabine and cyclophosphamide group and 32.5\xa0months in the fludarabine and cyclophosphamide group, with a hazard ratio of 0.60 (95% CI 0.48 to 0.76, p\xa0<\xa00.001). At the end of this follow-up period the statistically significant difference in overall survival was not maintained (hazard ratio 0.72, 95% CI 0.48 to 1.09, p\xa0=\xa00.13). However, the data remained highly censored, because the majority of people were still alive. A further analysis after a median follow-up of 25.5\xa0months reported a rate of progression-free survival of 76.6% in the rituximab in combination with fludarabine and cyclophosphamide group and 62.3% in the fludarabine and cyclophosphamide group (p\xa0<\xa00.001). At this follow-up point, the CLL-8 trial reported an overall response rate of 95% in the rituximab in combination with fludarabine and cyclophosphamide group and 88% in the fludarabine and cyclophosphamide group (p\xa0=\xa00.001). The overall survival rate was 91% in the rituximab in combination with fludarabine and cyclophosphamide group and 88% in the fludarabine and cyclophosphamide group (p\xa0=\xa00.18). In a further analysis after a median follow-up of 26.4\xa0months the reported mean progression-free survival was 37.1\xa0months in the rituximab in combination with fludarabine and cyclophosphamide group and 30.8\xa0months in the fludarabine and cyclophosphamide group (p\xa0<\xa00.001). The hazard ratio for progression-free survival was 0.6 (95% CI 0.47 to 0.75, p\xa0<\xa00.0001). Mean overall survival was 47.7\xa0months in the rituximab in combination with fludarabine and cyclophosphamide group and 48.2\xa0months in the fludarabine and cyclophosphamide group (p\xa0=\xa00.18).\n\nThe manufacturer presented a number of subgroup analyses. For the people with the p53 mutation the hazard ratio for progression-free survival was 0.6 (95% CI 0.31 to 1.19). The hazard ratio for progression-free survival for people with Binet stage\xa0A disease was 0.13 (95% CI 0.03 to 0.61, p\xa0=\xa00.01), Binet stage\xa0B disease was 0.46 (95% CI 0.32 to 0.63, p\xa0<\xa00.0001) and Binet stage\xa0C disease was 0.88 (95% CI 0.58 to 1.33, p\xa0=\xa00.54). The CLL-8 trial was not powered to detect differences in treatment effect for any of these subgroups.\n\nIn the CLL-8 trial, 77% of people in the rituximab in combination with fludarabine and cyclophosphamide group experienced a grade\xa03 or 4 adverse event compared with 62% in the fludarabine and cyclophosphamide group. In the rituximab in combination with fludarabine and cyclophosphamide group 46% of people experienced a serious adverse event; this figure was 41% of people in the fludarabine and cyclophosphamide group. The main adverse events were haematological toxicities, with neutropenia, leucopenia, febrile neutropenia and pancytopenia having a higher incidence (at least 2% difference) in the rituximab in combination with fludarabine and cyclophosphamide group, and thrombocytopenia, anaemia and pyrexia having a higher incidence (at least 2% difference) in the fludarabine and cyclophosphamide group. There were no differences in the rate of other adverse events between the trial groups.\n\nThe manufacturer provided data from four uncontrolled phase II trials on the efficacy and tolerability of combining rituximab with different chemotherapy regimens. The combination chemotherapies included fludarabine, pentostatin, cyclophosphamide and mitoxantrone for the first-line treatment of chronic lymphocytic leukaemia. One of the studies (n\xa0=\xa0300) compared a group of people treated with rituximab in combination with fludarabine and cyclophosphamide with a group of people who had been treated with fludarabine-based regimens in the past and provided data with a median follow-up of 6\xa0years. For the group receiving rituximab the rate of overall survival after 6\xa0years was 77% with a 95% overall response rate. Median time to progression was 80\xa0months. In comparison with the historical control group, rituximab in combination with fludarabine and cyclophosphamide was associated with statistically significant overall survival and was the strongest independent predictor of survival (hazard ratio 0.48, p\xa0<\xa00.001).\n\nIn their submission, the manufacturer also compared rituximab in combination with fludarabine and cyclophosphamide with chlorambucil using a mixed treatment comparison. A mixed treatment comparison was conducted because there were no head-to-head studies comparing rituximab with comparators other than fludarabine and cyclophosphamide. As well as chlorambucil, this analysis also included alemtuzumab, fludarabine alone and bendamustine. In addition to CLL-8, a further seven trials were identified and used to create a network of evidence to make indirect comparisons of rituximab in combination with fludarabine and cyclophosphamide with the other comparators. The studies were combined using a fixed effect model because there was no apparent gain in goodness of fit when a random effects model was used. The mixed treatment comparison showed that chlorambucil had the shortest progression-free survival and therefore this was used as the reference treatment. The mean hazard ratios for other treatments compared with chlorambucil were 0.24 for rituximab in combination with fludarabine and cyclophosphamide, 0.43 for fludarabine and cyclophosphamide, 0.59 for alemtuzumab and 0.86 for fludarabine alone. The mean hazard ratio for progression-free survival was 0.56 for rituximab in combination with fludarabine and cyclophosphamide compared with fludarabine and cyclophosphamide, 0.24 for rituximab in combination with fludarabine and cyclophosphamide compared with chlorambucil, 0.42 for rituximab in combination with fludarabine and cyclophosphamide compared with alemtuzumab and 0.28 for rituximab in combination with fludarabine and cyclophosphamide compared with fludarabine alone.\n\nThe manufacturer's submission presented an economic analysis comparing rituximab in combination with fludarabine and cyclophosphamide with fludarabine and cyclophosphamide, and rituximab in combination with fludarabine and cyclophosphamide with chlorambucil. The manufacturer developed a three-state Markov model with a cycle length of 1\xa0month and a 15-year time horizon (to represent a lifetime horizon). The health states in the model were 'progression-free survival', 'progressed', or 'death'. People entered the model in the progression-free survival health state. The probability of transition from the progression-free survival to the progressed health state was taken from the groups in CLL-8. For the transition from the progression-free survival to the death health state, trial data were used and supplemented with Office of National Statistics data to inform the background mortality rate. Transition from the progressed to the progression-free survival health state was not possible. For the transition from the progressed to the death health state, data for people from both groups of the trial were aggregated and a single probability from the trial applied as there was a non-significant difference in survival following progression between the groups in the trial.\n\nIn the model the drug costs were calculated assuming a body surface area of 1.93\xa0m², which reflects the average body surface area of the people in the CLL-8 trial. The CLL-8 trial used fludarabine and cyclophosphamide administered intravenously, but it is more common to use oral chemotherapy in the UK. In the model it was assumed that the efficacy of fludarabine and cyclophosphamide is the same regardless of the route of administration if the dosage is adjusted to ensure equivalent bioavailability. The costs of fludarabine and cyclophosphamide treatment in the model were adjusted to allow for the difference in the route of administration. The drug costs for rituximab were £1397 for the first cycle of treatment and £1746 for subsequent cycles. For six cycles of treatment the total drug cost of rituximab was £10,128. The total drug costs of fludarabine, cyclophosphamide and chlorambucil were calculated as £2790, £22 and £286, respectively. In the base case, all people received six cycles of therapy unless disease progression occurred before the end of the six cycles.\n\nThe model included costs for supportive care that varied between the health states. This included costs for blood transfusions and bone marrow transplant in the progression-free survival health state taken from the CLL-8 trial and costs for second-line therapies for the progressed health state. In the model rituximab had a cost for intravenous administration of £430 per cycle of treatment and the cost for an appointment to prescribe oral fludarabine and cyclophosphamide chemotherapy was £280. It was assumed that oral chemotherapy could be prescribed in the same appointment as rituximab so no additional cost of prescribing oral chemotherapy was included for the rituximab treatment group. Costs were also added for the pharmacist's time to prepare the infusion.\n\nThe utility values used in the manufacturer's submission were taken from a Health Technology Assessment report (Hancock et al. 2002) that assessed the cost effectiveness of fludarabine as a first-line treatment for chronic lymphocytic leukaemia. A utility of 0.8 was attached to the progression-free survival health state and 0.6 to the progressed health state. The estimates of utility were not preference based, and were estimated by the authors of the Health Technology Assessment report from condition-specific health-related quality-of-life data. No disutility for adverse events was included in the model. The manufacturer provided an interim analysis of 11 people from an observational study of utility in people with chronic lymphocytic leukaemia. The value for progression-free survival was consistent with that used in the manufacturer's submission. No conclusions could be drawn about the utility value appropriate for the progressed health state, as data for only two people were available.\n\nThe manufacturer provided a base-case estimate of incremental cost effectiveness of rituximab in combination with fludarabine and cyclophosphamide in comparison with fludarabine and cyclophosphamide. The incremental quality-adjusted life year (QALY) gain was 0.88 at an incremental cost of £11,617, giving an incremental cost-effectiveness ratio (ICER) of £13,189 per QALY gained. The probabilistic sensitivity analysis presented suggested that rituximab in combination with fludarabine and cyclophosphamide had a 91.9% probability of being cost effective at £20,000 and 98.6% probability of being cost effective at £30,000 when compared with fludarabine and cyclophosphamide. The manufacturer also provided an estimate of the incremental cost effectiveness of rituximab in combination with fludarabine and cyclophosphamide in comparison with chlorambucil. The incremental QALY gain was 1.91 at an incremental cost of £12,250, giving an ICER of £6422 per QALY gained. Probabilistic sensitivity analysis suggested that the probability of rituximab in combination with fludarabine and cyclophosphamide being cost effective in comparison with chlorambucil was 100% at both £20,000 and £30,000 per QALY gained.\n\nA sensitivity analysis was presented in the manufacturer's submission using different parametric models for the progression-free survival extrapolation. Additional sensitivity analyses were completed as follows:\n\nincluding costs for adverse events\n\nincluding costs for febrile neutropenia episodes (as in CLL-8)\n\nincreasing and decreasing supportive care costs for the health states by 50%\n\nassuming utility values for the health states such that the difference in the values between the health states was 0.4 and 0.1. The assumption of a similar rate of adverse events for chlorambucil and fludarabine and cyclophosphamide was tested by assuming no bone-marrow transplants, fewer transfusions and less febrile neutropenia for the chlorambucil arm. One-way sensitivity analyses suggested that the results were not sensitive to a variety of parameter assumptions including utility values, monthly supportive care costs and drug administration costs. The results were sensitive to the function used to extrapolate progression-free survival (exponential, Gompertz), and the highest ICER reported (using a Gompertz function) was £22,661 per QALY gained.\n\nThe manufacturer's submission also included a scenario analysis to explore the impact on the ICER of using intravenous administration of fludarabine and cyclophosphamide chemotherapy instead of oral administration. This analysis demonstrated that the ICER was not sensitive to assumptions about the mechanism of administration. A further scenario analysis modelled the cost effectiveness of rituximab in combination with chemotherapy agents other than fludarabine and cyclophosphamide. The results of this analysis suggested that the QALY gain from combining rituximab with chemotherapy would need to decrease to about 40% of that in the base case, all else remaining the same, for the ICER for rituximab to increase to over £30,000 per QALY gained.\n\nAt the request of the ERG, the manufacturer performed a further one-way sensitivity analysis to explore the impact on the ICER of using alternative assumptions about different mortality rates between the progression-free survival and progressed health states. The manufacturer increased the mortality rate in the rituximab in combination with fludarabine and cyclophosphamide group by 315% so that the life years gained in both treatment groups were the same (0.24 QALYs). In this scenario the incremental QALY gain was 0.24 at an incremental cost of £7226, giving an ICER of £30,336 per QALY gained.\n\nThe ERG considered that all the relevant studies had been identified. The ERG noted that the manufacturer's submission was based on only one completed clinical trial, and that this was unpublished. However, it considered this study to be of good quality. In addition, it noted that this study used intravenous administration of fludarabine and cyclophosphamide rather than oral administration which is normally used in UK clinical practice. The ERG considered the study population was appropriate. It noted that the subgroup of people with chronic lymphocytic leukaemia and the p53 deletion was only considered in relation to progression-free survival and not assessed in the cost–utility model. The ERG considered that the main comparators used in the cost-effectiveness analysis (fludarabine and cyclophosphamide, and chlorambucil) were appropriate. It noted that the mixed treatment comparison provided estimates of clinical effectiveness comparing rituximab in combination with fludarabine and cyclophosphamide with additional comparators, including alemtuzumab, fludarabine monotherapy and bendamustine. The ERG considered that the mixed treatment comparison completed by the manufacturer was appropriate.\n\nThe ERG considered the fact that in the manufacturer's economic model people in the progressed health state could not move back into the progression-free survival health state was unrealistic due to the natural history of chronic lymphocytic leukaemia. People with chronic lymphocytic leukaemia may receive further treatment at progression, which may then result in further periods of progression-free survival. The relapsing nature of chronic lymphocytic leukaemia means that subsequent relapses are less likely to respond to further treatment. This implies that subsequent relapses are likely to be associated with higher disease-related mortality. Therefore, the ERG considered that the manufacturer's assumption of a constant hazard of death after progression may not be appropriate. The ERG highlighted that the overall effect of the aggregated progressed health state and constant hazard of death from this health state was to imply a correlation between progression-free survival and overall survival which it did not consider had been empirically demonstrated in the manufacturer's submission. The ERG further considered that the sensitivity analyses presented by the manufacturer did not fully investigate the uncertainty associated with the extent to which gains in progression-free survival led to gains in overall survival.\n\nThe ERG performed an exploratory analysis of the comparison of rituximab in combination with fludarabine and cyclophosphamide with fludarabine and cyclophosphamide. First, it conducted a component analysis to examine the relative contributions to utility gain from the gain in progression-free survival and the gain in overall survival. This analysis showed that progression-free survival contributed to 0.24 QALYs and overall survival to 0.64 QALYs (of a total gain of 0.88 QALYs). The ERG concluded that this demonstrated that in the model the majority of the benefit is derived from overall survival, making it sensitive to changes in assumptions about overall survival benefits from rituximab. The ERG noted that within the model, because a single transition probability is attached to all people in the progressed health state, the benefit in overall survival is derived almost entirely from the different rate of transfer from the progression-free health state to the progressed health state.\n\nThe ERG repeated the analysis completed by the manufacturer (see section\xa03.18) that removed the differences in overall survival between the two groups in the model. This was done by decreasing the probability of death in the progressed health state for the fludarabine and cyclophosphamide group. A decrease in the probability of death in the fludarabine and cyclophosphamide group to 57% of the base-case level removed the difference in overall survival between the groups and resulted in a QALY gain of 0.24 at an incremental cost of £7228 and an ICER of £30,304 per QALY gained. When assuming no difference in overall survival between the two treatment groups in the analysis, the results suggested that the probability of rituximab in combination with fludarabine and cyclophosphamide being cost effective compared with fludarabine and cyclophosphamide at £20,000 per QALY gained was 29% and at £30,000 per QALY gained was 49%. The ERG identified that if it is assumed that there is no difference in overall survival between the rituximab in combination with fludarabine and cyclophosphamide and fludarabine and cyclophosphamide groups, the model outputs become sensitive to the assumed utility differences between the progression-free and the progressed health states. If the difference in utility between the health states is reduced by 0.1 (that is from 0.2 to 0.1), the ICER increases to £60,302 per QALY gained.\n\nThe ERG completed another exploratory analysis that assumed that the actual overall survival benefit from treatment with rituximab was somewhere between the manufacturer's base case and the assumption of no overall survival benefit. The ERG incorporated this assumption into the probabilistic sensitivity analysis by adding an additional variable, in which the decrease in probability of death in the fludarabine and cyclophosphamide group was sampled as a uniform distribution between 1 and 0.574. The results suggested that rituximab in combination with fludarabine and cyclophosphamide had a 72% probability of being cost effective compared with fludarabine and cyclophosphamide at £20,000 per QALY gained and 88% probability of being cost effective at £30,000 per QALY gained.\n\nIn response to consultation on the appraisal consultation document, the manufacturer submitted additional evidence in support of the combination of rituximab with chlorambucil compared with chlorambucil alone. The manufacturer presented data from four randomised controlled trials in follicular lymphoma, another low-grade B-cell cancer with a relapsing and remitting course. In these studies the addition of rituximab to a range of chemotherapy regimens showed a benefit in progression-free survival and response rates. A further phase\xa0II trial of rituximab in combination with chlorambucil in 29 people with a range of low-grade lymphoproliferative disorders showed an overall response rate of 89%, with a complete response rate of 63%.\n\nThe manufacturer also provided additional economic analysis comparing rituximab in combination with chlorambucil with chlorambucil alone. This used the same model as the original submission, with a number of amendments. The age of the cohort was increased to 70\xa0years to reflect the fact that people treated with chlorambucil in routine clinical practice are generally older than those treated with fludarabine and cyclophosphamide. The baseline risk for the chlorambucil group was taken from the mixed treatment comparison included in the original submission. It was assumed that the hazard ratio for the addition of rituximab to fludarabine and cyclophosphamide observed in the CLL-8 trial (0.595) could be applied to this baseline risk to estimate the effect of adding rituximab to chlorambucil. Drug and administrative costs for rituximab and chlorambucil were included and all other model inputs and assumptions remained the same. Assuming the same hazard ratio meant the relative effect of adding rituximab to chlorambucil was the same as adding rituximab to fludarabine and cyclophosphamide. However, the absolute treatment effect would be smaller because single agent chlorambucil is less effective than fludarabine and cyclophosphamide. The analysis suggested the incremental QALY gain was 0.51 at an incremental cost of £11,570, giving an ICER of £22,490 per QALY gained. A probabilistic sensitivity analysis using the 95% CIs around the assumed hazard ratios showed an 18.6% probability of the ICER being below £20,000 per QALY gained and a 99.7% probability of the ICER being below £30,000 per QALY gained.\n\nThe manufacturer also noted that a single arm phase II trial is underway of rituximab in combination with chlorambucil in people with untreated chronic lymphocytic leukaemia who are not fit for fludarabine-based treatment. The primary objective of the study is a safety analysis of the combination of rituximab and chlorambucil. Secondary objectives include: response rate, progression-free survival, overall survival, disease-free survival and duration of response. An interim analysis of the data is to be presented in December 2009 and a full analysis is expected towards the end of 2010.\n\nFull details of all the evidence are in the manufacturer's submission and the ERG report.", 'Consideration of the evidence': "The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of rituximab for the first-line treatment of chronic lymphocytic leukaemia, having considered evidence on the nature of the condition and the value placed on the benefits of rituximab by people with chronic lymphocytic leukaemia, those who represent them, and clinical specialists. It also took into account the effective use of NHS resources.\n\n# Clinical effectiveness\n\nThe Appraisal Committee discussed current standard clinical management of people with chronic lymphocytic leukaemia. The Committee heard from clinical specialists that approximately 90% of people with chronic lymphocytic leukaemia are asymptomatic and that diagnosis may be made as a chance finding on routine blood testing. People who are asymptomatic may not need immediate treatment, although some will need treatment later in life. The Committee heard that fludarabine in combination with cyclophosphamide is frequently used for people who need immediate treatment. However, chlorambucil alone is normally used for people with poor performance status or comorbidities, especially impaired renal function. The Committee heard from patient experts that people with chronic lymphocytic leukaemia who need treatment will often have a series of treatments following first-line treatment, with further lines of treatment used after each relapse. The Committee specifically considered the clinical management of people whose chronic lymphocytic leukaemia has the p53 mutation. The Committee heard from clinical specialists that these people have a poorer prognosis and are usually treated with alternative treatments (for example, alemtuzumab) rather than chemotherapy.\n\nThe Committee noted that the evidence of clinical effectiveness was based mainly on a single unpublished randomised controlled trial (the CLL-8 trial), which compared rituximab in combination with fludarabine and cyclophosphamide with fludarabine and cyclophosphamide. The Committee accepted that the CLL-8 trial demonstrated a benefit in progression-free survival, and increased overall and complete response rates for rituximab. The Committee heard from clinical specialists that the CLL-8 trial population was younger and fitter than the population of people with chronic lymphocytic leukaemia seen in routine practice within the NHS in England and Wales. However, for the study population fludarabine in combination with cyclophosphamide was the appropriate comparator, and these people reflected the group who would receive fludarabine in combination with cyclophosphamide in clinical practice. The Committee noted that an interim analysis of the clinical trial results had demonstrated a statistically significant gain in overall survival but this gain had not been maintained during longer follow-up. The Committee accepted that crossover and subsequent lines of treatment in the trial made the overall survival benefit difficult to prove. The Committee heard expert opinion that the degree of response to treatment and the duration of progression-free survival were generally accepted as surrogates for overall survival. In addition, the Committee heard that cohort studies using historical controls had also shown survival benefits for people treated with rituximab-containing regimens, although results may have been influenced by changing clinical management, such as earlier identification of people with chronic lymphocytic leukaemia. On balance, the Committee was persuaded that the benefits observed in progression-free survival and response rate were likely to lead to a gain in overall survival, although currently this would be difficult to quantify.\n\nThe Committee recognised that the manufacturer had also provided evidence from uncontrolled phase II trials that reported the benefits of adding rituximab to other chemotherapy regimens for the first-line treatment of people with chronic lymphocytic leukaemia. The Committee discussed the methodological limitations of obtaining an estimate of clinical effectiveness from uncontrolled and historical comparison studies. In addition, the Committee discussed the further evidence from comparative studies of follicular lymphoma provided by the manufacturer in response to consultation on the appraisal consultation document. The Committee was specifically mindful of comments from consultees about the addition of rituximab to chlorambucil for the treatment of people who are unable to tolerate fludarabine therapies. It accepted that it was reasonable to expect that rituximab would be of benefit when added to any chemotherapy regimen. However, the Committee considered that the additional comparative studies provided by the manufacturer involved the use of more toxic regimens than chlorambucil and were likely to have enrolled people who were on average younger and had a better performance status than people treated with chlorambucil in clinical practice. The Committee were not persuaded that the estimates of treatment effects from different studies were transferable. The Committee heard from clinical specialists that they considered that there was no evidence to support adding rituximab to chlorambucil, but that there was an ongoing trial investigating this. The Committee concluded that there was considerable uncertainty about the relative clinical benefit associated with adding rituximab to chemotherapy regimens other than fludarabine and cyclophosphamide in the treatment of chronic lymphocytic leukaemia.\n\nThe Committee was aware that fludarabine and cyclophosphamide were administered intravenously in the CLL-8 trial. It heard from clinical specialists that these chemotherapy agents were routinely administered orally in the NHS. The Committee accepted that the efficacy of both methods of administration was equivalent as long as doses were adjusted to ensure equivalent bioavailability.\n\nThe Committee heard from patient experts that progression-free survival was associated with a marked improvement in quality of life compared with the symptomatic progressed state. Patient experts commented that the first treatment-induced remission was likely to be the longest and associated with the most substantial improvements in quality of life. For this reason people with chronic lymphocytic leukaemia valued having a choice of first-line treatments.\n\n# Cost effectiveness\n\nThe Committee discussed the economic model submitted by the manufacturer. It noted that the manufacturer had only presented estimates of cost effectiveness for rituximab in combination with fludarabine and cyclophosphamide, and that this was compared with fludarabine in combination with cyclophosphamide and chlorambucil monotherapy. The Committee heard from clinical specialists that for those people for whom chlorambucil was the most appropriate treatment (that is, people with poor performance status or comorbidities), rituximab in combination with fludarabine and cyclophosphamide would not be considered an appropriate treatment option. Therefore the Committee was not persuaded that the comparison of rituximab in combination with fludarabine and cyclophosphamide with chlorambucil was valid as the chemotherapy regimens were used in different populations and such a choice between the two treatments was not expected to be clinically meaningful.\n\nThe Committee reviewed the manufacturer's economic model and the critique of it by the ERG. The Committee noted that the model was based on all people entering the model in the progression-free survival health state and moving to the progressed health state, and did not allow people to move from the progressed health state to the progression-free survival health state. The Committee was mindful that the economic model allowed for costs of subsequent lines of therapy to be included but noted that this did not allow any benefit from further therapy to be taken into account. More importantly a single transition probability from the progressed health state to death was applied to people from both trial groups in the progressed health state. The Committee recognised that although the manufacturer had not assumed any relative advantage in survival following progression, the use of a single transition probability from the progressed health state to death had the effect of associating improved progression-free survival with improved overall survival. The Committee considered that the assumed association between progression-free survival and overall survival in the model could overestimate the benefits of the clinical effectiveness of rituximab as taken from the CLL-8 trial, because this had not demonstrated a statistically significant difference in overall survival between treatment groups.\n\nThe Committee discussed the analysis by the ERG that suggested that two-thirds of the QALY gain (0.64 out of 0.88) in the model was because of the modelled improvement in overall survival, which is driven by gain in progression-free survival being reflected in gain in overall survival. The Committee noted that when the overall survival benefit was removed from the model the ICER increased from £13,000 to £30,000 per QALY gained. The Committee recognised therefore that the assumption about the amount of gain in overall survival from treatment with rituximab was an important assumption in the economic model and the use of different assumptions could have a large impact on the estimates of cost effectiveness.\n\nThe Committee noted that condition-specific quality-of-life data collected in the rituximab trial had not been fully reported in the manufacturer's submission and that the utility values used in the model were not consistent with the NICE reference case because they were not preference-based. The Committee considered that the manufacturer may have been able to map the health-related quality-of-life data from the rituximab trial to a preference-based measure to derive utilities and that this may have provided an alternative to the utility data used. The Committee noted that, if there was no difference in overall survival between the treatment groups in the model, the results became very sensitive to the difference between the utility values used for the progression-free survival health state and the progressed health state. The Committee considered the lack of appropriate utility data contributed to substantial uncertainty in the economic modelling.\n\nThe Committee discussed the additional exploratory analysis done by the ERG using an assumption that the actual survival benefit from treatment with rituximab was somewhere between that presented in the base case and an assumption that there was no gain in survival (see section\xa03.23). The Committee noted that the probability, using the base-case utilities (that is, 0.80 for the progression-free survival health state and 0.60 for the progressed health state), of rituximab in combination with fludarabine and cyclophosphamide being cost effective at £20,000 per QALY gained was 71% and at £30,000 per QALY gained was 87%. On balance, the Committee was persuaded that even taking into account the additional uncertainty about the utility values, the economic analysis had demonstrated that rituximab in combination with fludarabine and cyclophosphamide for the first-line treatment of chronic lymphocytic leukaemia was a cost-effective use of NHS resources.\n\nThe Committee considered the economic analysis provided by the manufacturer after consultation on the appraisal consultation document. It examined the assumptions used in the economic modelling for the comparison of rituximab and chlorambucil with chlorambucil alone. The Committee noted that the economic analysis assumed that the hazard ratio observed in the CLL-8 trial was exactly transferable to other chemotherapy regimens. However, the Committee noted that subgroup analyses of the CLL-8 trial demonstrated that there were differences in effect between different subgroups of patients based on age and staging. The Committee recognised that the marketing authorisation for rituximab allowed its use with any chemotherapy regimen. However, the Committee was not persuaded that the relative effects of the treatment or hazard ratio were transferable between various chemotherapies combined with rituximab and between different subgroups of people.\n\nThe Committee was also mindful that the base-case ICER for rituximab in combination with chlorambucil from the manufacturer's additional analysis was £22,000 per QALY gained (section\xa03.25). The Committee considered that this estimate would be higher if benefits in progression-free survival did not lead to benefits in overall survival (section\xa04.9). The Committee noted that these uncertainties had increased the base-case ICER estimate for rituximab in combination with fludarabine and cyclophosphamide compared with fludarabine and cyclophosphamide in the main analysis from £13,000 to £30,000 per QALY gained. This estimate was also associated with uncertainty because no preference-based utility values were available (section\xa04.10). The Committee was also aware that the analysis did not allow for the possibility of increased costs and disutilities because of adverse events that a population with poorer performance status or comorbidities may experience. The Committee considered that these uncertainties could make the ICER for rituximab in combination with chlorambucil considerably less favourable.\n\nThe Committee agreed that the uncertainty regarding the relative clinical effectiveness and the assumptions that had to be included in the additional economic analysis did not support the clinical and cost effectiveness of the use of rituximab in combination with chlorambucil. The Committee was therefore not persuaded that it could recommend rituximab in combination with chlorambucil as a cost-effective use of NHS resources. The Committee noted that the group of patients who are not suitable for a regimen of fludarabine in combination with cyclophosphamide, and who might therefore be treated with rituximab in combination with chlorambucil, would include a high proportion of people with poor performance status or comorbidities. The Committee considered whether the equalities legislation and the requirement for fairness meant that it should make a positive recommendation for rituximab in combination with chlorambucil for this group. However the Committee noted that a negative recommendation for rituximab in combination with chlorambucil did not appear to have an impact on any group protected by the equalities legislation. It is not obvious that there is a clear correlation between the comorbidity factors which rendered this patient group unsuitable for certain chemotherapies and 'disability' as defined in the Disability Discrimination Act 1995. The Committee could not be satisfied that a negative recommendation of rituximab in combination with chlorambucil represented less favourable treatment or loss of benefit, given the lack of clear evidence as to the relative clinical effectiveness of rituximab in combination with chlorambucil in this particular patient group. Given the lack of evidence for both the clinical and cost effectiveness of this combination, the Committee could not justify a positive recommendation of rituximab in combination with chlorambucil.\n\nThe Committee was aware that new data on the combination of rituximab with chlorambucil in chronic lymphocytic leukaemia would soon be available. It considered that even though this was not a comparative trial, the data could potentially provide more certain estimates of cost effectiveness of rituximab in combination with chlorambucil. The Committee therefore agreed that the current guidance should be reviewed when all data from the ongoing trial become available.", 'Related NICE guidance': 'Fludarabine monotherapy for the first-line treatment of chronic lymphocytic leukaemia. NICE technology appraisal guidance 119 (2007).\n\nImproving outcomes in haematological cancers. NICE cancer service guidance (2003).\n\nRituximab for the treatment of relapsed or refractory chronic lymphocytic leukaemia. NICE technology appraisal guidance 193 (2010).', 'Review of guidance': 'The guidance on this technology will be considered for review in 2012. The Guidance Executive will decide whether the technology should be reviewed based on information gathered by NICE, and in consultation with consultees and commentators.\n\nAndrew DillonChief ExecutiveJuly 2009', 'Changes after publication': 'February 2014: implementation section updated to clarify that rituximab is recommended as an option for treating chronic lymphocytic leukaemia. Additional minor maintenance update also carried out.\n\nMarch 2012: minor maintenance', 'About this guidance': 'NICE technology appraisal guidance is about the use of new and existing medicines and treatments in the NHS in England and Wales.\n\nThis guidance was developed using the NICE single technology appraisal process\n\nWe have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available.\n\nYour responsibility\n\nThis guidance represents the views of NICE and was arrived at after careful consideration of the evidence available. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. However, the guidance does not override the individual responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.\n\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.\n\nCopyright\n\n© National Institute for Health and Clinical Excellence 2009. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.'}	https://www.nice.org.uk/guidance/ta174	Evidence-based recommendations on rituximab for untreated chronic lymphocytic leukaemia in adults.
c7bfd36b9552389d50c0a27af354727c73b4bee9	nice	Sinus tarsi implant insertion for mobile flatfoot	Sinus tarsi implant insertion for mobile flatfoot # Guidance Current evidence on the safety and efficacy of sinus tarsi implant insertion for mobile flatfoot is inadequate in quality and quantity. Therefore this procedure should only be used with special arrangements for clinical governance, consent and audit or research. Clinicians wishing to undertake sinus tarsi implant insertion for mobile flatfoot should take the following actions. Inform the clinical governance leads in their Trusts. Ensure that patients and/or their parents/carers understand the uncertainty about the procedure's safety and efficacy in relation to symptom relief, quality of life, and long-term outcomes; that the success of the procedure may be dependent on the aetiology of their flatfoot; that there may be a need for adjunctive or subsequent procedures; and that the implant may need to be removed. Patients and parents or carers should be provided with clear written information. In addition, the use of NICE's information for patients ('Understanding NICE guidance') is recommended. Audit and review clinical outcomes of all patients having sinus tarsi implant insertion for mobile flatfoot (see section 3.1). Sinus tarsi implant insertion is not appropriate for most children with mobile flatfoot. The procedure may be used in selected children with persistent mobile flatfoot due to neuromuscular disorder, skeletal dysplasia or systemic ligamentous laxity, whose treatment is supervised by a multidisciplinary team. The procedure may be indicated rarely in highly selected adult patients. NICE encourages further research into sinus tarsi implant insertion for mobile flatfoot. Research studies should define patient selection criteria, address uncertainties about using the procedure in children and in adults, include descriptions of adjunctive procedures, and provide long-term outcome data. Studies comparing outcomes of the procedure with the natural history of mobile flatfoot would be useful. NICE may review the procedure upon publication of further evidence.# The procedure # Indications and current treatments In people with mobile flatfoot, the foot arch is effaced only on weight bearing. Manipulation or standing on tiptoe can restore it to normal appearance. Most children go through a self-resolving phase of mobile flatfoot during growth. In some children, it can be permanent as a result of neuromuscular disorders, skeletal dysplasias or ligamentous laxity. In adults, mobile flatfoot is common and may be associated with posterior tibial tendon insufficiency. The condition is usually asymptomatic, particularly in children, but some people may have foot pain. Orthotics and physiotherapy are normally used to treat children and young adults. Depending on the underlying cause, treatments may include corticosteroid injections (in adults), surgical decompression, tendon augmentation, and osteotomy or lengthening of the calcaneum. A number of different devices can be used for this procedure. # Outline of the procedure The procedure (also known as subtalar arthroereisis) can be performed with the patient under general or local anaesthesia. Exact technique and instrumentation vary. The sinus tarsi (between the calcaneum and the talus) is accessed by a lateral incision. A trial implant may be used, with intraoperative imaging and simulated weight bearing, to direct appropriate placement and degree of correction before a sized implant is inserted. Adjunctive bone or soft tissue procedures may also be carried out. Compression dressing or plaster cast (particularly with adjunctive procedures) and modified footwear and/or orthotics may be used postoperatively. The implant may need to be removed, particularly in children; exact timing for this varies. Sections 2.3 and 2.4 describe efficacy and safety outcomes which were available in the published literature and which the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview. # Efficacy In a case series of 54 patients (68 feet), 24%, 42%, 27% and 6% of patients (or their parents) respectively reported '100%', '75%', '50%' and 'either 25% or no' resolution of symptoms (mean follow-up 2 years). In a case series of 37 patients (65 feet), 59% (22/37) reported pain before and 5% (2/37) after the procedure (mean follow-up 26.5 months). In a case series of 23 patients (28 feet), the mean pain score decreased from 3.2 preoperatively to 1.6 postoperatively on a scale from 4 (severe pain) to 1 (no pain) (p < 0.0001) (mean follow-up 44 months). The Specialist Advisers listed key efficacy outcomes as quality of life, pain relief, X-ray angles, gait analysis, normal foot shape and footwear, clinical scoring scales and long-term correction. # Safety In 7 case series, less than 1% (2/234), 5% (4/80), 5% (3/65), 7% (3/41), 36% (8/22) and 39% (11/28) of feet and 10% of patients (exact number not stated) required implant removal (follow-up from 3 months to 10 years). In the case series of 23 patients, 1 patient had a fractured talus 6 years after implantation. Further studies reported avascular necrosis in 1 foot 10 years after bilateral surgery; bilateral intraosseous talus cysts and osteophytes in 1 patient after 2.5 years; talus bony sclerosis in 1 patient at 4 years; and talus spur formation in 1 foot at 3 months. The case series of 54 patients reported implant extrusion in 9% of feet after 1 year. A case series of 49 patients reported fragments in the sinus tarsi (unclear whether bone or implant) in 1 foot (follow-up not stated). The Specialist Advisers considered theoretical or anecdotal adverse events to include sural nerve injury and complete loss of subtalar movement.# Further information This guidance requires that clinicians undertaking the procedure make special arrangements for audit. NICE has identified relevant audit criteria and has developed audit support (which is for use at local discretion). For related NICE guidance see our website. # Information for patients NICE has produced information on this procedure for patients and carers ('Understanding NICE guidance'). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.# About this guidance NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland. This guidance was developed using the NICE interventional procedure guidance process. We have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available. Changes since publication January 2012: minor maintenance. Your responsibility This guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer. Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties. Copyright © National Institute for Health and Clinical Excellence 2009. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE. Contact NICE National Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT www.nice.org.uk nice@nice.org.uk	{'Guidance ': "Current evidence on the safety and efficacy of sinus tarsi implant insertion for mobile flatfoot is inadequate in quality and quantity. Therefore this procedure should only be used with special arrangements for clinical governance, consent and audit or research.\n\nClinicians wishing to undertake sinus tarsi implant insertion for mobile flatfoot should take the following actions.\n\nInform the clinical governance leads in their Trusts.\n\nEnsure that patients and/or their parents/carers understand the uncertainty about the procedure's safety and efficacy in relation to symptom relief, quality of life, and long-term outcomes; that the success of the procedure may be dependent on the aetiology of their flatfoot; that there may be a need for adjunctive or subsequent procedures; and that the implant may need to be removed. Patients and parents or carers should be provided with clear written information. In addition, the use of NICE's information for patients ('Understanding NICE guidance') is recommended.\n\nAudit and review clinical outcomes of all patients having sinus tarsi implant insertion for mobile flatfoot (see section 3.1).\n\nSinus tarsi implant insertion is not appropriate for most children with mobile flatfoot. The procedure may be used in selected children with persistent mobile flatfoot due to neuromuscular disorder, skeletal dysplasia or systemic ligamentous laxity, whose treatment is supervised by a multidisciplinary team. The procedure may be indicated rarely in highly selected adult patients.\n\nNICE encourages further research into sinus tarsi implant insertion for mobile flatfoot. Research studies should define patient selection criteria, address uncertainties about using the procedure in children and in adults, include descriptions of adjunctive procedures, and provide long-term outcome data. Studies comparing outcomes of the procedure with the natural history of mobile flatfoot would be useful. NICE may review the procedure upon publication of further evidence.", 'The procedure': "# Indications and current treatments\n\nIn people with mobile flatfoot, the foot arch is effaced only on weight bearing. Manipulation or standing on tiptoe can restore it to normal appearance.\n\nMost children go through a self-resolving phase of mobile flatfoot during growth.\n\nIn some children, it can be permanent as a result of neuromuscular disorders, skeletal dysplasias or ligamentous laxity.\n\nIn adults, mobile flatfoot is common and may be associated with posterior tibial tendon insufficiency.\n\nThe condition is usually asymptomatic, particularly in children, but some people may have foot pain.\n\nOrthotics and physiotherapy are normally used to treat children and young adults. Depending on the underlying cause, treatments may include corticosteroid injections (in adults), surgical decompression, tendon augmentation, and osteotomy or lengthening of the calcaneum.\n\nA number of different devices can be used for this procedure.\n\n# Outline of the procedure\n\nThe procedure (also known as subtalar arthroereisis) can be performed with the patient under general or local anaesthesia. Exact technique and instrumentation vary. The sinus tarsi (between the calcaneum and the talus) is accessed by a lateral incision. A trial implant may be used, with intraoperative imaging and simulated weight bearing, to direct appropriate placement and degree of correction before a sized implant is inserted. Adjunctive bone or soft tissue procedures may also be carried out.\n\nCompression dressing or plaster cast (particularly with adjunctive procedures) and modified footwear and/or orthotics may be used postoperatively.\n\nThe implant may need to be removed, particularly in children; exact timing for this varies.\n\nSections 2.3 and 2.4 describe efficacy and safety outcomes which were available in the published literature and which the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview.\n\n# Efficacy\n\nIn a case series of 54 patients (68 feet), 24%, 42%, 27% and 6% of patients (or their parents) respectively reported '100%', '75%', '50%' and 'either 25% or no' resolution of symptoms (mean follow-up 2 years).\n\nIn a case series of 37 patients (65 feet), 59% (22/37) reported pain before and 5% (2/37) after the procedure (mean follow-up 26.5 months). In a case series of 23 patients (28 feet), the mean pain score decreased from 3.2 preoperatively to 1.6 postoperatively on a scale from 4 (severe pain) to 1 (no pain) (p < 0.0001) (mean follow-up 44 months).\n\nThe Specialist Advisers listed key efficacy outcomes as quality of life, pain relief, X-ray angles, gait analysis, normal foot shape and footwear, clinical scoring scales and long-term correction.\n\n# Safety\n\nIn 7 case series, less than 1% (2/234), 5% (4/80), 5% (3/65), 7% (3/41), 36% (8/22) and 39% (11/28) of feet and 10% of patients (exact number not stated) required implant removal (follow-up from 3 months to 10 years).\n\nIn the case series of 23 patients, 1 patient had a fractured talus 6 years after implantation.\n\nFurther studies reported avascular necrosis in 1 foot 10 years after bilateral surgery; bilateral intraosseous talus cysts and osteophytes in 1 patient after 2.5 years; talus bony sclerosis in 1 patient at 4 years; and talus spur formation in 1 foot at 3 months.\n\nThe case series of 54 patients reported implant extrusion in 9% of feet after 1 year. A case series of 49 patients reported fragments in the sinus tarsi (unclear whether bone or implant) in 1 foot (follow-up not stated).\n\nThe Specialist Advisers considered theoretical or anecdotal adverse events to include sural nerve injury and complete loss of subtalar movement.", 'Further information': "This guidance requires that clinicians undertaking the procedure make special arrangements for audit. NICE has identified relevant audit criteria and has developed audit support (which is for use at local discretion).\n\nFor related NICE guidance see our website.\n\n# Information for patients\n\nNICE has produced information on this procedure for patients and carers ('Understanding NICE guidance'). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.", 'About this guidance': 'NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland.\n\nThis guidance was developed using the NICE interventional procedure guidance process.\n\nWe have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available.\n\nChanges since publication\n\nJanuary 2012: minor maintenance.\n\nYour responsibility\n\nThis guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.\n\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.\n\nCopyright\n\n© National Institute for Health and Clinical Excellence 2009. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.\n\nContact NICE\n\nNational Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT\n\nwww.nice.org.uk\n \n nice@nice.org.uk\n 0845 033 7780'}	https://www.nice.org.uk/guidance/ipg305
4c3fa2c5e8b3170e51873468ad10604d735ac315	nice	Prosthetic intervertebral disc replacement in the lumbar spine	Prosthetic intervertebral disc replacement in the lumbar spine # Guidance This document replaces previous guidance on prosthetic intervertebral disc replacement (interventional procedure guidance 100). Current evidence on the safety and efficacy of prosthetic intervertebral disc replacement in the lumbar spine is adequate to support the use of this procedure provided that normal arrangements are in place for clinical governance, consent and audit. A multidisciplinary team with specialist expertise in the treatment of degenerative spine disease should be involved in patient selection for prosthetic intervertebral disc replacement in the lumbar spine. The procedure should only be carried out in patients for whom conservative treatment options have failed or are contraindicated. The current evidence includes studies with a maximum follow-up of 13 years, but the majority of evidence is from studies with shorter durations of follow-up. NICE encourages clinicians to continue to collect and publish data on longer-term outcomes, which should include information about patient selection and the need for further surgery.# The procedure # Indications and current treatments Symptomatic degenerative disc disease of the lumbar spine occurs when the intervertebral discs supporting the vertebrae lose their elasticity. This can cause partial disc prolapse, which may be associated with chronic lower back and radicular pain. Conservative treatments include analgesics, non-steroidal anti-inflammatory medication and physical therapy. Epidural steroid injections can also be used. Interventions for people with chronic intractable pain or neurological complications include removal of the protruding disc (discectomy) and/or spinal fusion. # Outline of the procedure Artificial intervertebral discs are mobile implants that are inserted between the vertebrae. They are designed to resolve symptoms associated with disc degeneration and to reduce disc degeneration between adjacent lumbar vertebrae. With the patient under general anaesthesia, the intervertebral space is accessed through an abdominal incision using a transperitoneal or retroperitoneal approach. The damaged disc is partially or fully removed and the implant inserted, taking care to ensure that the size of the replacement disc and its position within the intervertebral space are optimised to promote osseous integration and to maximise disc mobility and patient comfort. Multiple discs can be replaced during the same procedure. Sections 2.3 and 2.4 describe efficacy and safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview. # Efficacy A randomised controlled trial (RCT) of 304 patients (205 treated with a prosthetic lumbar disc and 99 with spinal fusion) used the Oswestry Disability Index (ODI) to assess outcomes. The RCT reported significantly greater improvement in ODI score from baseline in patients treated by prosthetic disc implantation compared with spinal fusion at 6-week, 3-month, and 6-month follow-up (absolute figures and significance not stated). At 12-month and 24-month follow-up, the differences between the two patient groups in ODI scores from baseline was no longer significant (absolute figures not stated; p = 0.14, p = 0.54, respectively). An RCT of 236 patients (161 treated with a prosthetic lumbar disc and 75 with spinal fusion) reported that mean quality of life scores (using the Short Form-36 questionnaire) improved by 87% in the prosthetic disc group compared with 70% in those who underwent spinal fusion (p = 0.004) at 3-month follow-up. This difference was no longer significant at 24-month follow-up (p = 0.09). A case series of 106 patients treated with a prosthetic lumbar disc reported that 42% (45/106) had 'excellent', 40% (42/106) 'good', 8% (8/106) 'fair', and 10% (11/106) 'poor' clinical outcomes (on a 4-grade Stauffer–Coventry scale from poor to excellent ) at a mean follow-up of 13 years. In the same study, 90% (86/96) of patients eligible for work at baseline had returned to work, and 78% (28/36) had returned to manual labour (mean follow-up 13 years). Specialist Advisers listed key efficacy outcomes as pain relief measured by a visual analogue scale or ODI, disability, return to work, quality of life and reduced need for additional procedures. # Safety In an RCT of 67 patients, vertebral endplate fracture requiring further surgery occurred in 2% (1/44) of patients treated with prosthetic intervertebral discs in the lumbar spine. None of the 23 patients treated by spinal fusion had this complication. The RCT of 304 patients reported that the rate of major neurological adverse events (not otherwise described) was higher after fusion surgery (5.4%) than after prosthetic disc implantation (2.4%) at 42-day follow-up (absolute figures and significance not stated). A non-randomised controlled study of 688 patients reported a need for further surgery within 2 years in 9% (52/589) of patients treated with prosthetic lumbar discs compared with 10% (10/99) of patients treated by lumbar fusion (p = 0.7). A systematic review of 27 uncontrolled case series totalling 2490 patients reported that intervertebral disc disease (defined as clinically significant degeneration) occurred at an adjacent level in 14% (173/1216) of patients treated by lumbar fusion compared with 1% (7/595) of patients treated with prosthetic lumbar discs (p < 0.001) (follow-up varied between studies). The RCT of 236 patients reported that infection (not otherwise described) had occurred in 3% (2/75) of patients treated by lumbar fusion and 0% (0/161) of patients treated with prosthetic lumbar discs at 2-year follow-up (significance not stated). The Specialist Advisers listed anecdotal or published adverse outcomes as vascular injury, spinal endplate fracture, retrograde ejaculation, failure to control symptoms, device subsidence and wear debris from the device. The Specialist Advisers considered theoretical adverse events to include nerve injury (including cauda equina injury), bowel injury, haemorrhage, infection, impaired bladder function and device failure requiring revision surgery.# Further information For related NICE guidance see our website. # Information for patients NICE has produced information on this procedure for patients and carers ('Understanding NICE guidance'). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.# About this guidance NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland. This guidance was developed using the NICE interventional procedure guidance process. It updates and replaces NICE interventional procedure guidance 100. We have produced a summary of this guidance for patients and carers. Information about the evidence it is based on is also available. Changes since publication January 2012: minor maintenance. Your responsibility This guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer. Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties. Copyright © National Institute for Health and Clinical Excellence 2009. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE. Contact NICE National Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT www.nice.org.uk nice@nice.org.uk	{'Guidance': 'This document replaces previous guidance on prosthetic intervertebral disc replacement (interventional procedure guidance 100).\n\nCurrent evidence on the safety and efficacy of prosthetic intervertebral disc replacement in the lumbar spine is adequate to support the use of this procedure provided that normal arrangements are in place for clinical governance, consent and audit.\n\nA multidisciplinary team with specialist expertise in the treatment of degenerative spine disease should be involved in patient selection for prosthetic intervertebral disc replacement in the lumbar spine. The procedure should only be carried out in patients for whom conservative treatment options have failed or are contraindicated.\n\nThe current evidence includes studies with a maximum follow-up of 13 years, but the majority of evidence is from studies with shorter durations of follow-up. NICE encourages clinicians to continue to collect and publish data on longer-term outcomes, which should include information about patient selection and the need for further surgery.', 'The procedure': "# Indications and current treatments\n\nSymptomatic degenerative disc disease of the lumbar spine occurs when the intervertebral discs supporting the vertebrae lose their elasticity. This can cause partial disc prolapse, which may be associated with chronic lower back and radicular pain.\n\nConservative treatments include analgesics, non-steroidal anti-inflammatory medication and physical therapy. Epidural steroid injections can also be used. Interventions for people with chronic intractable pain or neurological complications include removal of the protruding disc (discectomy) and/or spinal fusion.\n\n# Outline of the procedure\n\nArtificial intervertebral discs are mobile implants that are inserted between the vertebrae. They are designed to resolve symptoms associated with disc degeneration and to reduce disc degeneration between adjacent lumbar vertebrae.\n\nWith the patient under general anaesthesia, the intervertebral space is accessed through an abdominal incision using a transperitoneal or retroperitoneal approach. The damaged disc is partially or fully removed and the implant inserted, taking care to ensure that the size of the replacement disc and its position within the intervertebral space are optimised to promote osseous integration and to maximise disc mobility and patient comfort. Multiple discs can be replaced during the same procedure.\n\nSections 2.3 and 2.4 describe efficacy and safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview.\n\n# Efficacy\n\nA randomised controlled trial (RCT) of 304 patients (205 treated with a prosthetic lumbar disc and 99 with spinal fusion) used the Oswestry Disability Index (ODI) to assess outcomes. The RCT reported significantly greater improvement in ODI score from baseline in patients treated by prosthetic disc implantation compared with spinal fusion at 6-week, 3-month, and 6-month follow-up (absolute figures and significance not stated). At 12-month and 24-month follow-up, the differences between the two patient groups in ODI scores from baseline was no longer significant (absolute figures not stated; p = 0.14, p = 0.54, respectively).\n\nAn RCT of 236 patients (161 treated with a prosthetic lumbar disc and 75 with spinal fusion) reported that mean quality of life scores (using the Short Form-36 questionnaire) improved by 87% in the prosthetic disc group compared with 70% in those who underwent spinal fusion (p = 0.004) at 3-month follow-up. This difference was no longer significant at 24-month follow-up (p = 0.09).\n\nA case series of 106 patients treated with a prosthetic lumbar disc reported that 42% (45/106) had 'excellent', 40% (42/106) 'good', 8% (8/106) 'fair', and 10% (11/106) 'poor' clinical outcomes (on a 4-grade Stauffer–Coventry scale from poor [no improvement or worse than preoperative condition] to excellent [no pain, treatment or medications]) at a mean follow-up of 13 years. In the same study, 90% (86/96) of patients eligible for work at baseline had returned to work, and 78% (28/36) had returned to manual labour (mean follow-up 13 years).\n\nSpecialist Advisers listed key efficacy outcomes as pain relief measured by a visual analogue scale or ODI, disability, return to work, quality of life and reduced need for additional procedures.\n\n# Safety\n\nIn an RCT of 67 patients, vertebral endplate fracture requiring further surgery occurred in 2% (1/44) of patients treated with prosthetic intervertebral discs in the lumbar spine. None of the 23 patients treated by spinal fusion had this complication.\n\nThe RCT of 304 patients reported that the rate of major neurological adverse events (not otherwise described) was higher after fusion surgery (5.4%) than after prosthetic disc implantation (2.4%) at 42-day follow-up (absolute figures and significance not stated).\n\nA non-randomised controlled study of 688 patients reported a need for further surgery within 2 years in 9% (52/589) of patients treated with prosthetic lumbar discs compared with 10% (10/99) of patients treated by lumbar fusion (p = 0.7).\n\nA systematic review of 27 uncontrolled case series totalling 2490 patients reported that intervertebral disc disease (defined as clinically significant degeneration) occurred at an adjacent level in 14% (173/1216) of patients treated by lumbar fusion compared with 1% (7/595) of patients treated with prosthetic lumbar discs (p < 0.001) (follow-up varied between studies).\n\nThe RCT of 236 patients reported that infection (not otherwise described) had occurred in 3% (2/75) of patients treated by lumbar fusion and 0% (0/161) of patients treated with prosthetic lumbar discs at 2-year follow-up (significance not stated).\n\nThe Specialist Advisers listed anecdotal or published adverse outcomes as vascular injury, spinal endplate fracture, retrograde ejaculation, failure to control symptoms, device subsidence and wear debris from the device. The Specialist Advisers considered theoretical adverse events to include nerve injury (including cauda equina injury), bowel injury, haemorrhage, infection, impaired bladder function and device failure requiring revision surgery.", 'Further information': "For related NICE guidance see our website.\n\n# Information for patients\n\nNICE has produced information on this procedure for patients and carers ('Understanding NICE guidance'). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.", 'About this guidance': 'NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland.\n\nThis guidance was developed using the NICE interventional procedure guidance process.\n\nIt updates and replaces NICE interventional procedure guidance 100.\n\nWe have produced a summary of this guidance for patients and carers. Information about the evidence it is based on is also available.\n\nChanges since publication\n\nJanuary 2012: minor maintenance.\n\nYour responsibility\n\nThis guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.\n\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.\n\nCopyright\n\n© National Institute for Health and Clinical Excellence 2009. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.\n\nContact NICE\n\nNational Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT\n\nwww.nice.org.uk\n \n nice@nice.org.uk\n 0845 033 7780'}	https://www.nice.org.uk/guidance/ipg306
3b3217e8b53fe326ae0954cb5f9b24703b51fca9	nice	Image-guided radiofrequency excision biopsy of breast lesions	Image-guided radiofrequency excision biopsy of breast lesions # Guidance Current evidence on the safety and efficacy of image-guided radiofrequency (RF) excision biopsy of breast lesions is inadequate in quantity and quality, and there are concerns about the possibility of false-negative biopsy results. Therefore, this procedure should only be used with special arrangements for clinical governance, consent and audit or research. Clinicians wishing to undertake image-guided RF excision biopsy of breast lesions should take the following actions. Inform the clinical governance leads in their Trusts. Ensure that patients and their carers understand the uncertainty about the procedure's safety and efficacy and provide them with clear written information. In addition, the use of NICE's information for patients ('Understanding NICE guidance') is recommended. Audit and review clinical outcomes of all patients having image-guided RF excision biopsy of breast lesions (see section 3.1). NICE encourages further research into image-guided RF excision biopsy of breast lesions. Research should be in the form of diagnostic studies aimed at quantifying the risk of false-negative results associated with the procedure. NICE may review the procedure on publication of further evidence.# The procedure # Indications and current treatments Breast abnormalities may be benign or malignant. Diagnosis is based on clinical findings, imaging and tissue sampling. Tissue sampling is usually by fine needle aspiration for cytology, or by needle core biopsy for histology. Histology allows for differentiation between benign tumours such as fibroadenomas (typically between 1 cm and 3 cm in size), and others such as non-invasive ductal carcinoma in situ (DCIS) and invasive ductal carcinoma (IDC). Open surgical biopsy or image-guided vacuum-assisted core biopsy may also be used to establish tumour type and grade. Breast cancer is the most common cancer in women in the UK. If cancer is diagnosed, treatment depends on the type, stage and grade of the tumour. In general terms, the more tissue retrieved with multiple core samples or larger tissue samples, the more accurate the diagnosis is likely to be. With this procedure, the whole lesion can be removed. # Outline of the procedure Image-guided RF excision biopsy of breast lesions aims to achieve minimally invasive retrieval of an intact specimen for histological examination, while minimising the risk of bleeding and haematoma formation. This procedure is not indicated currently for the therapeutic removal of known cancers unless there are no surgical options. The procedure is carried out with the patient under local anaesthesia. Using image guidance, a small incision is made in the breast. A probe with a unipolar RF cutting tip is advanced to the site of the lesion. Small wires and capturing arms are extended from the tip of the probe to surround the lesion, which is then dissected using the RF cutting tip. The sample is captured in the arms of the device and withdrawn. Probes of various diameters and expandable RF cutting tips can be used, depending on the diameter of the sample to be captured. Sections 2.3 and 2.4 describe efficacy and safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview. # Efficacy In a case series of 742 breast lesions (absolute number of patients not reported), 34 lesions were initially identified as atypical ductal hyperplasia (benign lesions) after RF excision biopsy. Following subsequent surgery and histological examination 9% (3/34) of these results were false negatives; the lesions were subsequently diagnosed as either DCIS or IDC. Similarly, 5% (6/119) of lesions initially diagnosed as DCIS following RF excision biopsy were subsequently diagnosed as IDC after surgical excision and biopsy. In a case series of 100 patients (106 lesions) with breast lesions diagnosed as fibroadenomas based on imaging findings, who were subsequently managed by RF excision biopsy, 93% (79/85) of patients showed no physical or imaging evidence of residual lesions at follow-ups of between 4 and 6 months. The Specialist Advisers listed key efficacy outcomes for this procedure, when used for benign lesions, as intact removal of the lesion and patient acceptability/cosmetic appearance. The Specialist Advisers listed additional efficacy outcomes, when used in early breast cancer, as delivery of an evaluable lesion for histology, and both local recurrence and survival. # Safety The case series of 742 lesions (absolute number of patients not stated) reported that infection (not otherwise defined) occurred in less than 1% (1/742) of biopsies (resolved with oral antibiotics) (follow-up not stated). The case series of 100 patients (106 lesions) recorded a mean pain score during the procedure of less than 1 point (using a visual analogue scale from 0 to 10 ). In the case series of 100 patients (106 lesions), bleeding occurred in 2% (2/106) of excision procedures but this was controlled by 'conservative measures' (not otherwise defined). The Specialist Advisers listed adverse events reported in the literature as haematoma, infection, skin burns and failure to deliver an adequate sample. They considered theoretical adverse events to include seeding of tumour cells along the biopsy tract, haemorrhage, pain (temporary) and fat necrosis due to thermal damage.# Further information This guidance requires that clinicians undertaking the procedure make special arrangements for audit. NICE has identified relevant audit criteria and has developed audit support (which is for use at local discretion). For related NICE guidance see our website. # Information for patients NICE has produced information on this procedure for patients and carers ('Understanding NICE guidance'). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.# About this guidance NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland. This guidance was developed using the NICE interventional procedure guidance process. It has been incorporated into the NICE pathway on early and locally advanced breast cancer, along with other related guidance and products. We have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available. Changes since publication January 2012: minor maintenance. Your responsibility This guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer. Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties. Copyright © National Institute for Health and Clinical Excellence 2009. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE. Contact NICE National Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT www.nice.org.uk nice@nice.org.uk	{'Guidance': "Current evidence on the safety and efficacy of image-guided radiofrequency (RF) excision biopsy of breast lesions is inadequate in quantity and quality, and there are concerns about the possibility of false-negative biopsy results. Therefore, this procedure should only be used with special arrangements for clinical governance, consent and audit or research.\n\nClinicians wishing to undertake image-guided RF excision biopsy of breast lesions should take the following actions.\n\nInform the clinical governance leads in their Trusts.\n\nEnsure that patients and their carers understand the uncertainty about the procedure's safety and efficacy and provide them with clear written information. In addition, the use of NICE's information for patients ('Understanding NICE guidance') is recommended.\n\nAudit and review clinical outcomes of all patients having image-guided RF excision biopsy of breast lesions (see section 3.1).\n\nNICE encourages further research into image-guided RF excision biopsy of breast lesions. Research should be in the form of diagnostic studies aimed at quantifying the risk of false-negative results associated with the procedure. NICE may review the procedure on publication of further evidence.", 'The procedure': "# Indications and current treatments\n\nBreast abnormalities may be benign or malignant. Diagnosis is based on clinical findings, imaging and tissue sampling. Tissue sampling is usually by fine needle aspiration for cytology, or by needle core biopsy for histology. Histology allows for differentiation between benign tumours such as fibroadenomas (typically between 1 cm and 3 cm in size), and others such as non-invasive ductal carcinoma in situ (DCIS) and invasive ductal carcinoma (IDC). Open surgical biopsy or image-guided vacuum-assisted core biopsy may also be used to establish tumour type and grade.\n\nBreast cancer is the most common cancer in women in the UK. If cancer is diagnosed, treatment depends on the type, stage and grade of the tumour.\n\nIn general terms, the more tissue retrieved with multiple core samples or larger tissue samples, the more accurate the diagnosis is likely to be. With this procedure, the whole lesion can be removed.\n\n# Outline of the procedure\n\nImage-guided RF excision biopsy of breast lesions aims to achieve minimally invasive retrieval of an intact specimen for histological examination, while minimising the risk of bleeding and haematoma formation. This procedure is not indicated currently for the therapeutic removal of known cancers unless there are no surgical options.\n\nThe procedure is carried out with the patient under local anaesthesia. Using image guidance, a small incision is made in the breast. A probe with a unipolar RF cutting tip is advanced to the site of the lesion. Small wires and capturing arms are extended from the tip of the probe to surround the lesion, which is then dissected using the RF cutting tip. The sample is captured in the arms of the device and withdrawn.\n\nProbes of various diameters and expandable RF cutting tips can be used, depending on the diameter of the sample to be captured.\n\nSections 2.3 and 2.4 describe efficacy and safety outcomes from the published literature that the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview.\n\n# Efficacy\n\nIn a case series of 742 breast lesions (absolute number of patients not reported), 34 lesions were initially identified as atypical ductal hyperplasia (benign lesions) after RF excision biopsy. Following subsequent surgery and histological examination 9% (3/34) of these results were false negatives; the lesions were subsequently diagnosed as either DCIS or IDC. Similarly, 5% (6/119) of lesions initially diagnosed as DCIS following RF excision biopsy were subsequently diagnosed as IDC after surgical excision and biopsy.\n\nIn a case series of 100 patients (106 lesions) with breast lesions diagnosed as fibroadenomas based on imaging findings, who were subsequently managed by RF excision biopsy, 93% (79/85) of patients showed no physical or imaging evidence of residual lesions at follow-ups of between 4 and 6 months.\n\nThe Specialist Advisers listed key efficacy outcomes for this procedure, when used for benign lesions, as intact removal of the lesion and patient acceptability/cosmetic appearance. The Specialist Advisers listed additional efficacy outcomes, when used in early breast cancer, as delivery of an evaluable lesion for histology, and both local recurrence and survival.\n\n# Safety\n\nThe case series of 742 lesions (absolute number of patients not stated) reported that infection (not otherwise defined) occurred in less than 1% (1/742) of biopsies (resolved with oral antibiotics) (follow-up not stated). The case series of 100 patients (106 lesions) recorded a mean pain score during the procedure of less than 1 point (using a visual analogue scale from 0 [no pain] to 10 [severe pain]).\n\nIn the case series of 100 patients (106 lesions), bleeding occurred in 2% (2/106) of excision procedures but this was controlled by 'conservative measures' (not otherwise defined).\n\nThe Specialist Advisers listed adverse events reported in the literature as haematoma, infection, skin burns and failure to deliver an adequate sample. They considered theoretical adverse events to include seeding of tumour cells along the biopsy tract, haemorrhage, pain (temporary) and fat necrosis due to thermal damage.", 'Further information': "This guidance requires that clinicians undertaking the procedure make special arrangements for audit. NICE has identified relevant audit criteria and has developed audit support (which is for use at local discretion).\n\nFor related NICE guidance see our website.\n\n# Information for patients\n\nNICE has produced information on this procedure for patients and carers ('Understanding NICE guidance'). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.", 'About this guidance': 'NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland.\n\nThis guidance was developed using the NICE interventional procedure guidance process.\n\nIt has been incorporated into the NICE pathway on early and locally advanced breast cancer, along with other related guidance and products.\n\nWe have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available.\n\nChanges since publication\n\nJanuary 2012: minor maintenance.\n\nYour responsibility\n\nThis guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.\n\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.\n\nCopyright\n\n© National Institute for Health and Clinical Excellence 2009. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.\n\nContact NICE\n\nNational Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT\n\nwww.nice.org.uk\n \n nice@nice.org.uk\n 0845 033 7780'}	https://www.nice.org.uk/guidance/ipg308
c3221e7550ab9e6426982fc59eb5bdbf66d859d6	nice	Percutaneous endoscopic laser cervical discectomy	Percutaneous endoscopic laser cervical discectomy # Guidance Current evidence on the safety and efficacy of percutaneous endoscopic laser cervical discectomy is inadequate in quantity and quality. Therefore this procedure should only be used with special arrangements for clinical governance, consent, and audit or research. Clinicians wishing to undertake percutaneous endoscopic laser cervical discectomy should take the following actions. Inform the clinical governance leads in their Trusts. Ensure that patients and their carers understand the uncertainty about the procedure's safety and efficacy and provide them with clear written information. In addition, the use of NICE's information for patients ('Understanding NICE guidance') is recommended. Audit and review clinical outcomes of all patients having percutaneous endoscopic laser cervical discectomy (see section 3.1). Clinicians undertaking this procedure should have specific training in the use of lasers and in endoscopy of the spinal canal. NICE may review the procedure on publication of further evidence.# The procedure # Indications and current treatments Symptomatic cervical disc prolapse occurs when part of the intervertebral disc protrudes into the spinal canal and impinges on a nerve root or the spinal cord. The protruding disc may compress one or more nerve roots, which may cause neck and shoulder pain, radicular arm pain, weakness and numbness. Many mild episodes settle spontaneously but, in severe cases, serious neurological sequelae may occur. Conservative treatments include analgesics and non-steroidal anti-inflammatory medication and physical therapy. Epidural steroid injections can also be used. Surgery to remove disc material is considered if there is evidence of nerve or spinal cord compression causing neurological loss or persistent symptoms that are unresponsive to conservative treatment. Surgical treatment options include open surgical decompression by discectomy with or without grafting or disc replacement. # Outline of the procedure The procedure is carried out with the patient under general anaesthesia and with endoscopic guidance. A small retractor port is inserted into the anterior neck to expose the disc. All or part of the disc material is removed using a combination of laser to ablate disc material and to shrink and contract the disc further (laser thermodiskoplasty), and curettes, microforceps and a discotome to decompress the nerve root or spinal cord. Sections 2.3 and 2.4 describe efficacy and safety outcomes which were available in the published literature and which the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview. # Efficacy A case series of 111 patients treated by percutaneous endoscopic laser cervical discectomy reported that 47% (52/111) of patients were classified as having an 'excellent' outcome, 33% (37/111) had a 'good' outcome, 8% (9/111) had a 'fair' outcome and 12% (13/111) had a 'poor' outcome (measured by the McNab criteria four-point scale, which ranges from poor to excellent ) (mean follow-up 49 months). The Specialist Advisers listed the key efficacy outcomes as pain measured by visual analogue scores for arm and neck pain, disability as measured by the Neck Disability Index, or Oswestry Disability Index and health status as measured by the SF36. # Safety The case series of 111 patients treated by percutaneous endoscopic laser cervical discectomy reported that 3% (3/111) of patients needed additional surgery because of incomplete decompression and 'symptom aggravation' (mean follow-up 49 months). A case series of 41 patients treated by percutaneous endoscopic laser cervical discectomy reported that vessel compromise because of guide wire positioning occurred in 5% (2/41) of patients; this was related to a jugular vein and a carotid artery (follow-up not stated). Discitis developed in 2% (1/41) of patients, leading to disc space collapse, and was treated by vertebral bone fusion (follow-up not stated). The Specialist Advisers considered the most important theoretical risk to be heat damage to nerve roots or to the spinal cord, potentially leading to quadriplegia. One Specialist Adviser stated that neurological damage had occurred in a patient as a result of using laser in the lumbar region of the spine. # Other comments The Committee noted that the extent to which laser ablation was used instead of, or in addition to, mechanical methods of removing prolapsed disc material was unclear in much of the published evidence.# Further information This guidance requires that clinicians undertaking the procedure make special arrangements for audit. NICE has identified relevant audit criteria and developed audit support (which is for use at local discretion). NICE has published interventional procedures guidance on prosthetic intervertebral disc replacement in the cervical spine. # Information for patients NICE has produced information on this procedure for patients and carers ('Understanding NICE guidance'). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.# Other NICE recommendations on percutaneous endoscopic laser discectomy The National Institute for Health and Clinical Excellence (NICE) issued full guidance to the NHS in England, Wales, Scotland and Northern Ireland on percutaneous endoscopic laser thoracic discectomy in June 2004. It was considered for review as part of the Institute's work programme. Although it did not meet the criteria to be re-assessed, percutaneous endoscopic laser cervical discectomy and percutaneous endoscopic laser lumbar discectomy were identified for consideration.# About this guidance NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland. This guidance was developed using the NICE interventional procedure guidance process. We have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available. Changes since publication January 2012: minor maintenance. Your responsibility This guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer. Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties. Copyright © National Institute for Health and Clinical Excellence 2009. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE. Contact NICE National Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT www.nice.org.uk nice@nice.org.uk	{'Guidance ': "Current evidence on the safety and efficacy of percutaneous endoscopic laser cervical discectomy is inadequate in quantity and quality. Therefore this procedure should only be used with special arrangements for clinical governance, consent, and audit or research.\n\nClinicians wishing to undertake percutaneous endoscopic laser cervical discectomy should take the following actions.\n\nInform the clinical governance leads in their Trusts.\n\nEnsure that patients and their carers understand the uncertainty about the procedure's safety and efficacy and provide them with clear written information. In addition, the use of NICE's information for patients ('Understanding NICE guidance') is recommended.\n\nAudit and review clinical outcomes of all patients having percutaneous endoscopic laser cervical discectomy (see section 3.1).\n\nClinicians undertaking this procedure should have specific training in the use of lasers and in endoscopy of the spinal canal.\n\nNICE may review the procedure on publication of further evidence.", 'The procedure': "# Indications and current treatments\n\nSymptomatic cervical disc prolapse occurs when part of the intervertebral disc protrudes into the spinal canal and impinges on a nerve root or the spinal cord. The protruding disc may compress one or more nerve roots, which may cause neck and shoulder pain, radicular arm pain, weakness and numbness. Many mild episodes settle spontaneously but, in severe cases, serious neurological sequelae may occur.\n\nConservative treatments include analgesics and non-steroidal anti-inflammatory medication and physical therapy. Epidural steroid injections can also be used. Surgery to remove disc material is considered if there is evidence of nerve or spinal cord compression causing neurological loss or persistent symptoms that are unresponsive to conservative treatment. Surgical treatment options include open surgical decompression by discectomy with or without grafting or disc replacement.\n\n# Outline of the procedure\n\nThe procedure is carried out with the patient under general anaesthesia and with endoscopic guidance. A small retractor port is inserted into the anterior neck to expose the disc. All or part of the disc material is removed using a combination of laser to ablate disc material and to shrink and contract the disc further (laser thermodiskoplasty), and curettes, microforceps and a discotome to decompress the nerve root or spinal cord.\n\nSections 2.3 and 2.4 describe efficacy and safety outcomes which were available in the published literature and which the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview.\n\n# Efficacy\n\nA case series of 111 patients treated by percutaneous endoscopic laser cervical discectomy reported that 47% (52/111) of patients were classified as having an 'excellent' outcome, 33% (37/111) had a 'good' outcome, 8% (9/111) had a 'fair' outcome and 12% (13/111) had a 'poor' outcome (measured by the McNab criteria four-point scale, which ranges from poor [no or insufficient improvement to enable an increase in activities] to excellent [no pain or restriction of activity]) (mean follow-up 49 months).\n\nThe Specialist Advisers listed the key efficacy outcomes as pain measured by visual analogue scores for arm and neck pain, disability as measured by the Neck Disability Index, or Oswestry Disability Index and health status as measured by the SF36.\n\n# Safety\n\nThe case series of 111 patients treated by percutaneous endoscopic laser cervical discectomy reported that 3% (3/111) of patients needed additional surgery because of incomplete decompression and 'symptom aggravation' (mean follow-up 49 months).\n\nA case series of 41 patients treated by percutaneous endoscopic laser cervical discectomy reported that vessel compromise because of guide wire positioning occurred in 5% (2/41) of patients; this was related to a jugular vein and a carotid artery (follow-up not stated). Discitis developed in 2% (1/41) of patients, leading to disc space collapse, and was treated by vertebral bone fusion (follow-up not stated).\n\nThe Specialist Advisers considered the most important theoretical risk to be heat damage to nerve roots or to the spinal cord, potentially leading to quadriplegia. One Specialist Adviser stated that neurological damage had occurred in a patient as a result of using laser in the lumbar region of the spine.\n\n# Other comments\n\nThe Committee noted that the extent to which laser ablation was used instead of, or in addition to, mechanical methods of removing prolapsed disc material was unclear in much of the published evidence.", 'Further information': "This guidance requires that clinicians undertaking the procedure make special arrangements for audit. NICE has identified relevant audit criteria and developed audit support (which is for use at local discretion).\n\nNICE has published interventional procedures guidance on prosthetic intervertebral disc replacement in the cervical spine.\n\n# Information for patients\n\nNICE has produced information on this procedure for patients and carers ('Understanding NICE guidance'). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.", 'Other NICE recommendations on percutaneous endoscopic laser discectomy': "The National Institute for Health and Clinical Excellence (NICE) issued full guidance to the NHS in England, Wales, Scotland and Northern Ireland on percutaneous endoscopic laser thoracic discectomy in June 2004. It was considered for review as part of the Institute's work programme. Although it did not meet the criteria to be re-assessed, percutaneous endoscopic laser cervical discectomy and percutaneous endoscopic laser lumbar discectomy were identified for consideration.", 'About this guidance': 'NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland.\n\nThis guidance was developed using the NICE interventional procedure guidance process.\n\nWe have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available.\n\nChanges since publication\n\nJanuary 2012: minor maintenance.\n\nYour responsibility\n\nThis guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.\n\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.\n\nCopyright\n\n© National Institute for Health and Clinical Excellence 2009. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.\n\nContact NICE\n\nNational Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT\n\nwww.nice.org.uk\n \n nice@nice.org.uk\n 0845 033 7780'}	https://www.nice.org.uk/guidance/ipg303
91e4d7c5db06a75324c55c908103f19e7e6906d0	nice	Corneal endothelial transplantation	Corneal endothelial transplantation # Guidance Current evidence on the safety and efficacy of corneal endothelial transplantation (also known as endothelial keratoplasty ) is adequate to support the use of this procedure provided that normal arrangements are in place for clinical governance and consent. NHS Blood and Transplant (formerly UK Transplant) runs a corneal transplant register, and clinicians should submit details about all patients undergoing corneal endothelial transplantation to this register. The procedure should only be carried out by surgeons with specific training in this technique. NICE encourages publication of long-term outcomes from register or research data.# The procedure # Indications and current treatments The corneal endothelium is a single layer of cells comprising the cornea's innermost layer. It helps maintain corneal transparency by removing excess fluid. Endothelial dysfunction leads to corneal clouding, resulting in visual impairment. Common causes of corneal endothelial dysfunction are Fuchs' dystrophy (a genetic disorder) and degeneration (bullous keratopathy). Other causes are trauma, infection and iatrogenic damage. Current surgical treatment for corneal endothelial disease is penetrating keratoplasty (PK) (whole cornea transplantation), which requires multiple sutures to anchor the donor cornea in the recipient eye. # Outline of the procedure Corneal endothelial transplantation uses a range of techniques to replace diseased corneal endothelium with a cadaveric donor endothelial graft, while retaining healthy portions of the patient's cornea. It may be performed under local or general anaesthesia. A scleral incision is made and an anterior chamber tunnel created. The diseased endothelium is dissected from the cornea and donor endothelial graft inserted through the scleral incision and placed against the posterior aspect of the host cornea. Topical and/or systemic antibiotics, steroids and immunosuppressants are often prescribed after surgery. Sections 2.3 and 2.4 describe efficacy and safety outcomes which were available in the published literature and which the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview. # Efficacy A randomised controlled trial (RCT) of 28 eyes reported significant improvement in mean uncorrected visual acuity (UCVA) in 13 EK-treated eyes, from 0.81 (standard deviation 0.19) to 0.60 (SD 0.20) at 6-month follow-up (p = 0.01). In 15 PK-treated eyes, no significant UCVA improvement from baseline was reported at 6-month follow-up (0.94 to 0.87 ) (significance not stated). A non-randomised comparative study of 177 eyes (129 EK-treated) reported significantly better UCVA after EK than after PK at 15-month follow-up (p = 0.05), without significant difference in contrast sensitivity between the groups (median follow-up 12 months). The non-randomised comparative study of 177 eyes reported that the astigmatism incidence was significantly lower after EK than after PK (p < 0.0001) (mean follow-up 15 months). A registry reported significantly different 1-year graft survival rates of 77% (95% confidence interval 63 to 86) and 98% (95% CI 91 to 99) among 75 EK- and 88 PK-treated patients with Fuchs' dystrophy, respectively (p = 0.0002). Significantly different 1-year graft survival rates of 79% (95% CI 65 to 88) and 88% (95% CI 75 to 94) were reported among 55 and 76 EK- and PK-treated patients with pseudophakic bullous keratopathy, respectively (p = 0.04). Specialist Advisers listed key efficacy outcomes as UCVA, visual rehabilitation speed, and quality of life measures such as the Visual Function Index (VF-14) score. # Safety Two case series and an RCT of 100, 118 and 28 eyes (13 EK-treated) reported PK conversion in 2% (2/100), 9% (11/118) and 19% (3/16) of procedures planned as EK. The studies of 100, 118 and 28 eyes reported need for repeat EK in 2% (2/98), 8% (10/118) and 8% (1/13) of eyes. A non-randomised comparative study of 907 eyes (199 EK-treated) reported significantly lower graft rejection rates for EK (8% ) than for PK (13% ) at 2-year follow-up (p = 0.04). The non-randomised comparative study of 907 eyes also reported that graft failure after rejection was lower for EK (7% ) than for PK (28% ) (p = 0.063). A non-randomised comparative study of 177 eyes (129 EK-treated) reported no significant difference between EK and PK in graft rejection (p = 0.78) or primary graft failure (p = 0.91) rates (mean follow-up 15 months). The non-randomised comparative study of 177 eyes reported that graft dislocation was significantly more common after EK than after PK (p = 0.0004). In a case series of 263 EK-treated eyes, cumulative endothelial cell loss (not otherwise defined) in a subset of 34 eyes with 2-year follow-up was 34% at 6 months, 36% at 12 months, and 41% at 24 months. A case series of 118 EK-treated eyes (41 with concomitant cataract surgery) reported retinal detachment in 4% (5/118) of patients (sequelae and follow-up not described). The Specialist Advisers listed adverse events reported in the literature or anecdotally as graft dislocation, graft failure and rejection, interface opacification, and loss of BSCVA (best spectacle-corrected visual acuity). # Other comments The Committee noted that UK Transplant Register data show lower graft survival rates after EK than after PK. The difference in graft survival between the two procedures is narrowing with increased experience in EK use. Endothelial keratoplasty can be repeated, while PK revision is more difficult. The Committee therefore felt that the current evidence on efficacy of the procedure was adequate, provided that thorough data collection continues, to allow future review of outcomes. The Committee noted that the techniques for this procedure continue to evolve. Anterior eye procedures are classified as having a medium risk of Creutzfeldt-Jakob disease (CJD) transmission.# Further information NICE has published interventional procedures guidance on patient safety and reduction of risk of transmission of CJD via interventional procedures. # Information for patients NICE has produced information on this procedure for patients and carers ('Understanding NICE guidance'). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind. A large print version is also available.# About this guidance NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland. This guidance was developed using the NICE interventional procedure guidance process. We have produced a summary of this guidance for patients and carers. Information about the evidence it is based on is also available. Changes since publication January 2012: minor maintenance. Your responsibility This guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer. Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties. Copyright © National Institute for Health and Clinical Excellence 2009. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE. Contact NICE National Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT www.nice.org.uk nice@nice.org.uk	{'Guidance ': 'Current evidence on the safety and efficacy of corneal endothelial transplantation (also known as endothelial keratoplasty [EK]) is adequate to support the use of this procedure provided that normal arrangements are in place for clinical governance and consent.\n\nNHS Blood and Transplant (formerly UK Transplant) runs a corneal transplant register, and clinicians should submit details about all patients undergoing corneal endothelial transplantation to this register.\n\nThe procedure should only be carried out by surgeons with specific training in this technique.\n\nNICE encourages publication of long-term outcomes from register or research data.', 'The procedure': "# Indications and current treatments\n\nThe corneal endothelium is a single layer of cells comprising the cornea's innermost layer. It helps maintain corneal transparency by removing excess fluid. Endothelial dysfunction leads to corneal clouding, resulting in visual impairment. Common causes of corneal endothelial dysfunction are Fuchs' dystrophy (a genetic disorder) and degeneration (bullous keratopathy). Other causes are trauma, infection and iatrogenic damage.\n\nCurrent surgical treatment for corneal endothelial disease is penetrating keratoplasty (PK) (whole cornea transplantation), which requires multiple sutures to anchor the donor cornea in the recipient eye.\n\n# Outline of the procedure\n\nCorneal endothelial transplantation uses a range of techniques to replace diseased corneal endothelium with a cadaveric donor endothelial graft, while retaining healthy portions of the patient's cornea. It may be performed under local or general anaesthesia. A scleral incision is made and an anterior chamber tunnel created. The diseased endothelium is dissected from the cornea and donor endothelial graft inserted through the scleral incision and placed against the posterior aspect of the host cornea.\n\nTopical and/or systemic antibiotics, steroids and immunosuppressants are often prescribed after surgery.\n\nSections 2.3 and 2.4 describe efficacy and safety outcomes which were available in the published literature and which the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview.\n\n# Efficacy\n\nA randomised controlled trial (RCT) of 28 eyes reported significant improvement in mean uncorrected visual acuity (UCVA) in 13 EK-treated eyes, from 0.81 (standard deviation [SD] 0.19) to 0.60 (SD 0.20) at 6-month follow-up (p = 0.01). In 15 PK-treated eyes, no significant UCVA improvement from baseline was reported at 6-month follow-up (0.94 [SD 0.38] to 0.87 [SD 0.30]) (significance not stated). A non-randomised comparative study of 177 eyes (129 EK-treated) reported significantly better UCVA after EK than after PK at 15-month follow-up (p = 0.05), without significant difference in contrast sensitivity between the groups (median follow-up 12 months).\n\nThe non-randomised comparative study of 177 eyes reported that the astigmatism incidence was significantly lower after EK than after PK (p < 0.0001) (mean follow-up 15 months).\n\nA registry reported significantly different 1-year graft survival rates of 77% (95% confidence interval [CI] 63 to 86) and 98% (95% CI 91 to 99) among 75 EK- and 88 PK-treated patients with Fuchs' dystrophy, respectively (p = 0.0002). Significantly different 1-year graft survival rates of 79% (95% CI 65 to 88) and 88% (95% CI 75 to 94) were reported among 55 and 76 EK- and PK-treated patients with pseudophakic bullous keratopathy, respectively (p = 0.04).\n\nSpecialist Advisers listed key efficacy outcomes as UCVA, visual rehabilitation speed, and quality of life measures such as the Visual Function Index (VF-14) score.\n\n# Safety\n\nTwo case series and an RCT of 100, 118 and 28 eyes (13 EK-treated) reported PK conversion in 2% (2/100), 9% (11/118) and 19% (3/16) of procedures planned as EK.\n\nThe studies of 100, 118 and 28 eyes reported need for repeat EK in 2% (2/98), 8% (10/118) and 8% (1/13) of eyes.\n\nA non-randomised comparative study of 907 eyes (199 EK-treated) reported significantly lower graft rejection rates for EK (8% [15/199]) than for PK (13% [92/708]) at 2-year follow-up (p = 0.04). The non-randomised comparative study of 907 eyes also reported that graft failure after rejection was lower for EK (7% [1/15]) than for PK (28% [26/92]) (p = 0.063). A non-randomised comparative study of 177 eyes (129 EK-treated) reported no significant difference between EK and PK in graft rejection (p = 0.78) or primary graft failure (p = 0.91) rates (mean follow-up 15 months).\n\nThe non-randomised comparative study of 177 eyes reported that graft dislocation was significantly more common after EK than after PK (p = 0.0004).\n\nIn a case series of 263 EK-treated eyes, cumulative endothelial cell loss (not otherwise defined) in a subset of 34 eyes with 2-year follow-up was 34% at 6 months, 36% at 12 months, and 41% at 24 months.\n\nA case series of 118 EK-treated eyes (41 with concomitant cataract surgery) reported retinal detachment in 4% (5/118) of patients (sequelae and follow-up not described).\n\nThe Specialist Advisers listed adverse events reported in the literature or anecdotally as graft dislocation, graft failure and rejection, interface opacification, and loss of BSCVA (best spectacle-corrected visual acuity).\n\n# Other comments\n\nThe Committee noted that UK Transplant Register data show lower graft survival rates after EK than after PK. The difference in graft survival between the two procedures is narrowing with increased experience in EK use. Endothelial keratoplasty can be repeated, while PK revision is more difficult. The Committee therefore felt that the current evidence on efficacy of the procedure was adequate, provided that thorough data collection continues, to allow future review of outcomes.\n\nThe Committee noted that the techniques for this procedure continue to evolve.\n\nAnterior eye procedures are classified as having a medium risk of Creutzfeldt-Jakob disease (CJD) transmission.", 'Further information': "NICE has published interventional procedures guidance on patient safety and reduction of risk of transmission of CJD via interventional procedures.\n\n# Information for patients\n\nNICE has produced information on this procedure for patients and carers ('Understanding NICE guidance'). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.\n\nA large print version is also available.", 'About this guidance': 'NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland.\n\nThis guidance was developed using the NICE interventional procedure guidance process.\n\nWe have produced a summary of this guidance for patients and carers. Information about the evidence it is based on is also available.\n\nChanges since publication\n\nJanuary 2012: minor maintenance.\n\nYour responsibility\n\nThis guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.\n\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.\n\nCopyright\n\n© National Institute for Health and Clinical Excellence 2009. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.\n\nContact NICE\n\nNational Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT\n\nwww.nice.org.uk\n \n nice@nice.org.uk\n 0845 033 7780'}	https://www.nice.org.uk/guidance/ipg304
a4496420e814c2ca153005a2b6a2157f4667c40a	nice	Tenotomy of horizontal eye muscles for nystagmus (with reattachment at their original insertions)	Tenotomy of horizontal eye muscles for nystagmus (with reattachment at their original insertions) # Guidance The evidence on tenotomy of horizontal eye muscles for nystagmus (with reattachment at their original insertions) raises no major safety concerns, but current evidence on its efficacy is inadequate in quantity. Therefore, this procedure should only be used with special arrangements for clinical governance, consent, and audit or research. Clinicians wishing to undertake tenotomy of horizontal eye muscles for nystagmus (with reattachment at their original insertions) should take the following actions. Inform the clinical governance leads in their Trusts. Ensure that patients and their carers understand the uncertainty about the procedure's safety and efficacy and provide them with clear written information. In addition, the use of NICE's information for patients ('Understanding NICE guidance') is recommended. Audit and review clinical outcomes of all patients having tenotomy of horizontal eye muscles for nystagmus (with reattachment at their original insertions) (see section 3.1). Patient selection and follow-up should take place in specialist units with experience in the management of ocular motility disorders. NICE encourages further collaborative data collection, including information on visual acuity and quality of life, and may review the procedure on publication of further evidence.# The procedure # Indications and current treatments Nystagmus is an involuntary oscillatory movement of the eyes, usually from side to side, but sometimes the eyes move up and down or in a circular motion. Most people with nystagmus have impaired vision. There are several types of nystagmus but there is no definitive classification system to describe them. Nystagmus may be present at birth, caused by defects in the eye or the visual pathway from the eye to the brain. It can occur in a wide range of childhood eye disorders and may be found in children with multiple disabilities. Nystagmus can also develop later in life as a symptom of a variety of conditions, including stroke, multiple sclerosis or head injury. There is currently no curative treatment for nystagmus. Spectacles or contact lenses may be worn to improve visual acuity but they do not correct the nystagmus. # Outline of the procedure Tenotomy for nystagmus is carried out with the patient under general anaesthesia, and involves division of the attachments of the two horizontal rectus muscles (lateral and medial) of each eye. A limbal incision is made in the conjunctiva and each muscle is detached from the sclera. The muscles are then reattached at their original places of insertion. The aims of the procedure are to reduce the frequency and amplitude of nystagmus (how often and how far the eyes oscillate) and to improve visual acuity. The exact mechanism by which this procedure might improve nystagmus is unknown. Sections 2.3 and 2.4 describe efficacy and safety outcomes which were available in the published literature and which the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview. # Efficacy In a case series of ten adults treated with tenotomy, nine patients had increased and one patient had decreased expanded Nystagmus Acuity Function (NAFX) scores at 1 year (this score is an objective measure used to predict visual acuity on the basis of the patient's foveation period, defined as their ability to fix an image on the fovea, the most visually precise part of the retina). A case series of nine patients with infantile nystagmus reported that eight patients had increased NAFX scores (mean 60%) at 1 year. The NAFX score remained unchanged in one patient at 1 year. All nine patients had reduced nystagmus amplitude (mean 33%) and increased foveation period (mean 104%) at 1 year. In a case series of five patients with infantile nystagmus, two were assessed for eye movement. The NAFX scores improved by 8% in one child at 1 year and by 36% in the other child at 6 months. Two case series of five children and ten adults reported improvements in best-corrected visual acuity of at least five letters on the Early Treatment Diabetic Retinopathy Study chart (corresponding to a one-line improvement on the Snellen chart) in four and five patients, respectively (assessed at 6 weeks and 12 months, respectively). The case series of nine patients reported that three patients had an improvement in visual acuity of at least one line, three had an improvement of a few letters and three had no change (method of assessment and follow-up was not described). In a case series of five patients, all patients had a reduced time to target acquisition (measured by infrared reflection or high-speed digital video) 1 year after the procedure (precise reduction not stated). The Specialist Advisers considered efficacy outcomes to include best-corrected binocular visual acuity under varying gaze angles, null point width, stereoacuity, ocular movement recordings, nystagmus, visual function in day-to-day life, quality of life, cosmesis and head posture. # Safety No adverse events were reported in the literature. The Specialist Advisers considered theoretical adverse events to include damage to the retina or perforation of the globe, infection and misalignment of muscles causing redness, swelling, diplopia, induced strabismus and possible loss of vision. Revision surgery may be needed to correct these adverse outcomes. One Specialist Adviser stated that development of a conjunctival cyst had been reported in the literature.# Further information This guidance requires that clinicians undertaking the procedure make special arrangements for audit. NICE has identified relevant audit criteria and has developed audit support (which is for use at local discretion). # Information for patients NICE has produced information on this procedure for patients and carers ('Understanding NICE guidance'). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind. A large print version is also available.# About this guidance NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland. This guidance was developed using the NICE interventional procedure guidance process. We have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available. Changes since publication January 2012: minor maintenance. Your responsibility This guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer. Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties. Copyright © National Institute for Health and Clinical Excellence 2009. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE. Contact NICE National Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT www.nice.org.uk nice@nice.org.uk	{'Guidance ': "The evidence on tenotomy of horizontal eye muscles for nystagmus (with reattachment at their original insertions) raises no major safety concerns, but current evidence on its efficacy is inadequate in quantity. Therefore, this procedure should only be used with special arrangements for clinical governance, consent, and audit or research.\n\nClinicians wishing to undertake tenotomy of horizontal eye muscles for nystagmus (with reattachment at their original insertions) should take the following actions.\n\nInform the clinical governance leads in their Trusts.\n\nEnsure that patients and their carers understand the uncertainty about the procedure's safety and efficacy and provide them with clear written information. In addition, the use of NICE's information for patients ('Understanding NICE guidance') is recommended.\n\nAudit and review clinical outcomes of all patients having tenotomy of horizontal eye muscles for nystagmus (with reattachment at their original insertions) (see section 3.1).\n\nPatient selection and follow-up should take place in specialist units with experience in the management of ocular motility disorders.\n\nNICE encourages further collaborative data collection, including information on visual acuity and quality of life, and may review the procedure on publication of further evidence.", 'The procedure': "# Indications and current treatments\n\nNystagmus is an involuntary oscillatory movement of the eyes, usually from side to side, but sometimes the eyes move up and down or in a circular motion. Most people with nystagmus have impaired vision.\n\nThere are several types of nystagmus but there is no definitive classification system to describe them. Nystagmus may be present at birth, caused by defects in the eye or the visual pathway from the eye to the brain. It can occur in a wide range of childhood eye disorders and may be found in children with multiple disabilities. Nystagmus can also develop later in life as a symptom of a variety of conditions, including stroke, multiple sclerosis or head injury.\n\nThere is currently no curative treatment for nystagmus. Spectacles or contact lenses may be worn to improve visual acuity but they do not correct the nystagmus.\n\n# Outline of the procedure\n\nTenotomy for nystagmus is carried out with the patient under general anaesthesia, and involves division of the attachments of the two horizontal rectus muscles (lateral and medial) of each eye. A limbal incision is made in the conjunctiva and each muscle is detached from the sclera. The muscles are then reattached at their original places of insertion.\n\nThe aims of the procedure are to reduce the frequency and amplitude of nystagmus (how often and how far the eyes oscillate) and to improve visual acuity. The exact mechanism by which this procedure might improve nystagmus is unknown.\n\nSections 2.3 and 2.4 describe efficacy and safety outcomes which were available in the published literature and which the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview.\n\n# Efficacy\n\nIn a case series of ten adults treated with tenotomy, nine patients had increased and one patient had decreased expanded Nystagmus Acuity Function (NAFX) scores at 1 year (this score is an objective measure used to predict visual acuity on the basis of the patient's foveation period, defined as their ability to fix an image on the fovea, the most visually precise part of the retina). A case series of nine patients with infantile nystagmus reported that eight patients had increased NAFX scores (mean 60%) at 1 year. The NAFX score remained unchanged in one patient at 1 year. All nine patients had reduced nystagmus amplitude (mean 33%) and increased foveation period (mean 104%) at 1 year. In a case series of five patients with infantile nystagmus, two were assessed for eye movement. The NAFX scores improved by 8% in one child at 1 year and by 36% in the other child at 6 months.\n\nTwo case series of five children and ten adults reported improvements in best-corrected visual acuity of at least five letters on the Early Treatment Diabetic Retinopathy Study chart (corresponding to a one-line improvement on the Snellen chart) in four and five patients, respectively (assessed at 6 weeks and 12 months, respectively). The case series of nine patients reported that three patients had an improvement in visual acuity of at least one line, three had an improvement of a few letters and three had no change (method of assessment and follow-up was not described).\n\nIn a case series of five patients, all patients had a reduced time to target acquisition (measured by infrared reflection or high-speed digital video) 1 year after the procedure (precise reduction not stated).\n\nThe Specialist Advisers considered efficacy outcomes to include best-corrected binocular visual acuity under varying gaze angles, null point width, stereoacuity, ocular movement recordings, nystagmus, visual function in day-to-day life, quality of life, cosmesis and head posture.\n\n# Safety\n\nNo adverse events were reported in the literature.\n\nThe Specialist Advisers considered theoretical adverse events to include damage to the retina or perforation of the globe, infection and misalignment of muscles causing redness, swelling, diplopia, induced strabismus and possible loss of vision. Revision surgery may be needed to correct these adverse outcomes. One Specialist Adviser stated that development of a conjunctival cyst had been reported in the literature.", 'Further information': "This guidance requires that clinicians undertaking the procedure make special arrangements for audit. NICE has identified relevant audit criteria and has developed audit support (which is for use at local discretion).\n\n# Information for patients\n\nNICE has produced information on this procedure for patients and carers ('Understanding NICE guidance'). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.\n\nA large print version is also available.", 'About this guidance': 'NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland.\n\nThis guidance was developed using the NICE interventional procedure guidance process.\n\nWe have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available.\n\nChanges since publication\n\nJanuary 2012: minor maintenance.\n\nYour responsibility\n\nThis guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.\n\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.\n\nCopyright\n\n© National Institute for Health and Clinical Excellence 2009. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.\n\nContact NICE\n\nNational Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT\n\nwww.nice.org.uk\n \n nice@nice.org.uk\n 0845 033 7780'}	https://www.nice.org.uk/guidance/ipg299
b5af5f1a0497f97d3ba59792fbbf729b2ed32a2e	nice	Transmyocardial laser revascularisation for refractory angina pectoris	Transmyocardial laser revascularisation for refractory angina pectoris # Guidance Current evidence on transmyocardial laser revascularisation (TMLR) for refractory angina pectoris shows no efficacy, based on objective measurements of myocardial function and survival. Current evidence on safety suggests that the procedure may pose unacceptable risks. Therefore, this procedure should not be used.# The procedure # Indications and current treatments Angina pectoris is chest discomfort, often described as pressure or pain, typically occurring on exertion. It is caused by inadequate delivery of oxygen to the heart muscle, usually because of coronary artery disease. Refractory angina is a severe angina form that cannot be controlled by normal medical or surgical treatment. Angina treatment depends on symptoms, medical history and angiography findings. Treatments include anti-anginal medication and revascularisation interventions (percutaneous coronary intervention or coronary artery bypass surgery). For patients with refractory angina, these treatments have either failed or are not clinically suitable. # Outline of the procedure Transmyocardial laser revascularisation for refractory angina pectoris is carried out with the patient under general anaesthesia. Ischaemic areas are selected for treatment using echocardiography or myocardial perfusion scan and coronary angiography before surgery. A left thoracotomy is performed and the pericardium opened. A laser device is then used to create a number of channels in the myocardium. Transoesophageal echocardiography confirms complete passage across the myocardial wall by the laser. A number of different types of laser can be used for this procedure. Sections 2.3 and 2.4 describe efficacy and safety outcomes which were available in the published literature and which the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview. # Efficacy A meta-analysis of ten randomised controlled trials (RCTs) (total 1359 patients) found no difference in 12-month mortality between TMLR-treated patients and controls (treated either medically or with coronary artery bypass grafting ) (odds ratio 0.89; 95% confidence interval 0.5 to 1.8). Nor was there any difference in mortality when studies comparing TMLR plus CABG against CABG alone were excluded (OR 0.8; 95% CI 0.5 to 1.2). An RCT of 100 patients treated either with TMLR or medically reported that myocardial contractility (assessed with stress echocardiography or single photon emission computed tomography ; lower value indicating worse function) was significantly lower in TMLR-treated patients (1.49 ± 0.44) than those treated medically (1.56 ± 0.47) at 12-month follow-up (p < 0.05). Six other RCTs found no significant difference in myocardial perfusion (examined with stress testing or perfusion scanning) in TMLR-treated patients, compared with patients treated medically. A meta-analysis of four RCTs (total 323 patients) reported greater mean improvement (from baseline) in total exercise time in TMLR-treated patients compared with those treated medically at 6-month follow-up (pooled mean difference 120.1 seconds; 95% CI 4.5 to 235.7). A meta-analysis of three studies (total 135 patients) reported an improvement from baseline in angina score (measured using four-point scales) in TMLR-treated patients compared with those treated medically, with a reduction in mean difference in angina score between TMLR and non-TMLR treatment groups of –1.8 (95% CI –2.4 to –1.1) at 6-month follow-up and –1.0 (95% CI –1.7 to –0.3) at 12-month follow-up. Five RCTs measured quality of life with different instruments. One RCT showed no significant difference between TMLR-treated patients and patients treated with thoracic sympathectomy, while the other four RCTs found significant improvements in quality of life for TMLR-treated patients compared with those treated medically (significance not stated). None of the studies had blinded patients to their treatment. Specialist Advisers listed key efficacy outcomes as angina severity reduction, exercise capacity improvement, reduced medicine use and increased quality of life. # Safety A meta-analysis of ten RCTs indicated no difference in postoperative mortality between TMLR-treated patients and controls treated medically or with CABG (pooled OR 0.78; 95% CI 0.34 to 1.7). However, when two trials comparing TMLR plus CABG against CABG alone were excluded, postoperative mortality was greater in TMLR-treated patients than controls (OR 0.35; 95% CI 0.13 to 0.93). In seven RCTs the subsequent myocardial infarction rate was higher in TMLR-treated patients than in controls (6% compared with 2% ; follow-up period 12 months; significance not stated). An RCT of 100 patients reported that postoperative heart failure occurred more frequently in TMLR-treated patients (34% ) than in medically treated patients (0% ) (significance not stated). An RCT of 182 patients reported that thromboembolic events occurred more frequently in TMLR-treated patients (10% ) than those treated medically (3% ) (significance and follow-up not stated). A case series of 169 TMLR-treated patients reported that 14% (23/169) developed acute non-inflammatory pericarditis following the procedure (sequelae not reported). In a case series of 20 TMLR-treated patients, acute mitral regurgitation was reported in 5% (1/20). An international multicentre case series of 932 patients reported cardiac tamponade in < 1% (5/932) of patients. A retrospective non-randomised controlled trial of 255 patients reported that neurological complications occurred more frequently after TMLR plus CABG (3% ) than after CABG alone (1% ) (significance and follow-up not stated). Specialist Advisers stated that adverse events reported in the literature included death, myocardial infarction, heart failure, arrhythmias, and wound and other infections. # Other comments The Committee noted that some studies showed improvements in symptoms and quality of life, but considered that these were likely to be placebo responses in the light of evidence that showed no objective benefits. The Committee considered evidence on TMLR alone for refractory angina pectoris, and also on TMLR performed concomitantly with CABG.# Further information NICE has published interventional procedures guidance on percutaneous laser revascularisation for refractory angina pectoris and technology appraisal guidance on myocardial perfusion scintigraphy for the diagnosis and management of angina and myocardial infarction. NICE is developing a clinical guideline on the management of stable angina . # Information for patients NICE has produced information on this procedure for patients and carers ('Understanding NICE guidance'). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.# About this guidance NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland. This guidance was developed using the NICE interventional procedure guidance process. We have produced a summary of this guidance for patients and carers. Information about the evidence it is based on is also available. Changes since publication January 2012: minor maintenance. Your responsibility This guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer. Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties. Copyright © National Institute for Health and Clinical Excellence 2009. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE. Contact NICE National Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT www.nice.org.uk nice@nice.org.uk	{'Guidance ': 'Current evidence on transmyocardial laser revascularisation (TMLR) for refractory angina pectoris shows no efficacy, based on objective measurements of myocardial function and survival. Current evidence on safety suggests that the procedure may pose unacceptable risks. Therefore, this procedure should not be used.', 'The procedure': '# Indications and current treatments\n\nAngina pectoris is chest discomfort, often described as pressure or pain, typically occurring on exertion. It is caused by inadequate delivery of oxygen to the heart muscle, usually because of coronary artery disease. Refractory angina is a severe angina form that cannot be controlled by normal medical or surgical treatment.\n\nAngina treatment depends on symptoms, medical history and angiography findings. Treatments include anti-anginal medication and revascularisation interventions (percutaneous coronary intervention or coronary artery bypass surgery). For patients with refractory angina, these treatments have either failed or are not clinically suitable.\n\n# Outline of the procedure\n\nTransmyocardial laser revascularisation for refractory angina pectoris is carried out with the patient under general anaesthesia. Ischaemic areas are selected for treatment using echocardiography or myocardial perfusion scan and coronary angiography before surgery. A left thoracotomy is performed and the pericardium opened. A laser device is then used to create a number of channels in the myocardium. Transoesophageal echocardiography confirms complete passage across the myocardial wall by the laser.\n\nA number of different types of laser can be used for this procedure.\n\nSections 2.3 and 2.4 describe efficacy and safety outcomes which were available in the published literature and which the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview.\n\n# Efficacy\n\nA meta-analysis of ten randomised controlled trials (RCTs) (total 1359 patients) found no difference in 12-month mortality between TMLR-treated patients and controls (treated either medically or with coronary artery bypass grafting [CABG]) (odds ratio [OR] 0.89; 95% confidence interval [CI] 0.5 to 1.8). Nor was there any difference in mortality when studies comparing TMLR plus CABG against CABG alone were excluded (OR 0.8; 95% CI 0.5 to 1.2).\n\nAn RCT of 100 patients treated either with TMLR or medically reported that myocardial contractility (assessed with stress echocardiography or single photon emission computed tomography [SPECT]; lower value indicating worse function) was significantly lower in TMLR-treated patients (1.49 ± 0.44) than those treated medically (1.56 ± 0.47) at 12-month follow-up (p < 0.05). Six other RCTs found no significant difference in myocardial perfusion (examined with stress testing or perfusion scanning) in TMLR-treated patients, compared with patients treated medically. A meta-analysis of four RCTs (total 323 patients) reported greater mean improvement (from baseline) in total exercise time in TMLR-treated patients compared with those treated medically at 6-month follow-up (pooled mean difference 120.1 seconds; 95% CI 4.5 to 235.7).\n\nA meta-analysis of three studies (total 135 patients) reported an improvement from baseline in angina score (measured using four-point scales) in TMLR-treated patients compared with those treated medically, with a reduction in mean difference in angina score between TMLR and non-TMLR treatment groups of –1.8 (95% CI –2.4 to –1.1) at 6-month follow-up and –1.0 (95% CI –1.7 to –0.3) at 12-month follow-up.\n\nFive RCTs measured quality of life with different instruments. One RCT showed no significant difference between TMLR-treated patients and patients treated with thoracic sympathectomy, while the other four RCTs found significant improvements in quality of life for TMLR-treated patients compared with those treated medically (significance not stated). None of the studies had blinded patients to their treatment.\n\nSpecialist Advisers listed key efficacy outcomes as angina severity reduction, exercise capacity improvement, reduced medicine use and increased quality of life.\n\n# Safety\n\nA meta-analysis of ten RCTs indicated no difference in postoperative mortality between TMLR-treated patients and controls treated medically or with CABG (pooled OR 0.78; 95% CI 0.34 to 1.7). However, when two trials comparing TMLR plus CABG against CABG alone were excluded, postoperative mortality was greater in TMLR-treated patients than controls (OR 0.35; 95% CI 0.13 to 0.93).\n\nIn seven RCTs the subsequent myocardial infarction rate was higher in TMLR-treated patients than in controls (6% [41/633] compared with 2% [11/651]; follow-up period 12 months; significance not stated).\n\nAn RCT of 100 patients reported that postoperative heart failure occurred more frequently in TMLR-treated patients (34% [17/50]) than in medically treated patients (0% [0/50]) (significance not stated). An RCT of 182 patients reported that thromboembolic events occurred more frequently in TMLR-treated patients (10% [9/92]) than those treated medically (3% [3/90]) (significance and follow-up not stated).\n\nA case series of 169 TMLR-treated patients reported that 14% (23/169) developed acute non-inflammatory pericarditis following the procedure (sequelae not reported). In a case series of 20 TMLR-treated patients, acute mitral regurgitation was reported in 5% (1/20). An international multicentre case series of 932 patients reported cardiac tamponade in < 1% (5/932) of patients.\n\nA retrospective non-randomised controlled trial of 255 patients reported that neurological complications occurred more frequently after TMLR plus CABG (3% [1/36]) than after CABG alone (1% [3/219]) (significance and follow-up not stated).\n\nSpecialist Advisers stated that adverse events reported in the literature included death, myocardial infarction, heart failure, arrhythmias, and wound and other infections.\n\n# Other comments\n\nThe Committee noted that some studies showed improvements in symptoms and quality of life, but considered that these were likely to be placebo responses in the light of evidence that showed no objective benefits.\n\nThe Committee considered evidence on TMLR alone for refractory angina pectoris, and also on TMLR performed concomitantly with CABG.', 'Further information': "NICE has published interventional procedures guidance on percutaneous laser revascularisation for refractory angina pectoris and technology appraisal guidance on myocardial perfusion scintigraphy for the diagnosis and management of angina and myocardial infarction. NICE is developing a clinical guideline on the management of stable angina [Now published as 'The management of stable angina'].\n\n# Information for patients\n\nNICE has produced information on this procedure for patients and carers ('Understanding NICE guidance'). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.", 'About this guidance': 'NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland.\n\nThis guidance was developed using the NICE interventional procedure guidance process.\n\nWe have produced a summary of this guidance for patients and carers. Information about the evidence it is based on is also available.\n\nChanges since publication\n\nJanuary 2012: minor maintenance.\n\nYour responsibility\n\nThis guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.\n\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.\n\nCopyright\n\n© National Institute for Health and Clinical Excellence 2009. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.\n\nContact NICE\n\nNational Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT\n\nwww.nice.org.uk\n \n nice@nice.org.uk\n 0845 033 7780'}	https://www.nice.org.uk/guidance/ipg301
3cd5fefa47950372578cc487ffd5ad485bbf1f07	nice	Percutaneous laser revascularisation for refractory angina pectoris	Percutaneous laser revascularisation for refractory angina pectoris Evidence-based recommendations on percutaneous laser revascularisation for refractory angina pectoris. This involves inserting a catheter into major vessels of the groin, which is advanced to the heart, to drill holes on the heart muscle using a laser beam. The aim is to enable blood flow from the heart chambers into the heart muscle, to relieve myocardial ischaemia and reduce chest pain. # Guidance Current evidence on percutaneous laser revascularisation (PLR) for refractory angina pectoris shows no efficacy and suggests that the procedure may pose unacceptable safety risks. Therefore, this procedure should not be used.# The procedure # Indications and current treatments Angina pectoris is chest discomfort, often described as pressure or pain, typically occurring on exertion. It is caused by inadequate delivery of oxygen to the heart muscle, usually because of coronary artery disease. Refractory angina is a severe angina form that cannot be controlled by normal medical or surgical treatment. Angina treatment depends on symptoms, medical history and angiography findings. Treatments include anti-anginal medication and revascularisation interventions (percutaneous coronary intervention or coronary artery bypass surgery). For patients with refractory angina, these treatments have either failed or are not clinically suitable. # Outline of the procedure Percutaneous laser revascularisation for refractory angina pectoris is carried out with the patient under local anaesthesia. A catheter is inserted through the femoral artery, and advanced to the heart under fluoroscopic guidance. Ischaemic areas are selected for treatment using echocardiography or myocardial perfusion scan and coronary angiography. A laser device is then used to create a number of channels in the myocardium. A number of different types of laser can be used for this procedure. # Efficacy Sections 2.3 and 2.4 describe efficacy and safety outcomes which were available in the published literature and which the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the systematic review. A meta-analysis of six randomised controlled trials (RCTs) involving 1040 patients reported no difference in mortality at 12-month follow-up between PLR-treated patients and medically managed patients (three RCTs), spinal cord stimulation (one RCT) or sham therapy (two RCTs) (pooled odds ratio 0.74; 95% confidence interval 0.32 to 1.7). An RCT of 298 patients reported no difference in mean myocardial perfusion test score (using single photon emission computed tomography imaging; scoring system not described) between patients treated with high-dose PLR (defined as 20–25 laser pulses), low-dose PLR (defined as 10–15 laser pulses) or sham therapy (17.7 points, 19.3 points and 17.3 points, respectively at 6-month follow-up ). An RCT of 221 patients comparing PLR with medical management reported no difference in mean left ventricular ejection fraction between PLR-treated patients (median 51%) and medically managed patients (median 50%) at 3-month follow-up (significance not stated). An RCT of 82 patients reported no difference in mean left ventricular ejection fraction between patients treated with PLR (64%) and sham therapy (63%) at 12-month follow-up (significance not stated). A meta-analysis of three RCTs reported no difference in post-procedural exercise tolerance using the Bruce Protocol Stress Test (a treadmill test) in patients treated with PLR compared with other interventions. A meta-analysis of five RCTs reported that exercise tolerance for PLR-treated patients was 17.7 seconds greater than in patients treated with comparators at 12-month follow-up (95% CI 4.4 to 31.0). When only studies with adequate patient blinding to allocated treatment were included in the meta-analysis, exercise tolerance differences at either 6 or 12 months were not significant. In the RCTs of 298 and 141 patients there was no difference in the proportion of patients whose Canadian Cardiac Society Angina (CCSA) score improved by two or more classes at 6-month follow-up (p = 0.33). In an RCT of 82 patients, the proportion of patients with an improved CCSA score of two or more classes compared with baseline was not significantly different from patients treated with sham therapy at 12-month follow-up (35% ; 14% , respectively) (p = 0.04). Specialist Advisers listed the key efficacy outcome as reduction of angina, which may or not be associated with objective measures, including improvement of perfusion scans, angina status and exercise capacity. # Safety A meta-analysis of five RCTs including 819 patients reported no difference in mortality (up to 30-day follow-up) between PLR-treated patients and medically managed patients (three RCTs), spinal cord stimulation (one RCT) or sham therapy (two RCTs) (OR 1.4; 95% CI 0.4 to 4.9). In six RCTs including 938 patients, the pooled myocardial infarction rate was higher in PLR-treated patients (7% ) than in the control groups (4% ). One RCT of 221 patients reported higher left bundle branch block rates following PLR (5% ) compared with medical management (1% ) (significance and follow-up not stated). Randomised controlled trials of 298 and 221 patients reported left ventricular perforation rates of 1% (2/196) and 3% (3/110), respectively, in PLR-treated patients (none were reported in patients treated with comparators; events occurring during 30-day follow-up or within 24 hours, respectively; significance not stated for either). In a case series of 25 patients treated with PLR, the myocardial perforation rate was 4% (1/25). A case series of 30 patients treated with PLR reported that 3% (1/30) of patients had pericardial tamponade during the procedure. Among four RCTs, cerebrovascular accident or transient ischaemic attack occurred more frequently in patients treated with PLR (4% ) than in patients in the control arms of the studies (2% ) (significance and follow-up not stated). The Specialist Advisers listed adverse events reported in the literature as myocardial infarction, arrhythmias and puncture site complications. They considered theoretical adverse events to include death, perforation of the cardiac muscle, damage to coronary arteries or other important structures, stroke and pericardial effusion.# Further information NICE has published interventional procedures guidance on transmyocardial laser revascularisation for refractory angina pectoris, technology appraisal guidance on myocardial perfusion scintigraphy for the diagnosis and management of angina and myocardial infarction, and a guideline on the management of stable angina. # Information for patients NICE has produced information on this procedure for patients and carers ('Understanding NICE guidance'). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.	{'Guidance ': 'Current evidence on percutaneous laser revascularisation (PLR) for refractory angina pectoris shows no efficacy and suggests that the procedure may pose unacceptable safety risks. Therefore, this procedure should not be used.', 'The procedure': '# Indications and current treatments\n\nAngina pectoris is chest discomfort, often described as pressure or pain, typically occurring on exertion. It is caused by inadequate delivery of oxygen to the heart muscle, usually because of coronary artery disease. Refractory angina is a severe angina form that cannot be controlled by normal medical or surgical treatment.\n\nAngina treatment depends on symptoms, medical history and angiography findings. Treatments include anti-anginal medication and revascularisation interventions (percutaneous coronary intervention or coronary artery bypass surgery). For patients with refractory angina, these treatments have either failed or are not clinically suitable.\n\n# Outline of the procedure\n\nPercutaneous laser revascularisation for refractory angina pectoris is carried out with the patient under local anaesthesia. A catheter is inserted through the femoral artery, and advanced to the heart under fluoroscopic guidance. Ischaemic areas are selected for treatment using echocardiography or myocardial perfusion scan and coronary angiography. A laser device is then used to create a number of channels in the myocardium.\n\nA number of different types of laser can be used for this procedure.\n\n# Efficacy\n\nSections 2.3 and 2.4 describe efficacy and safety outcomes which were available in the published literature and which the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the systematic review.\n\nA meta-analysis of six randomised controlled trials (RCTs) involving 1040 patients reported no difference in mortality at 12-month follow-up between PLR-treated patients and medically managed patients (three RCTs), spinal cord stimulation (one RCT) or sham therapy (two RCTs) (pooled odds ratio [OR] 0.74; 95% confidence interval [CI] 0.32 to 1.7).\n\nAn RCT of 298 patients reported no difference in mean myocardial perfusion test score (using single photon emission computed tomography [SPECT] imaging; scoring system not described) between patients treated with high-dose PLR (defined as 20–25 laser pulses), low-dose PLR (defined as 10–15 laser pulses) or sham therapy (17.7 points, 19.3 points and 17.3 points, respectively at 6-month follow-up [p = 0.35]).\n\nAn RCT of 221 patients comparing PLR with medical management reported no difference in mean left ventricular ejection fraction between PLR-treated patients (median 51%) and medically managed patients (median 50%) at 3-month follow-up (significance not stated). An RCT of 82 patients reported no difference in mean left ventricular ejection fraction between patients treated with PLR (64%) and sham therapy (63%) at 12-month follow-up (significance not stated).\n\nA meta-analysis of three RCTs reported no difference in post-procedural exercise tolerance using the Bruce Protocol Stress Test (a treadmill test) in patients treated with PLR compared with other interventions. A meta-analysis of five RCTs reported that exercise tolerance for PLR-treated patients was 17.7 seconds greater than in patients treated with comparators at 12-month follow-up (95% CI 4.4 to 31.0). When only studies with adequate patient blinding to allocated treatment were included in the meta-analysis, exercise tolerance differences at either 6 or 12 months were not significant.\n\nIn the RCTs of 298 and 141 patients there was no difference in the proportion of patients whose Canadian Cardiac Society Angina (CCSA) score improved by two or more classes at 6-month follow-up (p = 0.33). In an RCT of 82 patients, the proportion of patients with an improved CCSA score of two or more classes compared with baseline was not significantly different from patients treated with sham therapy at 12-month follow-up (35% [14/40]; 14% [6/42], respectively) (p = 0.04).\n\nSpecialist Advisers listed the key efficacy outcome as reduction of angina, which may or not be associated with objective measures, including improvement of perfusion scans, angina status and exercise capacity.\n\n# Safety\n\nA meta-analysis of five RCTs including 819 patients reported no difference in mortality (up to 30-day follow-up) between PLR-treated patients and medically managed patients (three RCTs), spinal cord stimulation (one RCT) or sham therapy (two RCTs) (OR 1.4; 95% CI 0.4 to 4.9).\n\nIn six RCTs including 938 patients, the pooled myocardial infarction rate was higher in PLR-treated patients (7% [34/515]) than in the control groups (4% [17/423]). One RCT of 221 patients reported higher left bundle branch block rates following PLR (5% [5/110]) compared with medical management (1% [1/111]) (significance and follow-up not stated).\n\nRandomised controlled trials of 298 and 221 patients reported left ventricular perforation rates of 1% (2/196) and 3% (3/110), respectively, in PLR-treated patients (none were reported in patients treated with comparators; events occurring during 30-day follow-up or within 24 hours, respectively; significance not stated for either). In a case series of 25 patients treated with PLR, the myocardial perforation rate was 4% (1/25). A case series of 30 patients treated with PLR reported that 3% (1/30) of patients had pericardial tamponade during the procedure.\n\nAmong four RCTs, cerebrovascular accident or transient ischaemic attack occurred more frequently in patients treated with PLR (4% [10/285]) than in patients in the control arms of the studies (2% [5/287]) (significance and follow-up not stated).\n\nThe Specialist Advisers listed adverse events reported in the literature as myocardial infarction, arrhythmias and puncture site complications. They considered theoretical adverse events to include death, perforation of the cardiac muscle, damage to coronary arteries or other important structures, stroke and pericardial effusion.', 'Further information': "NICE has published interventional procedures guidance on transmyocardial laser revascularisation for refractory angina pectoris, technology appraisal guidance on myocardial perfusion scintigraphy for the diagnosis and management of angina and myocardial infarction, and a guideline on the management of stable angina.\n\n# Information for patients\n\nNICE has produced information on this procedure for patients and carers ('Understanding NICE guidance'). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind."}	https://www.nice.org.uk/guidance/ipg302	Evidence-based recommendations on percutaneous laser revascularisation for refractory angina pectoris. This involves inserting a catheter into major vessels of the groin, which is advanced to the heart, to drill holes on the heart muscle using a laser beam. The aim is to enable blood flow from the heart chambers into the heart muscle, to relieve myocardial ischaemia and reduce chest pain.
20ab79cb513919e8d138dc9ae12ee8a6f09a56e1	nice	Rivaroxaban for the prevention of venous thromboembolism after total hip or total knee replacement in adults	Rivaroxaban for the prevention of venous thromboembolism after total hip or total knee replacement in adults Evidence-based recommendations on rivaroxaban (Xarelto) for preventing venous thromboembolism after total hip or total knee replacement in adults. # Guidance Rivaroxaban, within its marketing authorisation, is recommended as an option for the prevention of venous thromboembolism in adults having elective total hip replacement surgery or elective total knee replacement surgery.# The technology Rivaroxaban (Xarelto, Bayer HealthCare) is an anticoagulant that directly inhibits activated factor X (factor Xa). Inhibiting factor Xa interrupts the pathway of the blood coagulation cascade, inhibiting both thrombin formation and development of thrombi. Rivaroxaban has a marketing authorisation for the prevention of venous thromboembolism (VTE) in adult patients undergoing elective hip or knee replacement surgery. The summary of product characteristics (SPC) states that rivaroxaban should be taken orally once daily in 10-mg doses. The initial dose should be taken 6–10 hours after surgery, provided that haemostasis has been established. The SPC further states that the duration of treatment depends on the individual risk of the patient for VTE, which is determined by the type of orthopaedic surgery. Recommended treatment durations are 5 weeks for patients having major hip surgery, and 2 weeks for patients having major knee surgery. According to the SPC, approximately 14% of the treated patients across the phase III studies experienced adverse reactions. Bleeding and anaemia occurred in approximately 3.3% and 1% of patients, respectively. Other common adverse reactions were nausea and an increase in transaminases. The SPC states that the risk of bleeding may be increased in certain patient groups, for example those with uncontrolled severe arterial hypertension and/or those taking other treatments that affect haemostasis. For full details of side effects and contraindications, see the SPC. Rivaroxaban costs £45.00 for a pack of ten 10-mg tablets (£135.00 for 30 tablets), excluding VAT (NHS list price as reported by the manufacturer). The cost of treatment is estimated to be £63.00 (based on 14 tablets over 2 weeks) for knee replacement surgery and £157.50 for hip replacement surgery (based on 35 tablets over 5 weeks). Costs may vary in different settings because of negotiated procurement discounts.# The manufacturer's submission The Appraisal Committee (appendix A) considered evidence submitted by the manufacturer of rivaroxaban and a review of this submission by the Evidence Review Group (ERG; appendix B). The manufacturer's submission compared rivaroxaban with enoxaparin, a low molecular weight heparin (LMWH), using direct evidence from randomised controlled trials (RCTs), and with dabigatran, using RCT evidence in a mixed-treatment comparison. Outcomes analysed included: incidence of deep vein thrombosis (DVT); incidence of pulmonary embolism (PE); mortality; adverse effects of treatment including bleeding events; post-DVT complications including post-thrombotic syndrome; length of hospital stay; and health-related quality of life. The manufacturer's submission did not include analysis of outcomes at the site of the orthopaedic intervention, such as joint infection. There was no comparison with fondaparinux. The manufacturer conducted a systematic review that identified six RCTs comparing rivaroxaban with other therapies for the prevention of VTE. Four RCTs met the inclusion criteria (RCTs involving patients aged 18 years or older having hip or knee replacement, comparing rivaroxaban with other therapies including placebo): RECORD 1 and RECORD 2 recruited people having total hip replacement surgery and RECORD 3 and RECORD 4 recruited people having total knee replacement surgery. The other two trials were excluded because they were phase II, dose-ranging studies. The primary endpoint for all four included trials was a composite comprising any DVT, non-fatal PE and death from all causes. The RECORD 1 (n = 4541) and RECORD 2 (n = 2509) trials were multicentre, prospective, double-blind, parallel-group design RCTs comparing rivaroxaban with enoxaparin for the prevention of VTE after total hip replacement surgery. In RECORD 1, rivaroxaban was administered at a dosage of 10 mg once daily for 35 days starting on the day of surgery. Enoxaparin was administered at a dosage of 40 mg starting 1 day before surgery and for 35 days thereafter. For this study, the manufacturer reported a statistically significant difference in the incidence of the composite primary endpoint between rivaroxaban and enoxaparin based on a 'modified' intention to treat (MITT) analysis. The primary endpoint occurred in 1.1% of the rivaroxaban group compared with 3.7% of the enoxaparin group; relative risk reduction (RRR) was 70% (95% confidence interval 49 to 82, p < 0.001). The manufacturer further reported the results of the secondary endpoint: major VTE (a composite of proximal DVT, non-fatal PE and VTE-related death) for RECORD 1. In this study, in the MITT population, major VTE occurred in 4 (0.2%) patients receiving rivaroxaban compared with 33 (2.0%) patients receiving enoxaparin; the RRR was 88% (95% CI 66 to 96, p < 0.001). RECORD 2 was a comparison of 35 days of prophylaxis with rivaroxaban 10 mg daily compared with a shorter course (15 days) of enoxaparin prophylaxis at 40 mg daily. The manufacturer reported a statistically significant difference in the incidence of the composite primary endpoint between rivaroxaban and enoxaparin in the MITT analysis; 2.0% in the rivaroxaban group compared with 9.3% in the enoxaparin group (RRR 79%, 95% CI 65 to 87). The secondary endpoint, major VTE, occurred in 6 (0.6%) patients receiving rivaroxaban compared with 49 (5.1%) patients receiving enoxaparin (p < 0.0001). The RECORD 3 (n = 2531) and RECORD 4 (n = 3148) trials were multicentre, prospective, double-blind, parallel-group design RCTs comparing rivaroxaban with enoxaparin for the prevention of VTE after total knee replacement surgery. In both RECORD 3 and RECORD 4 rivaroxaban was administered at a dosage of 10 mg once daily for 10–14 days starting on the day of surgery. In RECORD 3 the comparator was enoxaparin at a dosage of 40 mg once daily, starting the day before surgery and for 10–14 days thereafter. The MITT analysis showed a statistically significant difference in the incidence of the composite primary endpoint: 9.6% in the rivaroxaban group compared with 18.9% in the enoxaparin group (RRR 49%, 95% CI 35 to 61). Major VTE occurred in 9 (1.0%) patients receiving rivaroxaban compared with 24 (2.6%) patients receiving enoxaparin (RRR 62%, 95% CI 18 to 82; p = 0.02). In RECORD 4 the comparator was enoxaparin at a higher dosage of 30 mg twice daily starting 1 day before surgery and continuing for 10–14 days thereafter. In this study, the composite primary outcome occurred in 6.9% and 10.1% of the rivaroxaban and enoxaparin groups, respectively (p < 0.012). RECORD 4 found a lower incidence of major VTE in patients treated with rivaroxaban compared with enoxaparin. The manufacturer used the per protocol population to test for non-inferiority of rivaroxaban compared with enoxaparin. The MITT analysis was used as supportive analysis in the test for superiority of rivaroxaban over enoxaparin. The manufacturer presented a range of meta-analyses that pooled the RECORD 1 and RECORD 2 studies for total hip replacement and the RECORD 3 and RECORD 4 studies for total knee replacement. Because of a lack of head-to-head trials between rivaroxaban and dabigatran, the manufacturer used an indirect comparison methodology that compared rivaroxaban and dabigatran, with enoxaparin as the common comparator. The analysis compared the incremental effect of rivaroxaban over enoxaparin to the incremental effect of dabigatran over enoxaparin. The comparison of these incremental effects allowed the indirect estimation of the incremental effect of rivaroxaban over dabigatran. The manufacturer stated that the indirect comparison methods used in this analysis were widely published and ensured that randomisation from the original trials was preserved. The results of these analyses were submitted to NICE in confidence and are not presented in this document. The main safety endpoint in the RECORD trials was the incidence of treatment-emergent major bleeding. The manufacturer reported the rates of major bleeding for patients treated with rivaroxaban and enoxaparin, respectively, as follows. RECORD 1: 0.3% vs 0.1%, p = 0.178; RECORD 2: 0.1% vs 0.1%, p = 0.98; RECORD 3: 0.6% vs 0.5%, p = 0.77; and RECORD 4: 0.7% vs 0.3%, p = 0.11. The incidence of non-major bleeding (comprising clinically relevant non-major bleeding, haemorrhagic wound complications and other non-major bleeding) was similarly low, for rivaroxaban and enoxaparin, respectively, as follows. RECORD 1: 5.8% vs 5.8%; RECORD 2: 6.5% vs 5.5%; RECORD 3: 4.3% vs 4.4%; and RECORD 4: 10.2% vs 9.2%. The ERG reviewed the literature search strategy and concluded that it effectively identified literature relevant to the decision problem and used relevant search techniques for systematic review and appraisal. The ERG was satisfied that the RECORD trials were of adequate methodological quality. It commented that reporting and interpretation of the safety data were good, and concluded that the manufacturer's submission appeared to contain an unbiased estimate of the effectiveness of rivaroxaban in relation to the main comparator, enoxaparin. The manufacturer submitted an economic model assessing the cost effectiveness of rivaroxaban compared with enoxaparin in VTE prevention after hip and knee replacement. The model comprised three modules: prophylaxis, post-prophylaxis, and long-term complications. The first two modules represented the acute phase in the form of a decision tree, and the third component represented the chronic phase and was developed as a Markov process. The prophylaxis part of the model was informed by clinical trial events (first 35 days for total hip replacement and 14 days for total knee replacement post-surgery). The post-prophylaxis component reflected the risk of symptomatic VTE events within the first 3 months, and the long-term complications component extrapolated any long-term complications resulting from symptomatic VTE events. Key assumptions in the economic evaluation included the assumption that asymptomatic VTE events would not incur any costs and did not have an impact on quality of life. It was assumed that all recurrent VTEs were DVTs. If the clinical trial or indirect comparison did not show a significant difference between the two arms, the probabilities were assumed to be equal in the model. It was also assumed that all PEs in the post-prophylaxis module were non fatal. The manufacturer presented base-case analyses based on RECORD 1 and RECORD 2 separately to reflect the different comparator regimens. The base case for the total knee replacement indication did not include an analysis based on RECORD 4 because the higher dosage of 30 mg twice daily for enoxaparin reflected practice in the US rather than the UK. However, the manufacturer presented pooled analysis by total hip replacement, total knee replacement and for all trials together. The results showed that rivaroxaban dominated enoxaparin in both total hip replacement (RECORD 1 and 2) and total knee replacement (RECORD 3). Deterministic sensitivity analysis for RECORD 1 showed that rivaroxaban generally dominated enoxaparin. However with a shorter treatment duration for enoxaparin (but maintaining 35 days' treatment benefits), the incremental cost-effectiveness ratio (ICER) for rivaroxaban compared with enoxaparin was £14,616 per QALY gained. When the benefits were also adjusted to reflect a reduced duration of prophylaxis, the ICER was £914 per QALY gained. In RECORD 2 the main variable that affected the ICER was excluding long-term complications caused by VTE events. This resulted in an ICER of £58,337 per QALY gained. The manufacturer attributed this change to lower prophylaxis drug costs for enoxaparin compared with rivaroxaban. The treatment duration for rivaroxaban was longer (35 days) compared with enoxaparin (15 days) in this trial, and therefore the prophylaxis drug costs for enoxaparin were lower. The indirect comparison with dabigatran showed that rivaroxaban dominated dabigatran in both total hip replacement and total knee replacement. The ERG considered that the approach to the economic modelling was reasonable. However, it noted that some potential events had been excluded from the model. The possibility of further VTE events other than DVT in the longer-term model was not considered and neither was the possibility of intracranial haemorrhage (a health state associated with marked disutility). The ERG noted that the conclusions on the cost effectiveness of rivaroxaban were dependent on the assumptions made about parameters that were not statistically significant, and on the appropriateness of pooling data. If all parameters where the p value was greater than 0.05 were set equivalent for rivaroxaban and the comparator, then assuming that all trials were pooled, rivaroxaban dominated the comparators. When the observed data were used and total hip replacement and total knee replacement were pooled separately, rivaroxaban did not always dominate enoxaparin and dabigatran in the total knee replacement indication. The ERG considered it more appropriate to model with observed data than by setting parameters to be equivalent when there was no statistically significant difference. The ERG also considered that pooling the data from all trials was reasonable in the circumstances. However, accepting these points, the differences in costs and QALYs gained across all analyses were extremely small. Full details of all the evidence are in the manufacturer's submission and the ERG report.# Consideration of the evidence The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of rivaroxaban for the prevention of VTE after elective total hip or knee replacement surgery in adults having considered evidence on the nature of the condition and the value placed on the benefits of rivaroxaban by people with experience of VTE, those who represent them, and clinical specialists. It was also mindful of the need to take account of the effective use of NHS resources. The Committee discussed the decision problem framework and in particular the major outcomes that were considered. The Committee was concerned that joint outcomes had not been included in the decision problem. It noted, however, that the main trials for total hip and total knee replacement did not evaluate joint outcomes. The Committee also noted that fondaparinux was not included in the manufacturer's decision problem, although the NICE clinical guideline 'Venous thromboembolism: reducing the risk of venous thromboembolism (deep vein thrombosis and pulmonary embolism) in inpatients undergoing surgery' (NICE clinical guideline 46 ) recommended that in addition to mechanical prophylaxis, people at increased risk of VTE and people undergoing orthopaedic surgery should be offered LMWH. The guideline also recommended that fondaparinux, within its licensed indications, may be used as an alternative to LMWH. The Committee noted that the manufacturer had not included fondaparinux as a comparator because it was used in less than 2% of patients in current UK clinical practice. The Committee noted comments from clinical specialists that drugs for the prevention of VTE are not routinely used by all orthopaedic surgeons because of concerns that they may increase the incidence, or worsen the consequences, of wound haemorrhage in the site of the orthopaedic surgery. The Committee discussed the clinical effectiveness of rivaroxaban compared with enoxaparin and dabigatran in people having elective hip or knee surgery. It noted the direct RCT evidence of a comparison of rivaroxaban and enoxaparin, and the indirect comparison of rivaroxaban versus dabigatran. The Committee agreed that the methodology used in the indirect comparison was plausible and therefore it was reasonable to consider the results of this comparison. The Committee considered evidence on the clinical effectiveness of rivaroxaban compared with enoxaparin. It discussed the applicability of the trials to UK clinical practice, noting that there is variation in prevention strategies. The Committee discussed the relevance of the RECORD 1, 2 and 3 trials, in which the patients in the control arm received 40 mg enoxaparin once daily, and agreed that the data from these trials were applicable to UK clinical practice. The Committee noted that the RECORD 4 study used an alternative dosing regimen of 30 mg enoxaparin twice daily that did not reflect the UK clinical setting, but agreed that the results of this study contributed to the overall evidence base and so were relevant for consideration. The Committee discussed the outcome data from these trials and was concerned about the use of surrogate outcomes as valid predictors of clinically relevant outcomes. Clinical specialists indicated that a major component of the composite primary outcome of the studies (DVT detected by venogram) was a surrogate outcome that was objectively assessed and allowed comparison between prevention strategies. Furthermore, the clinical specialists indicated that there was a direct relationship between venographically assessed outcomes and symptomatic outcomes. The Committee noted that the Guideline Development Group of NICE clinical guideline 46 had accepted venographically determined outcomes after careful consideration. The Committee discussed the results of the RECORD studies and concluded that rivaroxaban was at least as effective as enoxaparin in preventing VTE. The Committee considered adverse events such as bleeding, noting that the relative risk of major bleeding numerically favoured enoxaparin. The Committee noted that the chosen dose of rivaroxaban appeared to increase efficacy in prevention of VTE after surgery, with a small increase in risk of major bleeding when compared with enoxaparin. It concluded that rivaroxaban at its licensed dosage of 10 mg daily might be more efficacious than enoxaparin in preventing VTE but this was accompanied by a small increased risk of major bleeding. The Committee was persuaded by testimony from the clinical specialists that there was a 'trade off' to be made between increasing anticoagulant efficacy and the risk of adverse effects, including major bleeding. The Committee considered evidence on the clinical effectiveness of rivaroxaban compared indirectly with dabigatran that showed that rivaroxaban significantly reduced the relative risk of the major primary endpoints. However, the Committee noted that in this analysis the relative risk of major bleeding favoured dabigatranalthough this difference was not statistically significant. It agreed that on balance, rivaroxaban and dabigatran had broadly similar efficacy profiles, and noted the need to balance prevention of VTE with possible adverse effects, particularly the incidence of major bleeding events. The Committee discussed the benefits to patients of treatments given orally compared with subcutaneous injection. The Committee heard from the clinical specialists and patient experts that in general, oral dosing was preferred to subcutaneous injection. It discussed the implications of providing an option for oral administration in adherence to treatment. The Committee discussed whether a recommendation for an oral treatment rather than a subcutaneous injection would give rise to any issues related to equalities and diversity legislation. The Committee concluded that there were no issues related to equality of access to treatment that it would need to take into account when considering positively recommending rivaroxaban. The Committee also agreed that the option of oral treatment would be preferred by some patients and their clinicians. The Committee discussed the evidence submitted by the manufacturer on the cost effectiveness of rivaroxaban for the prevention of VTE in people having total hip or total knee replacement, the ERG's critique of the manufacturer's submission, and the manufacturer's response to the clarification requested by the ERG. The base-case analysis in the manufacturer's submission showed that rivaroxaban dominated enoxaparin and dabigatran in both total hip and total knee replacement. The Committee noted that this base-case analysis depended on the exclusion of the numerically increased adverse events for rivaroxaban compared with enoxaparin on the basis that they were not statistically significant. The Committee was concerned that this might not be in line with normal economic modelling procedures and took into account the ERG's preference for using observed data in the analysis. The Committee noted that the main variables that affected the output of the model were the rate of fatal PE and whether the model used observed values from the trials when there were insignificant differences in outcomes. The ERG's exploratory analysis showed that rivaroxaban did not always dominate enoxaparin and dabigatran in total knee replacement when the observed values from the trials were used. The Committee also noted the ERG's comments that the model did not incorporate the effect of fatal PE but concluded that there were very small differences in the costs and QALYs in any of the analyses presented. The Committee noted that although the primary clinical outcome data indicated that rivaroxaban was superior to enoxaparin and dabigatran, several of the point estimates in the economic analysis favoured enoxaparin. It also noted that the relative risk for major bleeding was in favour of enoxaparin and dabigatran. The Committee was mindful that the differences in the effectiveness and cost data were very small and therefore the ICERs were very sensitive to minor changes in assumptions. The Committee acknowledged that oral administration of rivaroxaban without the need for haematological monitoring would reduce administration costs and may support adherence to treatment. The Committee concluded that, on balance, rivaroxaban, enoxaparin and dabigatran had very similar costs and benefits in the prevention of VTE. Therefore, the Committee agreed that the use of rivaroxaban for the prevention of VTE is an appropriate use of NHS resources and that rivaroxaban should be recommended as an option for the prevention of venous thromboembolism in adults having elective total hip replacement surgery or elective total knee replacement surgery.# Recommendations for further research Further head-to-head trials of rivaroxaban compared with enoxaparin and dabigatran in both total hip replacement and total knee replacement would be useful to strengthen the evidence base for this comparison.# Related NICE guidance Dabigatran etexilate for the prevention of venous thromboembolim after hip or knee replacement surgery in adults. NICE technology appraisal guidance 157 (2008). Venous thromboembolism: reducing the risk of venous thromboembolism (deep vein thrombosis and pulmonary embolism) in inpatients undergoing surgery. NICE clinical guideline 46 (2007). # Review of guidance The review date for a technology appraisal refers to the month and year in which the Guidance Executive will consider whether the technology should be reviewed. This decision will be taken in the light of information gathered by the Institute, and in consultation with consultees and commentators. The guidance on this technology was considered for review in February 2012. Details are on the NICE website. Andrew DillonChief ExecutiveApril 2009# Changes after publication February 2014: implementation section updated to clarify that rivaroxaban is recommended as an option for preventing venous thromboembolism after total hip or total knee replacement in adults. Additional minor maintenance update also carried out. March 2012: minor maintenance# About this guidance NICE technology appraisal guidance is about the use of new and existing medicines and treatments in the NHS in England and Wales. This guidance was developed using the NICE single technology appraisal process. The recommendations from this guideline have been incorporated into a NICE Pathway. We have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available. Your responsibility This guidance represents the views of NICE and was arrived at after careful consideration of the evidence available. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. However, the guidance does not override the individual responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or guardian or carer. Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties. Copyright © National Institute for Health and Clinical Excellence 2009. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.	{'Guidance': 'Rivaroxaban, within its marketing authorisation, is recommended as an option for the prevention of venous thromboembolism in adults having elective total hip replacement surgery or elective total knee replacement surgery.', 'The technology ': 'Rivaroxaban (Xarelto, Bayer HealthCare) is an anticoagulant that directly inhibits activated factor X (factor Xa). Inhibiting factor Xa interrupts the pathway of the blood coagulation cascade, inhibiting both thrombin formation and development of thrombi. Rivaroxaban has a marketing authorisation for the prevention of venous thromboembolism (VTE) in adult patients undergoing elective hip or knee replacement surgery.\n\nThe summary of product characteristics (SPC) states that rivaroxaban should be taken orally once daily in 10-mg doses. The initial dose should be taken 6–10\xa0hours after surgery, provided that haemostasis has been established. The SPC further states that the duration of treatment depends on the individual risk of the patient for VTE, which is determined by the type of orthopaedic surgery. Recommended treatment durations are 5\xa0weeks for patients having major hip surgery, and 2\xa0weeks for patients having major knee surgery. According to the SPC, approximately 14% of the treated patients across the phase III studies experienced adverse reactions. Bleeding and anaemia occurred in approximately 3.3% and 1% of patients, respectively. Other common adverse reactions were nausea and an increase in transaminases. The SPC states that the risk of bleeding may be increased in certain patient groups, for example those with uncontrolled severe arterial hypertension and/or those taking other treatments that affect haemostasis. For full details of side effects and contraindications, see the SPC.\n\nRivaroxaban costs £45.00 for a pack of ten 10-mg tablets (£135.00 for 30 tablets), excluding VAT (NHS list price as reported by the manufacturer). The cost of treatment is estimated to be £63.00 (based on 14 tablets over 2\xa0weeks) for knee replacement surgery and £157.50 for hip replacement surgery (based on 35\xa0tablets over 5\xa0weeks). Costs may vary in different settings because of negotiated procurement discounts.', "The manufacturer's submission": "The Appraisal Committee (appendix A) considered evidence submitted by the manufacturer of rivaroxaban and a review of this submission by the Evidence Review Group (ERG; appendix B).\n\nThe manufacturer's submission compared rivaroxaban with enoxaparin, a low molecular weight heparin (LMWH), using direct evidence from randomised controlled trials (RCTs), and with dabigatran, using RCT evidence in a mixed-treatment comparison. Outcomes analysed included: incidence of deep vein thrombosis (DVT); incidence of pulmonary embolism (PE); mortality; adverse effects of treatment including bleeding events; post-DVT complications including post-thrombotic syndrome; length of hospital stay; and health-related quality of life. The manufacturer's submission did not include analysis of outcomes at the site of the orthopaedic intervention, such as joint infection. There was no comparison with fondaparinux.\n\nThe manufacturer conducted a systematic review that identified six RCTs comparing rivaroxaban with other therapies for the prevention of VTE. Four RCTs met the inclusion criteria (RCTs involving patients aged 18\xa0years or older having hip or knee replacement, comparing rivaroxaban with other therapies including placebo): RECORD 1 and RECORD 2 recruited people having total hip replacement surgery and RECORD 3 and RECORD 4 recruited people having total knee replacement surgery. The other two trials were excluded because they were phase II, dose-ranging studies. The primary endpoint for all four included trials was a composite comprising any DVT, non-fatal PE and death from all causes.\n\nThe RECORD 1 (n\xa0=\xa04541) and RECORD 2 (n\xa0=\xa02509) trials were multicentre, prospective, double-blind, parallel-group design RCTs comparing rivaroxaban with enoxaparin for the prevention of VTE after total hip replacement surgery. In RECORD 1, rivaroxaban was administered at a dosage of 10\xa0mg once daily for 35\xa0days starting on the day of surgery. Enoxaparin was administered at a dosage of 40\xa0mg starting 1\xa0day before surgery and for 35\xa0days thereafter. For this study, the manufacturer reported a statistically significant difference in the incidence of the composite primary endpoint between rivaroxaban and enoxaparin based on a 'modified' intention to treat (MITT) analysis. The primary endpoint occurred in 1.1% of the rivaroxaban group compared with 3.7% of the enoxaparin group; relative risk reduction (RRR) was 70% (95% confidence interval [CI] 49 to 82, p\xa0<\xa00.001). The manufacturer further reported the results of the secondary endpoint: major VTE (a composite of proximal DVT, non-fatal PE and VTE-related death) for RECORD 1. In this study, in the MITT population, major VTE occurred in 4 (0.2%) patients receiving rivaroxaban compared with 33 (2.0%) patients receiving enoxaparin; the RRR was 88% (95% CI 66 to\xa096, p\xa0<\xa00.001).\n\nRECORD\xa02 was a comparison of 35\xa0days of prophylaxis with rivaroxaban 10\xa0mg daily compared with a shorter course (15\xa0days) of enoxaparin prophylaxis at 40\xa0mg daily. The manufacturer reported a statistically significant difference in the incidence of the composite primary endpoint between rivaroxaban and enoxaparin in the MITT analysis; 2.0% in the rivaroxaban group compared with 9.3% in the enoxaparin group (RRR 79%, 95%\xa0CI 65 to 87). The secondary endpoint, major VTE, occurred in 6 (0.6%) patients receiving rivaroxaban compared with 49 (5.1%) patients receiving enoxaparin (p\xa0<\xa00.0001).\n\nThe RECORD\xa03 (n\xa0=\xa02531) and RECORD\xa04 (n\xa0= 3148) trials were multicentre, prospective, double-blind, parallel-group design RCTs comparing rivaroxaban with enoxaparin for the prevention of VTE after total knee replacement surgery. In both RECORD\xa03 and RECORD\xa04 rivaroxaban was administered at a dosage of 10\xa0mg once daily for 10–14\xa0days starting on the day of surgery. In RECORD\xa03 the comparator was enoxaparin at a dosage of 40\xa0mg once daily, starting the day before surgery and for 10–14\xa0days thereafter. The MITT analysis showed a statistically significant difference in the incidence of the composite primary endpoint: 9.6% in the rivaroxaban group compared with 18.9% in the enoxaparin group (RRR 49%, 95% CI 35 to 61). Major VTE occurred in 9 (1.0%) patients receiving rivaroxaban compared with 24 (2.6%) patients receiving enoxaparin (RRR 62%, 95% CI 18 to 82; p\xa0=\xa00.02).\n\nIn RECORD\xa04 the comparator was enoxaparin at a higher dosage of 30\xa0mg twice daily starting 1\xa0day before surgery and continuing for 10–14\xa0days thereafter. In this study, the composite primary outcome occurred in 6.9% and 10.1% of the rivaroxaban and enoxaparin groups, respectively (p\xa0<\xa00.012). RECORD\xa04 found a lower incidence of major VTE in patients treated with rivaroxaban compared with enoxaparin.\n\nThe manufacturer used the per protocol population to test for non-inferiority of rivaroxaban compared with enoxaparin. The MITT analysis was used as supportive analysis in the test for superiority of rivaroxaban over enoxaparin. The manufacturer presented a range of meta-analyses that pooled the RECORD\xa01 and RECORD\xa02 studies for total hip replacement and the RECORD\xa03 and RECORD\xa04 studies for total knee replacement. Because of a lack of head-to-head trials between rivaroxaban and dabigatran, the manufacturer used an indirect comparison methodology that compared rivaroxaban and dabigatran, with enoxaparin as the common comparator. The analysis compared the incremental effect of rivaroxaban over enoxaparin to the incremental effect of dabigatran over enoxaparin. The comparison of these incremental effects allowed the indirect estimation of the incremental effect of rivaroxaban over dabigatran. The manufacturer stated that the indirect comparison methods used in this analysis were widely published and ensured that randomisation from the original trials was preserved. The results of these analyses were submitted to NICE in confidence and are not presented in this document.\n\nThe main safety endpoint in the RECORD trials was the incidence of treatment-emergent major bleeding. The manufacturer reported the rates of major bleeding for patients treated with rivaroxaban and enoxaparin, respectively, as follows. RECORD\xa01: 0.3% vs 0.1%, p\xa0=\xa00.178; RECORD\xa02: 0.1% vs 0.1%, p\xa0=\xa00.98; RECORD\xa03: 0.6% vs 0.5%, p\xa0=\xa00.77; and RECORD\xa04: 0.7% vs 0.3%, p\xa0=\xa00.11. The incidence of non-major bleeding (comprising clinically relevant non-major bleeding, haemorrhagic wound complications and other non-major bleeding) was similarly low, for rivaroxaban and enoxaparin, respectively, as follows. RECORD\xa01: 5.8% vs 5.8%; RECORD\xa02: 6.5% vs 5.5%; RECORD\xa03: 4.3% vs 4.4%; and RECORD\xa04: 10.2% vs 9.2%.\n\nThe ERG reviewed the literature search strategy and concluded that it effectively identified literature relevant to the decision problem and used relevant search techniques for systematic review and appraisal. The ERG was satisfied that the RECORD trials were of adequate methodological quality. It commented that reporting and interpretation of the safety data were good, and concluded that the manufacturer's submission appeared to contain an unbiased estimate of the effectiveness of rivaroxaban in relation to the main comparator, enoxaparin.\n\nThe manufacturer submitted an economic model assessing the cost effectiveness of rivaroxaban compared with enoxaparin in VTE prevention after hip and knee replacement. The model comprised three modules: prophylaxis, post-prophylaxis, and long-term complications. The first two modules represented the acute phase in the form of a decision tree, and the third component represented the chronic phase and was developed as a Markov process. The prophylaxis part of the model was informed by clinical trial events (first 35\xa0days for total hip replacement and 14\xa0days for total knee replacement post-surgery). The post-prophylaxis component reflected the risk of symptomatic VTE events within the first 3\xa0months, and the long-term complications component extrapolated any long-term complications resulting from symptomatic VTE events.\n\nKey assumptions in the economic evaluation included the assumption that asymptomatic VTE events would not incur any costs and did not have an impact on quality of life. It was assumed that all recurrent VTEs were DVTs. If the clinical trial or indirect comparison did not show a significant difference between the two arms, the probabilities were assumed to be equal in the model. It was also assumed that all PEs in the post-prophylaxis module were non fatal.\n\nThe manufacturer presented base-case analyses based on RECORD\xa01 and RECORD\xa02 separately to reflect the different comparator regimens. The base case for the total knee replacement indication did not include an analysis based on RECORD\xa04 because the higher dosage of 30\xa0mg twice daily for enoxaparin reflected practice in the US rather than the UK. However, the manufacturer presented pooled analysis by total hip replacement, total knee replacement and for all trials together.\n\nThe results showed that rivaroxaban dominated enoxaparin in both total hip replacement (RECORD 1 and 2) and total knee replacement (RECORD\xa03). Deterministic sensitivity analysis for RECORD\xa01 showed that rivaroxaban generally dominated enoxaparin. However with a shorter treatment duration for enoxaparin (but maintaining 35\xa0days' treatment benefits), the incremental cost-effectiveness ratio (ICER) for rivaroxaban compared with enoxaparin was £14,616 per QALY gained. When the benefits were also adjusted to reflect a reduced duration of prophylaxis, the ICER was £914 per QALY gained. In RECORD\xa02 the main variable that affected the ICER was excluding long-term complications caused by VTE events. This resulted in an ICER of £58,337 per QALY gained. The manufacturer attributed this change to lower prophylaxis drug costs for enoxaparin compared with rivaroxaban. The treatment duration for rivaroxaban was longer (35\xa0days) compared with enoxaparin (15\xa0days) in this trial, and therefore the prophylaxis drug costs for enoxaparin were lower. The indirect comparison with dabigatran showed that rivaroxaban dominated dabigatran in both total hip replacement and total knee replacement.\n\nThe ERG considered that the approach to the economic modelling was reasonable. However, it noted that some potential events had been excluded from the model. The possibility of further VTE events other than DVT in the longer-term model was not considered and neither was the possibility of intracranial haemorrhage (a health state associated with marked disutility).\n\nThe ERG noted that the conclusions on the cost effectiveness of rivaroxaban were dependent on the assumptions made about parameters that were not statistically significant, and on the appropriateness of pooling data. If all parameters where the p\xa0value was greater than 0.05 were set equivalent for rivaroxaban and the comparator, then assuming that all trials were pooled, rivaroxaban dominated the comparators. When the observed data were used and total hip replacement and total knee replacement were pooled separately, rivaroxaban did not always dominate enoxaparin and dabigatran in the total knee replacement indication. The ERG considered it more appropriate to model with observed data than by setting parameters to be equivalent when there was no statistically significant difference. The ERG also considered that pooling the data from all trials was reasonable in the circumstances. However, accepting these points, the differences in costs and QALYs gained across all analyses were extremely small.\n\nFull details of all the evidence are in the manufacturer's submission and the ERG report.", 'Consideration of the evidence': "The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of rivaroxaban for the prevention of VTE after elective total hip or knee replacement surgery in adults having considered evidence on the nature of the condition and the value placed on the benefits of rivaroxaban by people with experience of VTE, those who represent them, and clinical specialists. It was also mindful of the need to take account of the effective use of NHS resources.\n\nThe Committee discussed the decision problem framework and in particular the major outcomes that were considered. The Committee was concerned that joint outcomes had not been included in the decision problem. It noted, however, that the main trials for total hip and total knee replacement did not evaluate joint outcomes. The Committee also noted that fondaparinux was not included in the manufacturer's decision problem, although the NICE clinical guideline 'Venous thromboembolism: reducing the risk of venous thromboembolism (deep vein thrombosis and pulmonary embolism) in inpatients undergoing surgery' (NICE clinical guideline\xa046 [Replaced by NICE clinical guideline 92]) recommended that in addition to mechanical prophylaxis, people at increased risk of VTE and people undergoing orthopaedic surgery should be offered LMWH. The guideline also recommended that fondaparinux, within its licensed indications, may be used as an alternative to LMWH. The Committee noted that the manufacturer had not included fondaparinux as a comparator because it was used in less than 2% of patients in current UK clinical practice. The Committee noted comments from clinical specialists that drugs for the prevention of VTE are not routinely used by all orthopaedic surgeons because of concerns that they may increase the incidence, or worsen the consequences, of wound haemorrhage in the site of the orthopaedic surgery.\n\nThe Committee discussed the clinical effectiveness of rivaroxaban compared with enoxaparin and dabigatran in people having elective hip or knee surgery. It noted the direct RCT evidence of a comparison of rivaroxaban and enoxaparin, and the indirect comparison of rivaroxaban versus dabigatran. The Committee agreed that the methodology used in the indirect comparison was plausible and therefore it was reasonable to consider the results of this comparison.\n\nThe Committee considered evidence on the clinical effectiveness of rivaroxaban compared with enoxaparin. It discussed the applicability of the trials to UK clinical practice, noting that there is variation in prevention strategies. The Committee discussed the relevance of the RECORD 1, 2 and 3 trials, in which the patients in the control arm received 40\xa0mg enoxaparin once daily, and agreed that the data from these trials were applicable to UK clinical practice. The Committee noted that the RECORD 4 study used an alternative dosing regimen of 30\xa0mg enoxaparin twice daily that did not reflect the UK clinical setting, but agreed that the results of this study contributed to the overall evidence base and so were relevant for consideration. The Committee discussed the outcome data from these trials and was concerned about the use of surrogate outcomes as valid predictors of clinically relevant outcomes. Clinical specialists indicated that a major component of the composite primary outcome of the studies (DVT detected by venogram) was a surrogate outcome that was objectively assessed and allowed comparison between prevention strategies. Furthermore, the clinical specialists indicated that there was a direct relationship between venographically assessed outcomes and symptomatic outcomes. The Committee noted that the Guideline Development Group of NICE clinical guideline 46 had accepted venographically determined outcomes after careful consideration.\n\nThe Committee discussed the results of the RECORD studies and concluded that rivaroxaban was at least as effective as enoxaparin in preventing VTE. The Committee considered adverse events such as bleeding, noting that the relative risk of major bleeding numerically favoured enoxaparin. The Committee noted that the chosen dose of rivaroxaban appeared to increase efficacy in prevention of VTE after surgery, with a small increase in risk of major bleeding when compared with enoxaparin. It concluded that rivaroxaban at its licensed dosage of 10\xa0mg daily might be more efficacious than enoxaparin in preventing VTE but this was accompanied by a small increased risk of major bleeding. The Committee was persuaded by testimony from the clinical specialists that there was a 'trade off' to be made between increasing anticoagulant efficacy and the risk of adverse effects, including major bleeding.\n\nThe Committee considered evidence on the clinical effectiveness of rivaroxaban compared indirectly with dabigatran that showed that rivaroxaban significantly reduced the relative risk of the major primary endpoints. However, the Committee noted that in this analysis the relative risk of major bleeding favoured dabigatranalthough this difference was not statistically significant. It agreed that on balance, rivaroxaban and dabigatran had broadly similar efficacy profiles, and noted the need to balance prevention of VTE with possible adverse effects, particularly the incidence of major bleeding events.\n\nThe Committee discussed the benefits to patients of treatments given orally compared with subcutaneous injection. The Committee heard from the clinical specialists and patient experts that in general, oral dosing was preferred to subcutaneous injection. It discussed the implications of providing an option for oral administration in adherence to treatment. The Committee discussed whether a recommendation for an oral treatment rather than a subcutaneous injection would give rise to any issues related to equalities and diversity legislation. The Committee concluded that there were no issues related to equality of access to treatment that it would need to take into account when considering positively recommending rivaroxaban. The Committee also agreed that the option of oral treatment would be preferred by some patients and their clinicians.\n\nThe Committee discussed the evidence submitted by the manufacturer on the cost effectiveness of rivaroxaban for the prevention of VTE in people having total hip or total knee replacement, the ERG's critique of the manufacturer's submission, and the manufacturer's response to the clarification requested by the ERG. The base-case analysis in the manufacturer's submission showed that rivaroxaban dominated enoxaparin and dabigatran in both total hip and total knee replacement. The Committee noted that this base-case analysis depended on the exclusion of the numerically increased adverse events for rivaroxaban compared with enoxaparin on the basis that they were not statistically significant. The Committee was concerned that this might not be in line with normal economic modelling procedures and took into account the ERG's preference for using observed data in the analysis. The Committee noted that the main variables that affected the output of the model were the rate of fatal PE and whether the model used observed values from the trials when there were insignificant differences in outcomes.\n\nThe ERG's exploratory analysis showed that rivaroxaban did not always dominate enoxaparin and dabigatran in total knee replacement when the observed values from the trials were used. The Committee also noted the ERG's comments that the model did not incorporate the effect of fatal PE but concluded that there were very small differences in the costs and QALYs in any of the analyses presented.\n\nThe Committee noted that although the primary clinical outcome data indicated that rivaroxaban was superior to enoxaparin and dabigatran, several of the point estimates in the economic analysis favoured enoxaparin. It also noted that the relative risk for major bleeding was in favour of enoxaparin and dabigatran. The Committee was mindful that the differences in the effectiveness and cost data were very small and therefore the ICERs were very sensitive to minor changes in assumptions. The Committee acknowledged that oral administration of rivaroxaban without the need for haematological monitoring would reduce administration costs and may support adherence to treatment.\n\nThe Committee concluded that, on balance, rivaroxaban, enoxaparin and dabigatran had very similar costs and benefits in the prevention of VTE. Therefore, the Committee agreed that the use of rivaroxaban for the prevention of VTE is an appropriate use of NHS resources and that rivaroxaban should be recommended as an option for the prevention of venous thromboembolism in adults having elective total hip replacement surgery or elective total knee replacement surgery.", 'Recommendations for further research': 'Further head-to-head trials of rivaroxaban compared with enoxaparin and dabigatran in both total hip replacement and total knee replacement would be useful to strengthen the evidence base for this comparison.', 'Related NICE guidance': 'Dabigatran etexilate for the prevention of venous thromboembolim after hip or knee replacement surgery in adults. NICE technology appraisal guidance 157 (2008).\n\nVenous thromboembolism: reducing the risk of venous thromboembolism (deep vein thrombosis and pulmonary embolism) in inpatients undergoing surgery. NICE clinical guideline 46 (2007). [Replaced by NICE clinical guideline 92]', 'Review of guidance': 'The review date for a technology appraisal refers to the month and year in which the Guidance Executive will consider whether the technology should be reviewed. This decision will be taken in the light of information gathered by the Institute, and in consultation with consultees and commentators.\n\nThe guidance on this technology was considered for review in February 2012. Details are on the NICE website.\n\nAndrew DillonChief ExecutiveApril 2009', 'Changes after publication': 'February 2014: implementation section updated to clarify that rivaroxaban is recommended as an option for preventing venous thromboembolism after total hip or total knee replacement in adults. Additional minor maintenance update also carried out.\n\nMarch 2012: minor maintenance', 'About this guidance': 'NICE technology appraisal guidance is about the use of new and existing medicines and treatments in the NHS in England and Wales.\n\nThis guidance was developed using the NICE single technology appraisal process.\n\nThe recommendations from this guideline have been incorporated into a NICE Pathway. We have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available.\n\nYour responsibility\n\nThis guidance represents the views of NICE and was arrived at after careful consideration of the evidence available. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. However, the guidance does not override the individual responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.\n\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.\n\nCopyright\n\n© National Institute for Health and Clinical Excellence 2009. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.'}	https://www.nice.org.uk/guidance/ta170	Evidence-based recommendations on rivaroxaban (Xarelto) for preventing venous thromboembolism after total hip or total knee replacement in adults.
c5cab873e75148952eaf4893b92b2e9566384567	nice	Diarrhoea and vomiting caused by gastroenteritis in under 5s: diagnosis and management	Diarrhoea and vomiting caused by gastroenteritis in under 5s: diagnosis and management This guideline covers diagnosing, managing and referring infants and young children younger than 5 years who present with acute diarrhoea (lasting up to 14 days) with or without vomiting. It aims to improve the diagnosis and management of infective gastroenteritis and appropriate escalation of care. # Introduction Infective gastroenteritis in young children is characterised by the sudden onset of diarrhoea, with or without vomiting. Most cases are due to an enteric virus, but some are caused by bacterial or protozoal infections. The illness usually resolves without treatment within days; however, symptoms are unpleasant and affect both the child and family or carers. Severe diarrhoea can quickly cause dehydration, which may be life threatening. Gastroenteritis is very common, with many children having more than one episode a year. Parents and carers often manage their child's illness at home, and may not seek professional advice. However, many parents and carers do seek advice from healthcare professionals either remotely (for example, through NHS Direct), in the community, or in primary or secondary care. Approximately 10% of children younger than 5 years present to healthcare services with gastroenteritis each year (Van Damme et al. 2007). In a UK study, diarrhoeal illness accounted for 16% of medical presentations to a major paediatric emergency department (Armon et al. 2001). Although most children with gastroenteritis do not need to be admitted to hospital, many are treated as inpatients each year and often remain in hospital for several days – thereby exposing other vulnerable hospitalised children to the illness. Gastroenteritis is a significant burden on health service resources. The management of gastroenteritis in children is multifaceted. There is evidence of variation in clinical practice, which may have a major impact on the use of healthcare resources. This guideline applies to children younger than 5 years who present to a healthcare professional for advice in any setting. It covers diagnosis, assessment of dehydration, fluid management, nutritional management and the role of antibiotics and other therapies. It provides recommendations on the advice to be given to parents and carers, and also considers when care should be escalated – from home management through to hospital admission. The guideline will assume that prescribers will use a drug's summary of product characteristics to inform their decisions for individual patients.# Recommendations People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care. Making decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding. The following guidance is based on the best available evidence. The full guideline gives details of the methods and the evidence used to develop the guidance. For the purposes of this guideline, an 'infant' is defined as a child younger than 1 year. 'Remote assessment' refers to situations in which a child is assessed by a healthcare professional who is unable to examine the child because the child is geographically remote from the assessor (for example, telephone calls to NHS Direct). # Diagnosis ## Clinical diagnosis Suspect gastroenteritis if there is a sudden change in stool consistency to loose or watery stools, and/or a sudden onset of vomiting. If you suspect gastroenteritis, ask about: recent contact with someone with acute diarrhoea and/or vomiting and exposure to a known source of enteric infection (possibly contaminated water or food) and recent travel abroad. Be aware that in children with gastroenteritis: diarrhoea usually lasts for 5–7 days, and in most it stops within 2 weeks vomiting usually lasts for 1–2 days, and in most it stops within 3 days. Consider any of the following as possible indicators of diagnoses other than gastroenteritis: fever: temperature of 38°C or higher in children younger than 3 months temperature of 39°C or higher in children aged 3 months or older shortness of breath or tachypnoea altered conscious state neck stiffness bulging fontanelle in infants non-blanching rash blood and/or mucus in stool bilious (green) vomit severe or localised abdominal pain abdominal distension or rebound tenderness. ## Laboratory investigations Consider performing stool microbiological investigations if: the child has recently been abroad or the diarrhoea has not improved by day 7 or there is uncertainty about the diagnosis of gastroenteritis. Perform stool microbiological investigations if: you suspect septicaemia or there is blood and/or mucus in the stool or the child is immunocompromised. Notify and act on the advice of the public health authorities if you suspect an outbreak of gastroenteritis. If stool microbiology is performed: collect, store and transport stool specimens as advised by the investigating laboratory provide the laboratory with relevant clinical information. Perform a blood culture if giving antibiotic therapy. In children with Shiga toxin-producing Escherichia coli (STEC) infection, seek specialist advice on monitoring for haemolytic uraemic syndrome. # Assessing dehydration and shock ## Clinical assessment During remote or face-to-face assessment ask whether the child: appears unwell has altered responsiveness, for example is irritable or lethargic has decreased urine output has pale or mottled skin has cold extremities. Recognise that the following are at increased risk of dehydration: children younger than 1 year, particularly those younger than 6 months infants who were of low birth weight children who have passed more than five diarrhoeal stools in the previous 24 hours children who have vomited more than twice in the previous 24 hours children who have not been offered or have not been able to tolerate supplementary fluids before presentation infants who have stopped breastfeeding during the illness children with signs of malnutrition. Use table 1 to detect clinical dehydration and shock. ## Table 1. Symptoms and signs of clinical dehydration and shock Interpret symptoms and signs taking risk factors for dehydration into account (see recommendation 1.2.1.2). Within the category of 'clinical dehydration' there is a spectrum of severity indicated by increasingly numerous and more pronounced symptoms and signs. For clinical shock, one or more of the symptoms and/or signs listed would be expected to be present. Dashes (–) indicate that these clinical features do not specifically indicate shock. Symptoms and signs with red flags may help to identify children at increased risk of progression to shock. If in doubt, manage as if there are symptoms and/or signs with red flags. No clinically detectable dehydration Clinical dehydration Clinical shock Appears well Red flag Appears to be unwell or deteriorating Alert and responsive Red flag Altered responsiveness (for example, irritable, lethargic) Decreased level of consciousness Normal urine output Decreased urine output Skin colour unchanged Skin colour unchanged Pale or mottled skin Warm extremities Warm extremities Cold extremities No clinically detectable dehydration Clinical dehydration Clinical shock Alert and responsive Red flag Altered responsiveness (for example, irritable, lethargic) Decreased level of consciousness Skin colour unchanged Skin colour unchanged Pale or mottled skin Warm extremities Warm extremities Cold extremities Eyes not sunken Red flag Sunken eyes Moist mucous membranes (except after a drink) Dry mucous membranes (except for 'mouth breather') Normal heart rate Red flag Tachycardia Tachycardia Normal breathing pattern Red flag Tachypnoea Tachypnoea Normal peripheral pulses Normal peripheral pulses Weak peripheral pulses Normal capillary refill time Normal capillary refill time Prolonged capillary refill time Normal skin turgor Red flag Reduced skin turgor Normal blood pressure Normal blood pressure Hypotension (decompensated shock) Suspect hypernatraemic dehydration if there are any of the following: jittery movements increased muscle tone hyperreflexia convulsions drowsiness or coma. ## Laboratory investigations for assessing dehydration Do not routinely perform blood biochemical testing. Measure plasma sodium, potassium, urea, creatinine and glucose concentrations if: intravenous fluid therapy is required or there are symptoms and/or signs that suggest hypernatraemia. Measure venous blood acid–base status and chloride concentration if shock is suspected or confirmed. # Fluid management ## Primary prevention of dehydration In children with gastroenteritis but without clinical dehydration: continue breastfeeding and other milk feeds encourage fluid intake discourage the drinking of fruit juices and carbonated drinks, especially in those at increased risk of dehydration (see recommendation 1.2.1.2) -ffer ORS solution as supplemental fluid to those at increased risk of dehydration (see recommendation 1.2.1.2). ## Treating dehydration Use ORS solution to rehydrate children, including those with hypernatraemia, unless intravenous fluid therapy is indicated (see recommendations 1.3.3.1 and 1.3.3.5). In children with clinical dehydration, including hypernatraemic dehydration: use low-osmolarity ORS solution (240–250 mOsm/l) for oral rehydration therapy (the BNF for children (BNFC) 2008 edition lists the following products with this composition: Dioralyte, Dioralyte Relief, Electrolade and Rapolyte) give 50 ml/kg for fluid deficit replacement over 4 hours as well as maintenance fluid give the ORS solution frequently and in small amounts consider supplementation with their usual fluids (including milk feeds or water, but not fruit juices or carbonated drinks) if they refuse to take sufficient quantities of ORS solution and do not have red flag symptoms or signs (see table 1) consider giving the ORS solution via a nasogastric tube if they are unable to drink it or if they vomit persistently monitor the response to oral rehydration therapy by regular clinical assessment. ## Intravenous fluid therapy Use intravenous fluid therapy for clinical dehydration if: shock is suspected or confirmed a child with red flag symptoms or signs (see table 1) shows clinical evidence of deterioration despite oral rehydration therapy a child persistently vomits the ORS solution, given orally or via a nasogastric tube. Treat suspected or confirmed shock with a rapid intravenous infusion of 10 ml/kg of 0.9% sodium chloride solution. If a child remains shocked after the first rapid intravenous infusion: immediately give another rapid intravenous infusion of 10 ml/kg of 0.9% sodium chloride solution and consider possible causes of shock other than dehydration. Consider consulting a paediatric intensive care specialist if a child remains shocked after the second rapid intravenous infusion. When symptoms and/or signs of shock resolve after rapid intravenous infusions, start rehydration with intravenous fluid therapy (see recommendation 1.3.3.6). If intravenous fluid therapy is required for rehydration (and the child is not hypernatraemic at presentation): use an isotonic solution such as 0.9% sodium chloride, or 0.9% sodium chloride with 5% glucose, for fluid deficit replacement and maintenance for those who required initial rapid intravenous fluid boluses for suspected or confirmed shock, add 100 ml/kg for fluid deficit replacement to maintenance fluid requirements, and monitor the clinical response for those who were not shocked at presentation, add 50 ml/kg for fluid deficit replacement to maintenance fluid requirements, and monitor the clinical response measure plasma sodium, potassium, urea, creatinine and glucose at the outset, monitor regularly, and alter the fluid composition or rate of administration if necessary consider providing intravenous potassium supplementation once the plasma potassium level is known. If intravenous fluid therapy is required in a child presenting with hypernatraemic dehydration: -btain urgent expert advice on fluid management use an isotonic solution such as 0.9% sodium chloride, or 0.9% sodium chloride with 5% glucose for fluid deficit replacement and maintenance replace the fluid deficit slowly – typically over 48 hours monitor the plasma sodium frequently, aiming to reduce it at a rate of less than 0.5 mmol/l per hour. Attempt early and gradual introduction of oral rehydration therapy during intravenous fluid therapy. If tolerated, stop intravenous fluids and complete rehydration with oral rehydration therapy. ## Fluid management after rehydration After rehydration: encourage breastfeeding and other milk feeds encourage fluid intake in children at increased risk of dehydration recurring, consider giving 5 ml/kg of ORS solution after each large watery stool. These include: children younger than 1 year, particularly those younger than 6 months infants who were of low birth weight children who have passed more than five diarrhoeal stools in the previous 24 hours children who have vomited more than twice in the previous 24 hours. Restart oral rehydration therapy if dehydration recurs after rehydration. # Nutritional management During rehydration therapy: continue breastfeeding do not give solid foods in children with red flag symptoms or signs (see table 1), do not give oral fluids other than ORS solution in children without red flag symptoms or signs (see table 1), do not routinely give oral fluids other than ORS solution; however, consider supplementation with the child's usual fluids (including milk feeds or water, but not fruit juices or carbonated drinks) if they consistently refuse ORS solution. After rehydration: give full-strength milk straight away reintroduce the child's usual solid food avoid giving fruit juices and carbonated drinks until the diarrhoea has stopped. # Antibiotic therapy Do not routinely give antibiotics to children with gastroenteritis. Give antibiotic treatment to all children: with suspected or confirmed septicaemia with extra-intestinal spread of bacterial infection younger than 6 months with salmonella gastroenteritis who are malnourished or immunocompromised with salmonella gastroenteritis with Clostridium difficile-associated pseudomembranous enterocolitis, giardiasis, dysenteric shigellosis, dysenteric amoebiasis or cholera. For children who have recently been abroad, seek specialist advice about antibiotic therapy. # Other therapies Do not use antidiarrhoeal medications. # Escalation of care During remote assessment: arrange emergency transfer to secondary care for children with symptoms suggesting shock (see table 1) refer for face-to-face assessment children: with symptoms suggesting an alternative serious diagnosis (see recommendation 1.1.1.4) or at high risk of dehydration, taking into account the risk factors listed in 1.2.1.2 or with symptoms suggesting clinical dehydration (see table 1) or whose social circumstances make remote assessment unreliable provide a 'safety net' for children who do not require referral. The safety net should include information for parents and carers on how to: recognise developing red flag symptoms (see table 1) and get immediate help from an appropriate healthcare professional if red flag symptoms develop. During face-to-face assessment: arrange emergency transfer to secondary care for children with symptoms or signs suggesting shock (see table 1) consider repeat face-to-face assessment or referral to secondary care for children: with symptoms and/or signs suggesting an alternative serious diagnosis (see recommendation 1.1.1.4) or with red flag symptoms and/or signs (see table 1) or whose social circumstances require continued involvement of healthcare professionals provide a safety net for children who will be managed at home. The safety net should include: information for parents and carers on how to recognise developing red flag symptoms (see table 1) and information on how to get immediate help from an appropriate healthcare professional if red flag symptoms develop and arrangements for follow-up at a specified time and place, if necessary. # Information and advice for parents and carers ## Caring for a child with diarrhoea and vomiting at home Inform parents and carers that: most children with gastroenteritis can be safely managed at home, with advice and support from a healthcare professional if necessary the following symptoms may indicate dehydration: appearing to get more unwell changing responsiveness (for example, irritability, lethargy) decreased urine output pale or mottled skin cold extremities they should contact a healthcare professional if symptoms of dehydration develop. Advise parents and carers of children: who are not clinically dehydrated and are not at increased risk of dehydration (see recommendation 1.2.1.2): to continue usual feeds, including breast or other milk feeds to encourage the child to drink plenty of fluids to discourage the drinking of fruit juices and carbonated drinks who are not clinically dehydrated but who are at increased risk of dehydration (see recommendation 1.2.1.2): to continue usual feeds, including breast or other milk feeds to encourage the child to drink plenty of fluids to discourage the drinking of fruit juices and carbonated drinks to offer ORS solution as supplemental fluid with clinical dehydration: that rehydration is usually possible with ORS solution to make up the ORS solution according to the instructions on the packaging to give 50 ml/kg of ORS solution for rehydration plus maintenance volume over a 4-hour period to give this amount of ORS solution in small amounts, frequently to seek advice if the child refuses to drink the ORS solution or vomits persistently to continue breastfeeding as well as giving the ORS solution not to give other oral fluids unless advised not to give solid foods. Advise parents and carers that after rehydration: the child should be encouraged to drink plenty of their usual fluids, including milk feeds if these were stopped they should avoid giving the child fruit juices and carbonated drinks until the diarrhoea has stopped they should reintroduce the child's usual diet they should give 5 ml/kg ORS solution after each large watery stool if you consider that the child is at increased risk of dehydration (see recommendation 1.2.1.2). Advise parents and carers that: the usual duration of diarrhoea is 5–7 days and in most children it stops within 2 weeks the usual duration of vomiting is 1 or 2 days and in most children it stops within 3 days they should seek advice from a specified healthcare professional if the child's symptoms do not resolve within these timeframes. ## Preventing primary spread of diarrhoea and vomiting Advise parents, carers and children that washing hands with soap (liquid if possible) in warm running water and careful drying are the most important factors in preventing the spread of gastroenteritis hands should be washed after going to the toilet (children) or changing nappies (parents/carers) and before preparing, serving or eating food towels used by infected children should not be shared children should not attend any school or other childcare facility while they have diarrhoea or vomiting caused by gastroenteritis children should not go back to their school or other childcare facility until at least 48 hours after the last episode of diarrhoea or vomiting children should not swim in swimming pools for 2 weeks after the last episode of diarrhoea. This recommendation is adapted from the following guidelines commissioned by the Department of Health: Public Health England (2017) Health protection in schools and other childcare facilities Working Group of the former PHLS Advisory Committee on Gastrointestinal Infections (2004) Preventing person-to-person spread following gastrointestinal infections: guidelines for public health physicians and environmental health officers. Communicable Disease and Public Health 7(4):362–384.# Recommendations for research The Guideline Development Group has made the following recommendations for research, based on its review of evidence, to improve NICE guidance and patient care in the future. The Guideline Development Group's full set of recommendations for research is detailed in the full guideline (see section 5). # Assessing dehydration and shock In children with gastroenteritis, what is the predictive value of clinical symptoms and signs in assessing the severity of dehydration, using post-rehydration weight gain as the reference standard, in primary and secondary care settings? ## Why this is important Evidence from a systematic review (Steiner et al. 2004) suggests that some symptoms and signs (for example, prolonged capillary refill time, abnormal skin turgor and abnormal respiratory pattern) are associated with dehydration, measured using the accepted 'gold standard' of the difference between pre-hydration and post-hydration weight. However, 10 of the 13 included studies were not blinded and had ill-defined selection criteria. Moreover, all these studies were conducted in secondary care where children with more severe dehydration are managed. Most children with gastroenteritis can and should be managed in the community (Hay et al. 2005) but there is a lack of evidence to help primary care healthcare professionals correctly identify children with more severe dehydration. Symptoms and signs that researchers may wish to investigate include overall appearance, irritability or lethargy, urine output, sunken eyes, absence of tears, changes in skin colour or warmth of extremities, dry mucous membranes, depressed fontanelle, heart rate, respiratory rate and effort, character of peripheral pulses, capillary refill time, skin turgor and blood pressure. # Administration of ORS solution by nasogastric tube In children who do not tolerate oral rehydration therapy, is ORS solution administration via nasogastric tube cost effective, safe and acceptable in treating dehydration compared with intravenous fluid therapy? ## Why this is important Oral rehydration therapy is normally preferable to intravenous fluid therapy for rehydration in children with gastroenteritis. However, some children may not tolerate oral rehydration therapy, either because they are unable to drink ORS solution in adequate quantities or because they persistently vomit. In such cases, ORS solution could be administered via a nasogastric tube, rather than changing to intravenous fluid therapy. This overcomes the problem of ORS solution refusal. Continuous infusion of ORS solution via a nasogastric tube might reduce the risk of vomiting. A well-conducted randomised controlled trial is needed to assess the cost effectiveness, safety and acceptability of rehydration using nasogastric tube administration of ORS solution compared with intravenous fluid therapy. # Fluid management In children who require intravenous fluid therapy for the treatment of dehydration, is rapid rehydration safe and cost effective compared with the common practice of rehydration over 24 hours? ## Why this is important Most children with clinical dehydration should be treated with oral rehydration therapy, but some require intravenous fluid therapy because they are shocked or they cannot tolerate oral rehydration therapy. Rehydration with oral rehydration therapy is usually carried out over a period of 4 hours. Rehydration with intravenous fluid therapy has traditionally been undertaken slowly – typically over 24 hours. The National Patient Safety Agency has advised that intravenous fluid deficit replacement should be over 24 hours or longer. (See, Reducing the risk of hyponatraemia when administering intravenous infusions to children. National Patient Safety Agency, Alert no. 22.) Consequently, children will remain dehydrated and in hospital for a prolonged period. The World Health Organization's manual for physicians and other senior health workers on the treatment of diarrhoea recommends that intravenous rehydration should be completed in 3 to 6 hours. Many experts now support rapid intravenous rehydration, suggesting that it allows oral fluids to be starter earlier and can shorten the duration of hospital treatment. Randomised controlled trials are needed urgently to examine the safety and cost effectiveness of rapid intravenous rehydration regimens compared with slow intravenous rehydration. # Other therapies: ondansetron In children with persistent vomiting caused by gastroenteritis, is oral ondansetron cost effective and safe compared with placebo therapy? ## Why this is important Several randomised controlled trials have shown that in children with persistent vomiting during oral rehydration therapy, administration of oral ondansetron, an anti-emetic agent, can increase the likelihood of successful oral rehydration. However, in two of these there was evidence suggesting that diarrhoea was more pronounced in those given ondansetron than in those in the placebo groups. In one, in children given ondansetron, the number of stools passed during the rehydration phase was significantly greater, and in the other the number of stools passed in the first and second 24-hour period after rehydration was significantly greater. In those studies, diarrhoea was not a primary outcome, and it was reported as an adverse event. The reliability of the finding was therefore somewhat uncertain. If ondansetron does worsen diarrhoea it would be crucially important to determine the clinical significance of this effect, for example in relation to the risk of dehydration recurring or re-admission to hospital. If ondansetron is shown to be both effective and safe in secondary care then studies should also be undertaken to evaluate its use in primary care. # Other therapies: probiotics Are probiotics effective and safe compared with a placebo in the treatment of children with gastroenteritis in the UK? Which specific probiotic is most effective and in what specific treatment regimen? ## Why this is important The available studies of probiotic therapy frequently report benefits, particularly in terms of reduced duration of diarrhoea or stool frequency. However, most of the published studies have methodological limitations. Moreover, there is great variation in the specific probiotics evaluated and in the treatment regimens used. Many of these studies were conducted in developing countries where the response to probiotic therapy may differ. Good-quality randomised controlled trials should be conducted in the UK to evaluate the effectiveness and safety of specific probiotics, using clearly defined treatment regimens and outcome measures.	{'Introduction': "Infective gastroenteritis in young children is characterised by the sudden onset of diarrhoea, with or without vomiting. Most cases are due to an enteric virus, but some are caused by bacterial or protozoal infections. The illness usually resolves without treatment within days; however, symptoms are unpleasant and affect both the child and family or carers. Severe diarrhoea can quickly cause dehydration, which may be life threatening.\n\nGastroenteritis is very common, with many children having more than one episode a year. Parents and carers often manage their child's illness at home, and may not seek professional advice. However, many parents and carers do seek advice from healthcare professionals either remotely (for example, through NHS Direct), in the community, or in primary or secondary care. Approximately 10% of children younger than 5 years present to healthcare services with gastroenteritis each year (Van Damme et al. 2007). In a UK study, diarrhoeal illness accounted for 16% of medical presentations to a major paediatric emergency department (Armon et al. 2001). Although most children with gastroenteritis do not need to be admitted to hospital, many are treated as inpatients each year and often remain in hospital for several days – thereby exposing other vulnerable hospitalised children to the illness. Gastroenteritis is a significant burden on health service resources.\n\nThe management of gastroenteritis in children is multifaceted. There is evidence of variation in clinical practice, which may have a major impact on the use of healthcare resources.\n\nThis guideline applies to children younger than 5\xa0years who present to a healthcare professional for advice in any setting. It covers diagnosis, assessment of dehydration, fluid management, nutritional management and the role of antibiotics and other therapies. It provides recommendations on the advice to be given to parents and carers, and also considers when care should be escalated – from home management through to hospital admission.\n\nThe guideline will assume that prescribers will use a drug's summary of product characteristics to inform their decisions for individual patients.", 'Recommendations': "People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.\n\nMaking decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.\n\nThe following guidance is based on the best available evidence. The full guideline gives details of the methods and the evidence used to develop the guidance.\n\nFor the purposes of this guideline, an 'infant' is defined as a child younger than 1 year. 'Remote assessment' refers to situations in which a child is assessed by a healthcare professional who is unable to examine the child because the child is geographically remote from the assessor (for example, telephone calls to NHS Direct).\n\n# Diagnosis\n\n## Clinical diagnosis\n\nSuspect gastroenteritis if there is a sudden change in stool consistency to loose or watery stools, and/or a sudden onset of vomiting.\n\nIf you suspect gastroenteritis, ask about:\n\nrecent contact with someone with acute diarrhoea and/or vomiting and\n\nexposure to a known source of enteric infection (possibly contaminated water or food) and\n\nrecent travel abroad.\n\nBe aware that in children with gastroenteritis:\n\ndiarrhoea usually lasts for 5–7\xa0days, and in most it stops within 2\xa0weeks\n\nvomiting usually lasts for 1–2\xa0days, and in most it stops within 3\xa0days.\n\nConsider any of the following as possible indicators of diagnoses other than gastroenteritis:\n\nfever:\n\n\n\ntemperature of 38°C or higher in children younger than 3\xa0months\n\ntemperature of 39°C or higher in children aged 3 months or\xa0older\n\n\n\nshortness of breath or tachypnoea\n\naltered conscious state\n\nneck stiffness\n\nbulging fontanelle in infants\n\nnon-blanching rash\n\nblood and/or mucus in stool\n\nbilious (green) vomit\n\nsevere or localised abdominal pain\n\nabdominal distension or rebound tenderness.\n\n## Laboratory investigations\n\nConsider performing stool microbiological investigations if:\n\nthe child has recently been abroad or\n\nthe diarrhoea has not improved by day 7 or\n\nthere is uncertainty about the diagnosis of gastroenteritis.\n\nPerform stool microbiological investigations if:\n\nyou suspect septicaemia or\n\nthere is blood and/or mucus in the stool or\n\nthe child is immunocompromised.\n\nNotify and act on the advice of the public health authorities if you suspect an outbreak of gastroenteritis.\n\nIf stool microbiology is performed:\n\ncollect, store and transport stool specimens as advised by the investigating laboratory\n\nprovide the laboratory with relevant clinical information.\n\nPerform a blood culture if giving antibiotic therapy.\n\nIn children with Shiga toxin-producing Escherichia coli (STEC) infection, seek specialist advice on monitoring for haemolytic uraemic syndrome.\n\n# Assessing dehydration and shock\n\n## Clinical assessment\n\nDuring remote or face-to-face assessment ask whether the child:\n\nappears unwell\n\nhas altered responsiveness, for example is irritable or lethargic\n\nhas decreased urine output\n\nhas pale or mottled skin\n\nhas cold extremities.\n\nRecognise that the following are at increased risk of dehydration:\n\nchildren younger than 1\xa0year, particularly those younger than 6\xa0months\n\ninfants who were of low birth weight\n\nchildren who have passed more than five diarrhoeal stools in the previous 24\xa0hours\n\nchildren who have vomited more than twice in the previous 24\xa0hours\n\nchildren who have not been offered or have not been able to tolerate supplementary fluids before presentation\n\ninfants who have stopped breastfeeding during the illness\n\nchildren with signs of malnutrition.\n\nUse table 1 to detect clinical dehydration and shock.\n\n## Table 1. Symptoms and signs of clinical dehydration and shock\n\nInterpret symptoms and signs taking risk factors for dehydration into account (see recommendation 1.2.1.2). Within the category of 'clinical dehydration' there is a spectrum of severity indicated by increasingly numerous and more pronounced symptoms and signs. For clinical shock, one or more of the symptoms and/or signs listed would be expected to be present. Dashes (–) indicate that these clinical features do not specifically indicate shock. Symptoms and signs with red flags may help to identify children at increased risk of progression to shock. If in doubt, manage as if there are symptoms and/or signs with red flags.\n\nNo clinically detectable dehydration\n\nClinical dehydration\n\nClinical shock\n\nAppears well\n\nRed flag Appears to be unwell or deteriorating\n\n–\n\nAlert and responsive\n\nRed flag Altered responsiveness (for example, irritable, lethargic)\n\nDecreased level of consciousness\n\nNormal urine output\n\nDecreased urine output\n\n–\n\nSkin colour unchanged\n\nSkin colour unchanged\n\nPale or mottled skin\n\nWarm extremities\n\nWarm extremities\n\nCold extremities\n\nNo clinically detectable dehydration\n\nClinical dehydration\n\nClinical shock\n\nAlert and responsive\n\nRed flag Altered responsiveness (for example, irritable, lethargic)\n\nDecreased level of consciousness\n\nSkin colour unchanged\n\nSkin colour unchanged\n\nPale or mottled skin\n\nWarm extremities\n\nWarm extremities\n\nCold extremities\n\nEyes not sunken\n\nRed flag Sunken eyes\n\n–\n\nMoist mucous membranes (except after a drink)\n\nDry mucous membranes (except for 'mouth breather')\n\n–\n\nNormal heart rate\n\nRed flag Tachycardia\n\nTachycardia\n\nNormal breathing pattern\n\nRed flag Tachypnoea\n\nTachypnoea\n\nNormal peripheral pulses\n\nNormal peripheral pulses\n\nWeak peripheral pulses\n\nNormal capillary refill time\n\nNormal capillary refill time\n\nProlonged capillary refill time\n\nNormal skin turgor\n\nRed flag Reduced skin turgor\n\n–\n\nNormal blood pressure\n\nNormal blood pressure\n\nHypotension (decompensated shock)\n\nSuspect hypernatraemic dehydration if there are any of the following:\n\njittery movements\n\nincreased muscle tone\n\nhyperreflexia\n\nconvulsions\n\ndrowsiness or coma.\n\n## Laboratory investigations for assessing dehydration\n\nDo not routinely perform blood biochemical testing.\n\nMeasure plasma sodium, potassium, urea, creatinine and glucose concentrations if:\n\nintravenous fluid therapy is required or\n\nthere are symptoms and/or signs that suggest hypernatraemia.\n\nMeasure venous blood acid–base status and chloride concentration if shock is suspected or confirmed.\n\n# Fluid management\n\n## Primary prevention of dehydration\n\nIn children with gastroenteritis but without clinical dehydration:\n\ncontinue breastfeeding and other milk feeds\n\nencourage fluid intake\n\ndiscourage the drinking of fruit juices and carbonated drinks, especially in those at increased risk of dehydration (see recommendation 1.2.1.2)\n\noffer ORS solution as supplemental fluid to those at increased risk of dehydration (see recommendation 1.2.1.2).\n\n## Treating dehydration\n\nUse ORS solution to rehydrate children, including those with hypernatraemia, unless intravenous fluid therapy is indicated (see recommendations\xa01.3.3.1 and 1.3.3.5).\n\nIn children with clinical dehydration, including hypernatraemic dehydration:\n\nuse low-osmolarity ORS solution (240–250\xa0mOsm/l) for oral rehydration therapy (the BNF for children (BNFC) 2008 edition lists the following products with this composition: Dioralyte, Dioralyte Relief, Electrolade and Rapolyte)\n\ngive 50\xa0ml/kg for fluid deficit replacement over 4\xa0hours as well as maintenance fluid\n\ngive the ORS solution frequently and in small amounts\n\nconsider supplementation with their usual fluids (including milk feeds or water, but not fruit juices or carbonated drinks) if they refuse to take sufficient quantities of ORS solution and do not have red flag symptoms or signs (see table\xa01)\n\nconsider giving the ORS solution via a nasogastric tube if they are unable to drink it or if they vomit persistently\n\nmonitor the response to oral rehydration therapy by regular clinical assessment.\n\n## Intravenous fluid therapy\n\nUse intravenous fluid therapy for clinical dehydration if:\n\nshock is suspected or confirmed\n\na child with red flag symptoms or signs (see table\xa01) shows clinical evidence of deterioration despite oral rehydration therapy\n\na child persistently vomits the ORS solution, given orally or via a nasogastric tube.\n\nTreat suspected or confirmed shock with a rapid intravenous infusion of 10\xa0ml/kg of 0.9%\xa0sodium chloride solution.\n\nIf a child remains shocked after the first rapid intravenous infusion:\n\nimmediately give another rapid intravenous infusion of 10\xa0ml/kg of 0.9% sodium chloride solution and\n\nconsider possible causes of shock other than dehydration.\n\nConsider consulting a paediatric intensive care specialist if a child remains shocked after the second rapid intravenous infusion.\n\n\n\nWhen symptoms and/or signs of shock resolve after rapid intravenous infusions, start rehydration with intravenous fluid therapy (see recommendation 1.3.3.6).\n\n\n\nIf intravenous fluid therapy is required for rehydration (and the child is not hypernatraemic at presentation):\n\nuse an isotonic solution such as 0.9% sodium chloride, or 0.9% sodium chloride with 5% glucose, for fluid deficit replacement and maintenance\n\nfor those who required initial rapid intravenous fluid boluses for suspected or confirmed shock, add 100 ml/kg for fluid deficit replacement to maintenance fluid requirements, and monitor the clinical response\n\nfor those who were not shocked at presentation, add 50\xa0ml/kg for fluid deficit replacement to maintenance fluid requirements, and monitor the clinical response\n\nmeasure plasma sodium, potassium, urea, creatinine and glucose at the outset, monitor regularly, and alter the fluid composition or rate of administration if necessary\n\nconsider providing intravenous potassium supplementation once the plasma potassium level is known.\n\nIf intravenous fluid therapy is required in a child presenting with hypernatraemic dehydration:\n\nobtain urgent expert advice on fluid management\n\nuse an isotonic solution such as 0.9% sodium chloride, or 0.9% sodium chloride with 5% glucose for fluid deficit replacement and maintenance\n\nreplace the fluid deficit slowly – typically over 48\xa0hours\n\nmonitor the plasma sodium frequently, aiming to reduce it at a rate of less than 0.5\xa0mmol/l per hour.\n\nAttempt early and gradual introduction of oral rehydration therapy during intravenous fluid therapy. If tolerated, stop intravenous fluids and complete rehydration with oral rehydration therapy.\n\n## Fluid management after rehydration\n\nAfter rehydration:\n\nencourage breastfeeding and other milk feeds\n\nencourage fluid intake\n\nin children at increased risk of dehydration recurring, consider giving 5\xa0ml/kg of ORS solution after each large watery stool. These include:\n\n\n\nchildren younger than 1\xa0year, particularly those younger than 6\xa0months\n\ninfants who were of low birth weight\n\nchildren who have passed more than five diarrhoeal stools in the previous 24\xa0hours\n\nchildren who have vomited more than twice in the previous 24\xa0hours.\n\n\n\nRestart oral rehydration therapy if dehydration recurs after rehydration.\n\n# Nutritional management\n\nDuring rehydration therapy:\n\ncontinue breastfeeding\n\ndo not give solid foods\n\nin children with red flag symptoms or signs (see table\xa01), do not give oral fluids other than ORS solution\n\nin children without red flag symptoms or signs (see table 1), do not routinely give oral fluids other than ORS solution; however, consider supplementation with the child's usual fluids (including milk feeds or water, but not fruit juices or carbonated drinks) if they consistently refuse ORS solution.\n\nAfter rehydration:\n\ngive full-strength milk straight away\n\nreintroduce the child's usual solid food\n\navoid giving fruit juices and carbonated drinks until the diarrhoea has stopped.\n\n# Antibiotic therapy\n\nDo not routinely give antibiotics to children with gastroenteritis.\n\nGive antibiotic treatment to all children:\n\nwith suspected or confirmed septicaemia\n\nwith extra-intestinal spread of bacterial infection\n\nyounger than 6\xa0months with salmonella gastroenteritis\n\nwho are malnourished or immunocompromised with salmonella gastroenteritis\n\nwith Clostridium difficile-associated pseudomembranous enterocolitis, giardiasis, dysenteric shigellosis, dysenteric amoebiasis or cholera.\n\nFor children who have recently been abroad, seek specialist advice about antibiotic therapy.\n\n# Other therapies\n\nDo not use antidiarrhoeal medications.\n\n# Escalation of care\n\nDuring remote assessment:\n\narrange emergency transfer to secondary care for children with symptoms suggesting shock (see table 1)\n\nrefer for face-to-face assessment children:\n\n\n\nwith symptoms suggesting an alternative serious diagnosis (see recommendation 1.1.1.4) or\n\nat high risk of dehydration, taking into account the risk factors listed in 1.2.1.2 or\n\nwith symptoms suggesting clinical dehydration (see table\xa01)\xa0or\n\nwhose social circumstances make remote assessment unreliable\n\n\n\nprovide a 'safety net' for children who do not require referral. The safety net should include information for parents and carers on how to:\n\n\n\nrecognise developing red flag symptoms (see table\xa01) and\n\nget immediate help from an appropriate healthcare professional if red flag symptoms develop.\n\n\n\nDuring face-to-face assessment:\n\narrange emergency transfer to secondary care for children with symptoms or signs suggesting shock (see table 1)\n\nconsider repeat face-to-face assessment or referral to secondary care for children:\n\n\n\nwith symptoms and/or signs suggesting an alternative serious diagnosis (see recommendation 1.1.1.4) or\n\nwith red flag symptoms and/or signs (see table\xa01) or\n\nwhose social circumstances require continued involvement of healthcare professionals\n\n\n\nprovide a safety net for children who will be managed at home. The safety net should include:\n\n\n\ninformation for parents and carers on how to recognise developing red flag symptoms (see table\xa01) and\n\ninformation on how to get immediate help from an appropriate healthcare professional if red flag symptoms develop and\n\narrangements for follow-up at a specified time and place, if necessary.\n\n\n\n# Information and advice for parents and carers\n\n## Caring for a child with diarrhoea and vomiting at home\n\nInform parents and carers that:\n\nmost children with gastroenteritis can be safely managed at home, with advice and support from a healthcare professional if necessary\n\nthe following symptoms may indicate dehydration:\n\n\n\nappearing to get more unwell\n\nchanging responsiveness (for example, irritability, lethargy)\n\ndecreased urine output\n\npale or mottled skin\n\ncold extremities\n\n\n\nthey should contact a healthcare professional if symptoms of dehydration develop.\n\nAdvise parents and carers of children:\n\nwho are not clinically dehydrated and are not at increased risk of dehydration (see recommendation 1.2.1.2):\n\n\n\nto continue usual feeds, including breast or other milk feeds\n\nto encourage the child to drink plenty of fluids\n\nto discourage the drinking of fruit juices and carbonated drinks\n\n\n\nwho are not clinically dehydrated but who are at increased risk of dehydration (see recommendation 1.2.1.2):\n\n\n\nto continue usual feeds, including breast or other milk feeds\n\nto encourage the child to drink plenty of fluids\n\nto discourage the drinking of fruit juices and carbonated drinks\n\nto offer ORS solution as supplemental fluid\n\n\n\nwith clinical dehydration:\n\n\n\nthat rehydration is usually possible with ORS solution\n\nto make up the ORS solution according to the instructions on the packaging\n\nto give 50\xa0ml/kg of ORS solution for rehydration plus maintenance volume over a 4-hour period\n\nto give this amount of ORS solution in small amounts, frequently\n\nto seek advice if the child refuses to drink the ORS solution or vomits persistently\n\nto continue breastfeeding as well as giving the ORS solution\n\nnot to give other oral fluids unless advised\n\nnot to give solid foods.\n\n\n\nAdvise parents and carers that after rehydration:\n\nthe child should be encouraged to drink plenty of their usual fluids, including milk feeds if these were stopped\n\nthey should avoid giving the child fruit juices and carbonated drinks until the diarrhoea has stopped\n\nthey should reintroduce the child's usual diet\n\nthey should give 5\xa0ml/kg ORS solution after each large watery stool if you consider that the child is at increased risk of dehydration (see recommendation 1.2.1.2).\n\nAdvise parents and carers that:\n\nthe usual duration of diarrhoea is 5–7\xa0days and in most children it stops within 2\xa0weeks\n\nthe usual duration of vomiting is 1 or 2\xa0days and in most children it stops within 3\xa0days\n\nthey should seek advice from a specified healthcare professional if the child's symptoms do not resolve within these timeframes.\n\n## Preventing primary spread of diarrhoea and vomiting\n\nAdvise parents, carers and children that\n\nwashing hands with soap (liquid if possible) in warm running water and careful drying are the most important factors in preventing the spread of gastroenteritis\n\nhands should be washed after going to the toilet (children) or changing nappies (parents/carers) and before preparing, serving or eating food\n\ntowels used by infected children should not be shared\n\nchildren should not attend any school or other childcare facility while they have diarrhoea or vomiting caused by gastroenteritis\n\nchildren should not go back to their school or other childcare facility until at least 48\xa0hours after the last episode of diarrhoea or vomiting\n\nchildren should not swim in swimming pools for 2\xa0weeks after the last episode of diarrhoea.\n\nThis recommendation is adapted from the following guidelines commissioned by the Department of Health:\n\nPublic Health England (2017)\xa0Health protection in schools and other childcare facilities\n\nWorking Group of the former PHLS Advisory Committee on Gastrointestinal Infections (2004) Preventing person-to-person spread following gastrointestinal infections: guidelines for public health physicians and environmental health officers. Communicable Disease and Public Health 7(4):362–384.", 'Recommendations for research': "The Guideline Development Group has made the following recommendations for research, based on its review of evidence, to improve NICE guidance and patient care in the future. The Guideline Development Group's full set of recommendations for research is detailed in the full guideline (see section 5).\n\n# Assessing dehydration and shock\n\nIn children with gastroenteritis, what is the predictive value of clinical symptoms and signs in assessing the severity of dehydration, using post-rehydration weight gain as the reference standard, in primary and secondary care settings?\n\n## Why this is important\n\nEvidence from a systematic review (Steiner et al. 2004) suggests that some symptoms and signs (for example, prolonged capillary refill time, abnormal skin turgor and abnormal respiratory pattern) are associated with dehydration, measured using the accepted 'gold standard' of the difference between pre-hydration and post-hydration weight. However, 10 of the 13 included studies were not blinded and had ill-defined selection criteria. Moreover, all these studies were conducted in secondary care where children with more severe dehydration are managed.\n\nMost children with gastroenteritis can and should be managed in the community (Hay et al. 2005) but there is a lack of evidence to help primary care healthcare professionals correctly identify children with more severe dehydration. Symptoms and signs that researchers may wish to investigate include overall appearance, irritability or lethargy, urine output, sunken eyes, absence of tears, changes in skin colour or warmth of extremities, dry mucous membranes, depressed fontanelle, heart rate, respiratory rate and effort, character of peripheral pulses, capillary refill time, skin turgor and blood pressure.\n\n# Administration of ORS solution by nasogastric tube\n\nIn children who do not tolerate oral rehydration therapy, is ORS solution administration via nasogastric tube cost effective, safe and acceptable in treating dehydration compared with intravenous fluid therapy?\n\n## Why this is important\n\nOral rehydration therapy is normally preferable to intravenous fluid therapy for rehydration in children with gastroenteritis. However, some children may not tolerate oral rehydration therapy, either because they are unable to drink ORS solution in adequate quantities or because they persistently vomit. In such cases, ORS solution could be administered via a nasogastric tube, rather than changing to intravenous fluid therapy. This overcomes the problem of ORS solution refusal. Continuous infusion of ORS solution via a nasogastric tube might reduce the risk of vomiting. A well-conducted randomised controlled trial is needed to assess the cost effectiveness, safety and acceptability of rehydration using nasogastric tube administration of ORS solution compared with intravenous fluid therapy.\n\n# Fluid management\n\nIn children who require intravenous fluid therapy for the treatment of dehydration, is rapid rehydration safe and cost effective compared with the common practice of rehydration over 24 hours?\n\n## Why this is important\n\nMost children with clinical dehydration should be treated with oral rehydration therapy, but some require intravenous fluid therapy because they are shocked or they cannot tolerate oral rehydration therapy. Rehydration with oral rehydration therapy is usually carried out over a period of 4 hours. Rehydration with intravenous fluid therapy has traditionally been undertaken slowly – typically over 24 hours. The National Patient Safety Agency has advised that intravenous fluid deficit replacement should be over 24 hours or longer. (See, Reducing the risk of hyponatraemia when administering intravenous infusions to children. National Patient Safety Agency, Alert no. 22.) Consequently, children will remain dehydrated and in hospital for a prolonged period. The World Health Organization's manual for physicians and other senior health workers on the treatment of diarrhoea recommends that intravenous rehydration should be completed in 3 to 6 hours. Many experts now support rapid intravenous rehydration, suggesting that it allows oral fluids to be starter earlier and can shorten the duration of hospital treatment. Randomised controlled trials are needed urgently to examine the safety and cost effectiveness of rapid intravenous rehydration regimens compared with slow intravenous rehydration.\n\n# Other therapies: ondansetron\n\nIn children with persistent vomiting caused by gastroenteritis, is oral ondansetron cost effective and safe compared with placebo therapy?\n\n## Why this is important\n\nSeveral randomised controlled trials have shown that in children with persistent vomiting during oral rehydration therapy, administration of oral ondansetron, an anti-emetic agent, can increase the likelihood of successful oral rehydration. However, in two of these there was evidence suggesting that diarrhoea was more pronounced in those given ondansetron than in those in the placebo groups. In one, in children given ondansetron, the number of stools passed during the rehydration phase was significantly greater, and in the other the number of stools passed in the first and second 24-hour period after rehydration was significantly greater. In those studies, diarrhoea was not a primary outcome, and it was reported as an adverse event. The reliability of the finding was therefore somewhat uncertain. If ondansetron does worsen diarrhoea it would be crucially important to determine the clinical significance of this effect, for example in relation to the risk of dehydration recurring or re-admission to hospital. If ondansetron is shown to be both effective and safe in secondary care then studies should also be undertaken to evaluate its use in primary care.\n\n# Other therapies: probiotics\n\nAre probiotics effective and safe compared with a placebo in the treatment of children with gastroenteritis in the UK? Which specific probiotic is most effective and in what specific treatment regimen?\n\n## Why this is important\n\nThe available studies of probiotic therapy frequently report benefits, particularly in terms of reduced duration of diarrhoea or stool frequency. However, most of the published studies have methodological limitations. Moreover, there is great variation in the specific probiotics evaluated and in the treatment regimens used. Many of these studies were conducted in developing countries where the response to probiotic therapy may differ. Good-quality randomised controlled trials should be conducted in the UK to evaluate the effectiveness and safety of specific probiotics, using clearly defined treatment regimens and outcome measures."}	https://www.nice.org.uk/guidance/cg84	This guideline covers diagnosing, managing and referring infants and young children younger than 5 years who present with acute diarrhoea (lasting up to 14 days) with or without vomiting. It aims to improve the diagnosis and management of infective gastroenteritis and appropriate escalation of care.
1590bec5bb8341548154998d4affc55ae0001cb0	nice	Ex-vivo hepatic resection and reimplantation for liver cancer	Ex-vivo hepatic resection and reimplantation for liver cancer # Guidance Current evidence on ex-vivo hepatic resection and reimplantation for liver cancer raises concerns about the safety and efficacy of the procedure. Therefore this procedure should only be used with special arrangements for clinical governance, consent and audit or research. It should only be used for patients who would otherwise not survive and for whom other treatment options have failed or are inappropriate. Clinicians wishing to undertake ex-vivo hepatic resection and reimplantation for liver cancer should take the following actions. Inform the clinical governance leads in their Trusts. Ensure that patients understand the uncertainty about the procedure's safety and efficacy; specifically the risks of death or serious morbidity, and the possible need for liver transplantation. Clear written information should be provided. In addition, the use of NICE's information for patients ('Understanding NICE guidance') is recommended. Audit and review clinical outcomes of all patients having ex-vivo hepatic resection and reimplantation for liver cancer (see section 3.1).# The procedure # Indications and current treatments This procedure can be carried out in patients with primary or secondary (metastatic) liver cancer. Treatment strategies for patients with liver cancer depend on tumour type, location, number and size. Most patients with liver cancer cannot benefit from surgical treatment and are treated with palliative intent. For some patients, liver resection surgery, either on its own or in combination with other treatments, may be beneficial. # Outline of the procedure The procedure is carried out with the patient under general anaesthesia. The liver is removed through an abdominal incision and is perfused with a preservative solution. A bloodless resection of the diseased hepatic parenchyma is then performed, allowing complex reconstruction of the hepatic and portal vein structures, and the liver is reimplanted into the patient. The procedure can be performed with or without venovenous bypass. Sections 2.3 and 2.4 describe efficacy and safety outcomes which were available in the published literature and which the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview. # Efficacy In a case series of 24 patients (22 with cancer) treated by ex-vivo hepatic resection and reimplantation, it was possible to resect and reimplant the liver in 91% (20/22) of the patients with cancer. In the case series of 24 patients (22 with cancer), 59% (13/22) survived the procedure and were discharged. Of the 13 patients who survived the procedure, 77% (10/13) died of tumour recurrence at between 12-month and 36-month follow-up. In a case series of 8 patients with liver metastases from colorectal cancer, 4 patients were treated by ex-vivo resection, of whom 2 were alive at 5-month follow-up (1 patient with tumour recurrence in the bone). The third patient died after 30 months and the fourth died 15 days after the operation. In a case series of 16 patients treated by liver resection with hepatic vein reconstruction, 2 patients were treated by ex-vivo resection. One of the 2 patients, with hepatocellular carcinoma, was alive and disease free at 52-month follow-up. The other patient, with colorectal metastases, was free of hepatic involvement at death following small bowel perforation after 4 months of follow-up. A case report of a single patient with hepatocellular carcinoma reported that the patient was alive with no recurrence 1 year after ex-vivo hepatic resection. In the case series of 24 patients (22 with cancer), the mean operative time was 13.54 hours, and the mean anhepatic phase was 6.67 hours. The Specialist Advisers stated that the key efficacy outcome of this procedure is survival. # Safety Of the 22 patients with cancer in the case series of 24 patients treated by ex-vivo liver resection, 41% (9/22) died postoperatively during the same admission episode as the operation (exact timing of death not stated). In the same study, 32% of patients (7/22) required donor liver transplantation either immediately (2 patients) or at a subsequent procedure (5 patients; exact timing of transplantation not stated). In the case series of 8 patients, of the 4 patients undergoing ex-vivo resection, 1 patient died after 15 days from respiratory failure, renal failure and haemopneumothorax; and 1 patient developed inferior vena caval obstruction requiring stenting and pleural effusion requiring drainage. The Specialist Advisers stated that adverse events (reported in the literature or anecdotally) include mortality, liver failure and bleeding/requirement for blood transfusion. The Specialist Advisers also commented that the procedure may increase the demand for donor livers.# Further information This guidance requires that clinicians undertaking the procedure make special arrangements for audit. NICE has identified relevant audit criteria and has developed audit support (which is for use at local discretion). NICE has published interventional procedures guidance on radiofrequency ablation for the treatment of colorectal metastases in the liver, selective internal radiation therapy for colorectal metastases in the liver, microwave ablation for the treatment of metastases in the liver, radiofrequency-assisted liver resection, living-donor transplantation, laparoscopic liver resection and radiofrequency ablation of hepatocellular carcinoma. # Information for patients NICE has produced information on this procedure for patients and carers ('Understanding NICE guidance'). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.# About this guidance NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland. This guidance was developed using the NICE interventional procedure guidance process. We have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available. Changes since publication January 2012: minor maintenance. Your responsibility This guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer. Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties. Copyright © National Institute for Health and Clinical Excellence 2009. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE. Contact NICE National Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT www.nice.org.uk nice@nice.org.uk	{'Guidance ': "Current evidence on ex-vivo hepatic resection and reimplantation for liver cancer raises concerns about the safety and efficacy of the procedure. Therefore this procedure should only be used with special arrangements for clinical governance, consent and audit or research. It should only be used for patients who would otherwise not survive and for whom other treatment options have failed or are inappropriate.\n\nClinicians wishing to undertake ex-vivo hepatic resection and reimplantation for liver cancer should take the following actions.\n\nInform the clinical governance leads in their Trusts.\n\nEnsure that patients understand the uncertainty about the procedure's safety and efficacy; specifically the risks of death or serious morbidity, and the possible need for liver transplantation. Clear written information should be provided. In addition, the use of NICE's information for patients ('Understanding NICE guidance') is recommended.\n\nAudit and review clinical outcomes of all patients having ex-vivo hepatic resection and reimplantation for liver cancer (see section 3.1).", 'The procedure': '# Indications and current treatments\n\nThis procedure can be carried out in patients with primary or secondary (metastatic) liver cancer.\n\nTreatment strategies for patients with liver cancer depend on tumour type, location, number and size. Most patients with liver cancer cannot benefit from surgical treatment and are treated with palliative intent. For some patients, liver resection surgery, either on its own or in combination with other treatments, may be beneficial.\n\n# Outline of the procedure\n\nThe procedure is carried out with the patient under general anaesthesia. The liver is removed through an abdominal incision and is perfused with a preservative solution. A bloodless resection of the diseased hepatic parenchyma is then performed, allowing complex reconstruction of the hepatic and portal vein structures, and the liver is reimplanted into the patient. The procedure can be performed with or without venovenous bypass.\n\nSections 2.3 and 2.4 describe efficacy and safety outcomes which were available in the published literature and which the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview.\n\n# Efficacy\n\nIn a case series of 24 patients (22 with cancer) treated by ex-vivo hepatic resection and reimplantation, it was possible to resect and reimplant the liver in 91% (20/22) of the patients with cancer. In the case series of 24 patients (22 with cancer), 59% (13/22) survived the procedure and were discharged. Of the 13 patients who survived the procedure, 77% (10/13) died of tumour recurrence at between 12-month and 36-month follow-up. In a case series of 8 patients with liver metastases from colorectal cancer, 4 patients were treated by ex-vivo resection, of whom 2 were alive at 5-month follow-up (1 patient with tumour recurrence in the bone). The third patient died after 30 months and the fourth died 15 days after the operation. In a case series of 16 patients treated by liver resection with hepatic vein reconstruction, 2 patients were treated by ex-vivo resection. One of the 2 patients, with hepatocellular carcinoma, was alive and disease free at 52-month follow-up. The other patient, with colorectal metastases, was free of hepatic involvement at death following small bowel perforation after 4 months of follow-up. A case report of a single patient with hepatocellular carcinoma reported that the patient was alive with no recurrence 1 year after ex-vivo hepatic resection.\n\nIn the case series of 24 patients (22 with cancer), the mean operative time was 13.54 hours, and the mean anhepatic phase was 6.67 hours.\n\nThe Specialist Advisers stated that the key efficacy outcome of this procedure is survival.\n\n# Safety\n\nOf the 22 patients with cancer in the case series of 24 patients treated by ex-vivo liver resection, 41% (9/22) died postoperatively during the same admission episode as the operation (exact timing of death not stated). In the same study, 32% of patients (7/22) required donor liver transplantation either immediately (2 patients) or at a subsequent procedure (5 patients; exact timing of transplantation not stated).\n\nIn the case series of 8 patients, of the 4 patients undergoing ex-vivo resection, 1 patient died after 15 days from respiratory failure, renal failure and haemopneumothorax; and 1 patient developed inferior vena caval obstruction requiring stenting and pleural effusion requiring drainage.\n\nThe Specialist Advisers stated that adverse events (reported in the literature or anecdotally) include mortality, liver failure and bleeding/requirement for blood transfusion. The Specialist Advisers also commented that the procedure may increase the demand for donor livers.', 'Further information': "This guidance requires that clinicians undertaking the procedure make special arrangements for audit. NICE has identified relevant audit criteria and has developed audit support (which is for use at local discretion).\n\nNICE has published interventional procedures guidance on radiofrequency ablation for the treatment of colorectal metastases in the liver, selective internal radiation therapy for colorectal metastases in the liver, microwave ablation for the treatment of metastases in the liver, radiofrequency-assisted liver resection, living-donor transplantation, laparoscopic liver resection and radiofrequency ablation of hepatocellular carcinoma.\n\n# Information for patients\n\nNICE has produced information on this procedure for patients and carers ('Understanding NICE guidance'). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.", 'About this guidance': 'NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland.\n\nThis guidance was developed using the NICE interventional procedure guidance process.\n\nWe have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available.\n\nChanges since publication\n\nJanuary 2012: minor maintenance.\n\nYour responsibility\n\nThis guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.\n\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.\n\nCopyright\n\n© National Institute for Health and Clinical Excellence 2009. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.\n\nContact NICE\n\nNational Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT\n\nwww.nice.org.uk\n \n nice@nice.org.uk\n 0845 033 7780'}	https://www.nice.org.uk/guidance/ipg298
cefe75d028fdf68af33281981be4ac1badd4e86a	nice	Endoscopic mastectomy and endoscopic wide local excision for breast cancer	Endoscopic mastectomy and endoscopic wide local excision for breast cancer # Guidance Current evidence on the safety and efficacy of endoscopic mastectomy and endoscopic wide local excision for breast cancer is inadequate in quantity. Therefore, these procedures should only be used in the context of research. The research should include adequacy of resection margins, survival, recurrence or reoperation rates, tumour size and location, patient breast size, quality of life, and cosmesis. Research should be conducted only in units specialising in the management of breast cancer, by surgeons trained in both breast cancer surgery and endoscopy. NICE may review the procedure on publication of further evidence.# The procedure # Indications and current treatments Breast cancer is the most common cancer in women in the UK. It can be categorised into four stages, from stage 1 (an isolated tumour less than 2 cm in diameter) to stage 4 (advanced cancer), and three grades, from grade 1 (slow-growing cancer) to grade 3 (fast-growing cancer). It may be classified further, depending on protein markers present. Treatment depends on the breast cancer type, stage and grade. Surgery is often the first option for early breast cancer and may involve removing the whole breast (mastectomy) or part of the breast ('conservative' or 'breast conserving' surgery). Adjuvant radiotherapy, chemotherapy or endocrine therapy may be offered to reduce the risk of local tumour recurrence. # Outline of the procedure Endoscopic mastectomy and endoscopic wide local excision for breast cancer are performed with the patient under general anaesthesia. These procedures can be performed through an axillary incision (usually), a periareolar incision, or using both types of incision. Under endoscopic guidance, carbon dioxide insufflation is used to create a working space and the breast tissue is dissected. Haemostasis is achieved by ligation and electrical coagulation. For endoscopic mastectomy, the breast tissue, including the tumour, is separated from the muscle and subcutaneous tissues, and removed. For endoscopic wide excision, the breast part containing the tumour is removed, with adequate healthy breast tissue margins. Drains are inserted and the incisions closed. Immediate reconstructive surgery may be performed if appropriate. As with other types of breast cancer surgery, adjuvant radiotherapy, chemotherapy or endocrine therapy may also be offered. Sections 2.3 and 2.4 describe efficacy and safety outcomes which were available in the published literature and which the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview. # Efficacy A non-randomised controlled trial compared outcomes in 21 patients treated by endoscopic mastectomy and 25 patients treated by subcutaneous mastectomy without an endoscope, for early stage breast cancer (stage 1 or 2). The trial reported that all patients were alive at a median 19-month follow-up (range 5.8–35.2 months). A case series of 551 patients treated by endoscopic mastectomy reported distant-metastasis-free survival to be 100% in those with ductal carcinoma in situ (a very early form of breast cancer) (n = 47), 96% in those with T1 tumours (less than 2 cm diameter) (n = 190), and 91% in those with T2 tumours (2–5 cm diameter) (n = 314) at 66-month follow-up. The case series of 551 patients reported local recurrence in 4% (23/551) of patients after a mean follow-up of 38.4 months. A case series of 20 breast cancer patients reported that, at 6-month mammography, 1 patient had microcalcification in her remaining breast, requiring total endoscopic mastectomy for multifocal carcinoma. In the non-randomised controlled trial of 46 patients, histological examination revealed positive resection margins requiring radiation therapy 4 weeks after surgery in 5% (1/21) and 8% (2/25) of patients. Two case series of 20 and 6 patients reported positive histological margins in 1 patient each, the first requiring endoscopic total mastectomy (10 days after the first operation) and the second requiring additional adjuvant radiotherapy. The case series of 551 patients reported overall patient satisfaction results from a postal questionnaire. Of the 481 respondents, 76% (366/481) reported 'good' results, 14% (66/481) reported 'fair' results and 10% (49/481) reported 'poor' results (not further defined) at 6-month follow-up. The Specialist Advisers considered key efficacy outcomes to include long-term survival, adequacy of tumour clearance, tumour recurrence, cosmesis, patient satisfaction, postoperative pain control, time to return to work and length of hospital stay. # Safety Case series of 33 and 551 patients reported nipple necrosis in 9% (3/33), skin necrosis in 4% (22/551) and fat and/or muscle flap necrosis in 3% (17/551) of patients (time of occurrence not stated).. A case series of 82 patients with malignant tumours reported second-degree burns in 4 patients (one burn occurred during skin flap formation near the nipple and three burns occurred during additional resection for positive surgical margins found on fast-frozen sections). In a case series of 7 patients, skin burns caused by the electrocautery were reported in 2 patients; 1 patient required skin debridement. The case series of 82 patients reported subcutaneous haemorrhage in 7 patients and haematoma in 2 patients (reoperation not required). The Specialist Advisers considered theoretical adverse events to include major neurovascular injury, pneumothorax, non-viable skin flaps and longer operating time than traditional open surgery. # Other comments The Committee noted that these procedures have also been used for benign breast lesions. The Committee noted that most of the evidence relates to East Asian patient populations with generally small breast sizes. The technique may be different in women with larger breasts.# Further information NICE has published cancer service guidance, interventional procedures guidance, technology appraisals guidance and clinical guidelines on breast cancer. For more information see our website. # Information for patients NICE has produced information on this procedure for patients and carers ('Understanding NICE guidance'). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.# About this guidance NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland. This guidance was developed using the NICE interventional procedure guidance process. It has been incorporated into the NICE pathway on early and locally advanced breast cancer, along with other related guidance and products. We have produced a summary of this guidance for patients and carers. Information about the evidence it is based on is also available. Changes since publication January 2012: minor maintenance. Your responsibility This guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer. Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties. Copyright © National Institute for Health and Clinical Excellence 2009. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE. Contact NICE National Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT www.nice.org.uk nice@nice.org.uk	{'Guidance ': 'Current evidence on the safety and efficacy of endoscopic mastectomy and endoscopic wide local excision for breast cancer is inadequate in quantity. Therefore, these procedures should only be used in the context of research. The research should include adequacy of resection margins, survival, recurrence or reoperation rates, tumour size and location, patient breast size, quality of life, and cosmesis.\n\nResearch should be conducted only in units specialising in the management of breast cancer, by surgeons trained in both breast cancer surgery and endoscopy.\n\nNICE may review the procedure on publication of further evidence.', 'The procedure': "# Indications and current treatments\n\nBreast cancer is the most common cancer in women in the UK. It can be categorised into four stages, from stage 1 (an isolated tumour less than 2 cm in diameter) to stage 4 (advanced cancer), and three grades, from grade 1 (slow-growing cancer) to grade 3 (fast-growing cancer). It may be classified further, depending on protein markers present.\n\nTreatment depends on the breast cancer type, stage and grade. Surgery is often the first option for early breast cancer and may involve removing the whole breast (mastectomy) or part of the breast ('conservative' or 'breast conserving' surgery). Adjuvant radiotherapy, chemotherapy or endocrine therapy may be offered to reduce the risk of local tumour recurrence.\n\n# Outline of the procedure\n\nEndoscopic mastectomy and endoscopic wide local excision for breast cancer are performed with the patient under general anaesthesia. These procedures can be performed through an axillary incision (usually), a periareolar incision, or using both types of incision. Under endoscopic guidance, carbon dioxide insufflation is used to create a working space and the breast tissue is dissected. Haemostasis is achieved by ligation and electrical coagulation. For endoscopic mastectomy, the breast tissue, including the tumour, is separated from the muscle and subcutaneous tissues, and removed. For endoscopic wide excision, the breast part containing the tumour is removed, with adequate healthy breast tissue margins. Drains are inserted and the incisions closed. Immediate reconstructive surgery may be performed if appropriate.\n\nAs with other types of breast cancer surgery, adjuvant radiotherapy, chemotherapy or endocrine therapy may also be offered.\n\nSections 2.3 and 2.4 describe efficacy and safety outcomes which were available in the published literature and which the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview.\n\n# Efficacy\n\nA non-randomised controlled trial compared outcomes in 21 patients treated by endoscopic mastectomy and 25 patients treated by subcutaneous mastectomy without an endoscope, for early stage breast cancer (stage 1 or 2). The trial reported that all patients were alive at a median 19-month follow-up (range 5.8–35.2 months). A case series of 551 patients treated by endoscopic mastectomy reported distant-metastasis-free survival to be 100% in those with ductal carcinoma in situ (a very early form of breast cancer) (n = 47), 96% in those with T1 tumours (less than 2 cm diameter) (n = 190), and 91% in those with T2 tumours (2–5 cm diameter) (n = 314) at 66-month follow-up.\n\nThe case series of 551 patients reported local recurrence in 4% (23/551) of patients after a mean follow-up of 38.4 months.\n\nA case series of 20 breast cancer patients reported that, at 6-month mammography, 1 patient had microcalcification in her remaining breast, requiring total endoscopic mastectomy for multifocal carcinoma.\n\nIn the non-randomised controlled trial of 46 patients, histological examination revealed positive resection margins requiring radiation therapy 4 weeks after surgery in 5% (1/21) and 8% (2/25) of patients. Two case series of 20 and 6 patients reported positive histological margins in 1 patient each, the first requiring endoscopic total mastectomy (10 days after the first operation) and the second requiring additional adjuvant radiotherapy.\n\nThe case series of 551 patients reported overall patient satisfaction results from a postal questionnaire. Of the 481 respondents, 76% (366/481) reported 'good' results, 14% (66/481) reported 'fair' results and 10% (49/481) reported 'poor' results (not further defined) at 6-month follow-up.\n\nThe Specialist Advisers considered key efficacy outcomes to include long-term survival, adequacy of tumour clearance, tumour recurrence, cosmesis, patient satisfaction, postoperative pain control, time to return to work and length of hospital stay.\n\n# Safety\n\nCase series of 33 and 551 patients reported nipple necrosis in 9% (3/33), skin necrosis in 4% (22/551) and fat and/or muscle flap necrosis in 3% (17/551) of patients (time of occurrence not stated)..\n\nA case series of 82 patients with malignant tumours reported second-degree burns in 4 patients (one burn occurred during skin flap formation near the nipple and three burns occurred during additional resection for positive surgical margins found on fast-frozen sections). In a case series of 7 patients, skin burns caused by the electrocautery were reported in 2 patients; 1 patient required skin debridement.\n\nThe case series of 82 patients reported subcutaneous haemorrhage in 7 patients and haematoma in 2 patients (reoperation not required).\n\nThe Specialist Advisers considered theoretical adverse events to include major neurovascular injury, pneumothorax, non-viable skin flaps and longer operating time than traditional open surgery.\n\n# Other comments\n\nThe Committee noted that these procedures have also been used for benign breast lesions.\n\nThe Committee noted that most of the evidence relates to East Asian patient populations with generally small breast sizes. The technique may be different in women with larger breasts.", 'Further information': "NICE has published cancer service guidance, interventional procedures guidance, technology appraisals guidance and clinical guidelines on breast cancer. For more information see our website.\n\n# Information for patients\n\nNICE has produced information on this procedure for patients and carers ('Understanding NICE guidance'). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.", 'About this guidance': 'NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland.\n\nThis guidance was developed using the NICE interventional procedure guidance process.\n\nIt has been incorporated into the NICE pathway on early and locally advanced breast cancer, along with other related guidance and products.\n\nWe have produced a summary of this guidance for patients and carers. Information about the evidence it is based on is also available.\n\nChanges since publication\n\nJanuary 2012: minor maintenance.\n\nYour responsibility\n\nThis guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.\n\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.\n\nCopyright\n\n© National Institute for Health and Clinical Excellence 2009. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.\n\nContact NICE\n\nNational Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT\n\nwww.nice.org.uk\n \n nice@nice.org.uk\n 0845 033 7780'}	https://www.nice.org.uk/guidance/ipg296
41f40db906250fffe4013500904636a3e8b8b141	nice	Combined bony and soft tissue reconstruction for hip joint stabilisation in proximal focal femoral deficiency (PFFD)	Combined bony and soft tissue reconstruction for hip joint stabilisation in proximal focal femoral deficiency (PFFD) # Guidance Current evidence on the safety and efficacy of combined bony and soft tissue reconstruction for hip joint stabilisation in proximal focal femoral deficiency (PFFD) is inadequate in quantity, quality and consistency. Therefore this procedure should only be used with special arrangements for clinical governance, consent and audit or research. Clinicians wishing to undertake combined bony and soft tissue reconstruction for hip joint stabilisation in PFFD should take the following actions. Inform the clinical governance leads in their Trusts. Ensure that parents or carers understand the uncertainty about the procedure's safety and efficacy. They should understand that multiple procedures may be needed and that the procedure may not result in a fully functioning limb. Parents or carers should be provided with clear written information. In addition, the use of NICE's information for patients ('Understanding NICE guidance') is recommended. Audit and review clinical outcomes of all patients having combined bony and soft tissue reconstruction for hip joint stabilisation in PFFD (see section 3.1). The procedure should only be carried out in units that specialise in limb reconstruction, by surgeons with specialist knowledge of neonatal hip dysplasias and expertise in limb lengthening procedures.# The procedure # Indications and current treatments Proximal focal femoral deficiency is a congenital syndrome typically characterised by poor hip joint development and femoral shortening. The severity of the syndrome is variable. In severe cases, there may be no hip joint and the femur may be very short. In addition, PFFD may be associated with other lower limb abnormalities, such as an abnormal knee joint, lower limb malrotation, inadequacy of the proximal musculature and limb length discrepancy. Treatment options depend on the extent of the PFFD. In patients with severe forms of PFFD, it may not be possible to produce a leg that is functional and of the correct length, so partial limb amputation and fitting of a prosthesis may be the preferred management. In patients with relatively mild PFFD, an attempt can be made to correct the abnormalities of the hip joint and the upper femur. # Outline of the procedure Combined bony and soft tissue reconstruction for hip joint stabilisation in PFFD is carried out with the patient under general anaesthesia. There are several variations on the procedure. Hip stabilisation involves a long incision on the outer side of the thigh. With the soft tissues retracted or released, the upper femur deformity is corrected by bone division and fixation. If needed, the pelvic bone may also be divided and moved to help reconstruct the hip joint. After surgery, the joint may need to be immobilised in a plaster cast. If the hip joint cannot be salvaged, the upper femur may be stabilised against the pelvis using a pelvic support osteotomy, and this may be combined with leg lengthening procedures. Several additional procedures may be required to achieve reconstruction or to enable prosthetic attachment, either at the same time or afterwards as separate procedures. These may include leg lengthening, epiphysiodesis of the normal (opposite) femur, knee reconstruction, Van Nes rotationplasty, and 'above-the-knee' amputation. Sections 2.3 and 2.4 describe efficacy and safety outcomes which were available in the published literature and which the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview. # Efficacy A case series of 14 patients reported that 64% (9/14) of patients had a good clinical outcome after hip stabilisation, leg lengthening and external fixation (based on a composite measure of gait, range of movement, degree of dislocation and residual shortening), at a mean follow-up of 17 years. At final follow-up, the mean difference in patients' limb length was 11.6 cm (range 1–20 cm) (duration of follow-up not stated). Angular deformity was reported in 21% (3/14) of patients (mean follow-up 17 years). A case report of 3 patients who had plaster casts for 3 months then valgus osteotomy described successful reorientation and stabilisation of the hip and straightening of the femur. Femoral lengthening was undertaken in 1 patient and planned in 2 others at a follow-up of 2.3–8 years. The case series of 14 patients reported that 43% (6/14) needed more than one lengthening procedure. The Specialist Advisers considered key efficacy outcomes to be overall limb function and a reduced need for repeat procedures. The Specialist Advisers also stated that for some patients, the result may not be as good as would have been achieved by amputation and fitting of a prosthesis. # Safety The case series of 14 patients reported osteitis in 43% (6/14) of patients, fracture (not otherwise described) in 7% (1/14) of patients, and pseudoarthritis in 7% (1/14) of patients (mean follow-up 17 years). The Specialist Advisers stated that adverse events (reported in the literature or anecdotally) include significant hip and knee stiffness as a result of excessive lengthening, hip dislocation and recurrent deformity. The Specialist Advisers also considered theoretical adverse events to include avascular necrosis, bone non-union, infection, nerve or vascular injury, poor limb function, recurrence of contractures and wound dehiscence.# Further information This guidance requires that clinicians undertaking the procedure make special arrangements for audit. NICE has identified relevant audit criteria and has developed audit support (which is for use at local discretion). NICE has published interventional procedures guidance on intramedullary distraction for lower limb lengthening. # Information for patients NICE has produced information on this procedure for patients and carers ('Understanding NICE guidance'). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.# About this guidance NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland. This guidance was developed using the NICE interventional procedure guidance process. We have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available. Changes since publication January 2012: minor maintenance. Your responsibility This guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer. Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties. Copyright © National Institute for Health and Clinical Excellence 2009. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE. Contact NICE National Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT www.nice.org.uk nice@nice.org.uk	{'Guidance ': "Current evidence on the safety and efficacy of combined bony and soft tissue reconstruction for hip joint stabilisation in proximal focal femoral deficiency (PFFD) is inadequate in quantity, quality and consistency. Therefore this procedure should only be used with special arrangements for clinical governance, consent and audit or research.\n\nClinicians wishing to undertake combined bony and soft tissue reconstruction for hip joint stabilisation in PFFD should take the following actions.\n\nInform the clinical governance leads in their Trusts.\n\nEnsure that parents or carers understand the uncertainty about the procedure's safety and efficacy. They should understand that multiple procedures may be needed and that the procedure may not result in a fully functioning limb. Parents or carers should be provided with clear written information. In addition, the use of NICE's information for patients ('Understanding NICE guidance') is recommended.\n\nAudit and review clinical outcomes of all patients having combined bony and soft tissue reconstruction for hip joint stabilisation in PFFD (see section 3.1).\n\nThe procedure should only be carried out in units that specialise in limb reconstruction, by surgeons with specialist knowledge of neonatal hip dysplasias and expertise in limb lengthening procedures.", 'The procedure': "# Indications and current treatments\n\nProximal focal femoral deficiency is a congenital syndrome typically characterised by poor hip joint development and femoral shortening. The severity of the syndrome is variable. In severe cases, there may be no hip joint and the femur may be very short. In addition, PFFD may be associated with other lower limb abnormalities, such as an abnormal knee joint, lower limb malrotation, inadequacy of the proximal musculature and limb length discrepancy.\n\nTreatment options depend on the extent of the PFFD. In patients with severe forms of PFFD, it may not be possible to produce a leg that is functional and of the correct length, so partial limb amputation and fitting of a prosthesis may be the preferred management. In patients with relatively mild PFFD, an attempt can be made to correct the abnormalities of the hip joint and the upper femur.\n\n# Outline of the procedure\n\nCombined bony and soft tissue reconstruction for hip joint stabilisation in PFFD is carried out with the patient under general anaesthesia. There are several variations on the procedure. Hip stabilisation involves a long incision on the outer side of the thigh. With the soft tissues retracted or released, the upper femur deformity is corrected by bone division and fixation. If needed, the pelvic bone may also be divided and moved to help reconstruct the hip joint. After surgery, the joint may need to be immobilised in a plaster cast. If the hip joint cannot be salvaged, the upper femur may be stabilised against the pelvis using a pelvic support osteotomy, and this may be combined with leg lengthening procedures.\n\nSeveral additional procedures may be required to achieve reconstruction or to enable prosthetic attachment, either at the same time or afterwards as separate procedures. These may include leg lengthening, epiphysiodesis of the normal (opposite) femur, knee reconstruction, Van Nes rotationplasty, and 'above-the-knee' amputation.\n\nSections 2.3 and 2.4 describe efficacy and safety outcomes which were available in the published literature and which the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview.\n\n# Efficacy\n\nA case series of 14 patients reported that 64% (9/14) of patients had a good clinical outcome after hip stabilisation, leg lengthening and external fixation (based on a composite measure of gait, range of movement, degree of dislocation and residual shortening), at a mean follow-up of 17 years. At final follow-up, the mean difference in patients' limb length was 11.6 cm (range 1–20 cm) (duration of follow-up not stated). Angular deformity was reported in 21% (3/14) of patients (mean follow-up 17 years).\n\nA case report of 3 patients who had plaster casts for 3 months then valgus osteotomy described successful reorientation and stabilisation of the hip and straightening of the femur. Femoral lengthening was undertaken in 1 patient and planned in 2 others at a follow-up of 2.3–8 years. The case series of 14 patients reported that 43% (6/14) needed more than one lengthening procedure.\n\nThe Specialist Advisers considered key efficacy outcomes to be overall limb function and a reduced need for repeat procedures. The Specialist Advisers also stated that for some patients, the result may not be as good as would have been achieved by amputation and fitting of a prosthesis.\n\n# Safety\n\nThe case series of 14 patients reported osteitis in 43% (6/14) of patients, fracture (not otherwise described) in 7% (1/14) of patients, and pseudoarthritis in 7% (1/14) of patients (mean follow-up 17 years).\n\nThe Specialist Advisers stated that adverse events (reported in the literature or anecdotally) include significant hip and knee stiffness as a result of excessive lengthening, hip dislocation and recurrent deformity. The Specialist Advisers also considered theoretical adverse events to include avascular necrosis, bone non-union, infection, nerve or vascular injury, poor limb function, recurrence of contractures and wound dehiscence.", 'Further information': "This guidance requires that clinicians undertaking the procedure make special arrangements for audit. NICE has identified relevant audit criteria and has developed audit support (which is for use at local discretion).\n\nNICE has published interventional procedures guidance on intramedullary distraction for lower limb lengthening.\n\n# Information for patients\n\nNICE has produced information on this procedure for patients and carers ('Understanding NICE guidance'). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.", 'About this guidance': 'NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland.\n\nThis guidance was developed using the NICE interventional procedure guidance process.\n\nWe have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available.\n\nChanges since publication\n\nJanuary 2012: minor maintenance.\n\nYour responsibility\n\nThis guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.\n\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.\n\nCopyright\n\n© National Institute for Health and Clinical Excellence 2009. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.\n\nContact NICE\n\nNational Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT\n\nwww.nice.org.uk\n \n nice@nice.org.uk\n 0845 033 7780'}	https://www.nice.org.uk/guidance/ipg297
6994f18f37f7307f934b90e858ffb984b88b819e	nice	Percutaneous (non-thoracoscopic) epicardial catheter radiofrequency ablation for atrial fibrillation	Percutaneous (non-thoracoscopic) epicardial catheter radiofrequency ablation for atrial fibrillation # Guidance Current evidence on the safety and efficacy of percutaneous (non-thoracoscopic) epicardial catheter radiofrequency ablation for atrial fibrillation (AF) is inadequate in quantity. Therefore this procedure should only be used with special arrangements for clinical governance and consent. Clinicians wishing to undertake percutaneous (non-thoracoscopic) epicardial catheter radiofrequency ablation for AF should take the following actions. Inform the clinical governance leads in their Trusts. Ensure that patients understand the uncertainty about the procedure's safety and efficacy and provide them with clear written information. In addition, the use of NICE's information for patients ('Understanding NICE guidance') is recommended. Patient selection and treatment should be carried out only by a team specialising in the treatment of cardiac arrhythmias that includes experts in electrophysiology and ablation. The procedure should only be carried out by interventional cardiologists with specific training in electrophysiology, and in accessing the pericardial space and performing complex ablation procedures. The procedure should only be carried out in units with arrangements for emergency cardiac surgical support in case of complications. The NHS Information Centre for health and social care runs the UK Central Cardiac Audit Database, and clinicians should enter details about all patients undergoing percutaneous (non-thoracoscopic) epicardial catheter radiofrequency ablation for AF onto this database. Clinicians are encouraged to enter patients into research studies that aim to provide more information about patient selection, the use of this procedure as an adjunct to other procedures, freedom from AF in the long term and relief of associated symptoms, and the safety profile of the procedure. NICE may review the procedure on publication of further evidence.# The procedure # Indications and current treatments Atrial fibrillation is the most common type of cardiac arrhythmia, and is caused by the irregular and rapid beating of the atria. It can be classified as paroxysmal, persistent or permanent, depending on episode duration and the patient's response to treatment. People with AF may be asymptomatic or they may have symptoms such as palpitations, dizziness, breathlessness and fatigue. Atrial fibrillation is associated with increased risk of death and of embolic stroke from atrial thrombus. Anticoagulation treatment is used to reduce this risk. Antiarrhythmic medication is used either to help maintain a normal cardiac rhythm following successful cardioversion or to help reduce the heart rate. Ablation procedures can be used when drug therapy is either not tolerated or is ineffective. # Outline of the procedure The procedure is carried out with the patient under sedation or general anaesthesia. The pericardial space is accessed by a subxiphoid needle puncture under fluoroscopic guidance. A guidewire is introduced through the needle and a sheath is advanced over the guidewire so that the tip is placed inside the pericardial sac. The sheath is aspirated to check for bleeding. A radiofrequency catheter is inserted into the sheath. After electrophysiological mapping to determine target sites for ablation, radiofrequency energy pulses are applied to the epicardium. During the procedure, catheter position is monitored with a three-dimensional mapping system to avoid collateral damage. Saline is placed in the pericardial space to reduce the risk of oesophageal injury, and steroids are administered to reduce the risk of pericarditis. Patients can have a combined procedure that includes electrophysiological mapping and ablation by both endocardial and epicardial approaches. Sections 2.3 and 2.4 describe efficacy and safety outcomes which were available in the published literature and which the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview. # Efficacy In a case series of five patients, all of them had percutaneous epicardial catheter radiofrequency ablation after failed endocardial ablation. Four patients were AF free and not on antiarrhythmic medication at 2-month, 6-month, 13-month and 15-month follow-up, respectively. The fifth patient was AF free but on antiarrhythmic medication at 4-month follow-up. A case report of a patient with persistent AF (refractory to antiarrhythmic medication and with two previous failed electrical cardioversions) reported that the patient was symptom free at 1 month postoperatively. One Specialist Adviser thought that the key efficacy outcome was freedom from AF. One Specialist Adviser commented that there was uncertainty about the efficacy of the procedure because of the small number of cases reported in the literature. # Safety In the case series of five patients, one patient developed haemopericardium during the percutaneous epicardial puncture, which was successfully drained. In another patient, a tachycardia originating from the left inferior pulmonary vein was observed during the procedure but this was successfully terminated with delivery of further epicardial and endocardial radiofrequency pulses. The Specialist Advisers considered that potential safety concerns included myocardial puncture; pericarditis; coronary artery damage; perforation of the right ventricle; damage to the oesophagus, bronchi and phrenic nerve; gastric puncture; and damage to abdominal vessels and organs when accessing the pericardial space. One Specialist Adviser considered there to be uncertainty about the long-term safety of the procedure.# Further information NICE has published a clinical guideline on AF and interventional procedures guidance on several procedures for AF, with or without cardiac surgery. NICE has also published interventional procedures guidance on percutaneous (non-thoracoscopic) epicardial catheter radiofrequency ablation for ventricular tachycardia. For more information see our website. # Information for patients NICE has produced information on this procedure for patients and carers ('Understanding NICE guidance'). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.# About this guidance NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland. This guidance was developed using the NICE interventional procedure guidance process. We have produced a summary of this guidance for patients and carers. Information about the evidence it is based on is also available. Changes since publication May 2012: minor maintenance. Your responsibility This guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer. Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties. Copyright © National Institute for Health and Clinical Excellence 2009. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE. Contact NICE National Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT www.nice.org.uk nice@nice.org.uk	{'Guidance ': "Current evidence on the safety and efficacy of percutaneous (non-thoracoscopic) epicardial catheter radiofrequency ablation for atrial fibrillation (AF) is inadequate in quantity. Therefore this procedure should only be used with special arrangements for clinical governance and consent.\n\nClinicians wishing to undertake percutaneous (non-thoracoscopic) epicardial catheter radiofrequency ablation for AF should take the following actions.\n\nInform the clinical governance leads in their Trusts.\n\nEnsure that patients understand the uncertainty about the procedure's safety and efficacy and provide them with clear written information. In addition, the use of NICE's information for patients ('Understanding NICE guidance') is recommended.\n\nPatient selection and treatment should be carried out only by a team specialising in the treatment of cardiac arrhythmias that includes experts in electrophysiology and ablation.\n\nThe procedure should only be carried out by interventional cardiologists with specific training in electrophysiology, and in accessing the pericardial space and performing complex ablation procedures.\n\nThe procedure should only be carried out in units with arrangements for emergency cardiac surgical support in case of complications.\n\nThe NHS Information Centre for health and social care runs the UK Central Cardiac Audit Database, and clinicians should enter details about all patients undergoing percutaneous (non-thoracoscopic) epicardial catheter radiofrequency ablation for AF onto this database.\n\nClinicians are encouraged to enter patients into research studies that aim to provide more information about patient selection, the use of this procedure as an adjunct to other procedures, freedom from AF in the long term and relief of associated symptoms, and the safety profile of the procedure. NICE may review the procedure on publication of further evidence.", 'The procedure': "# Indications and current treatments\n\nAtrial fibrillation is the most common type of cardiac arrhythmia, and is caused by the irregular and rapid beating of the atria. It can be classified as paroxysmal, persistent or permanent, depending on episode duration and the patient's response to treatment. People with AF may be asymptomatic or they may have symptoms such as palpitations, dizziness, breathlessness and fatigue. Atrial fibrillation is associated with increased risk of death and of embolic stroke from atrial thrombus. Anticoagulation treatment is used to reduce this risk.\n\nAntiarrhythmic medication is used either to help maintain a normal cardiac rhythm following successful cardioversion or to help reduce the heart rate. Ablation procedures can be used when drug therapy is either not tolerated or is ineffective.\n\n# Outline of the procedure\n\nThe procedure is carried out with the patient under sedation or general anaesthesia. The pericardial space is accessed by a subxiphoid needle puncture under fluoroscopic guidance. A guidewire is introduced through the needle and a sheath is advanced over the guidewire so that the tip is placed inside the pericardial sac. The sheath is aspirated to check for bleeding. A radiofrequency catheter is inserted into the sheath. After electrophysiological mapping to determine target sites for ablation, radiofrequency energy pulses are applied to the epicardium.\n\nDuring the procedure, catheter position is monitored with a three-dimensional mapping system to avoid collateral damage. Saline is placed in the pericardial space to reduce the risk of oesophageal injury, and steroids are administered to reduce the risk of pericarditis. Patients can have a combined procedure that includes electrophysiological mapping and ablation by both endocardial and epicardial approaches.\n\nSections 2.3 and 2.4 describe efficacy and safety outcomes which were available in the published literature and which the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview.\n\n# Efficacy\n\nIn a case series of five patients, all of them had percutaneous epicardial catheter radiofrequency ablation after failed endocardial ablation. Four patients were AF free and not on antiarrhythmic medication at 2-month, 6-month, 13-month and 15-month follow-up, respectively. The fifth patient was AF free but on antiarrhythmic medication at 4-month follow-up.\n\nA case report of a patient with persistent AF (refractory to antiarrhythmic medication and with two previous failed electrical cardioversions) reported that the patient was symptom free at 1 month postoperatively.\n\nOne Specialist Adviser thought that the key efficacy outcome was freedom from AF. One Specialist Adviser commented that there was uncertainty about the efficacy of the procedure because of the small number of cases reported in the literature.\n\n# Safety\n\nIn the case series of five patients, one patient developed haemopericardium during the percutaneous epicardial puncture, which was successfully drained. In another patient, a tachycardia originating from the left inferior pulmonary vein was observed during the procedure but this was successfully terminated with delivery of further epicardial and endocardial radiofrequency pulses.\n\nThe Specialist Advisers considered that potential safety concerns included myocardial puncture; pericarditis; coronary artery damage; perforation of the right ventricle; damage to the oesophagus, bronchi and phrenic nerve; gastric puncture; and damage to abdominal vessels and organs when accessing the pericardial space. One Specialist Adviser considered there to be uncertainty about the long-term safety of the procedure.", 'Further information': "NICE has published a clinical guideline on AF and interventional procedures guidance on several procedures for AF, with or without cardiac surgery. NICE has also published interventional procedures guidance on percutaneous (non-thoracoscopic) epicardial catheter radiofrequency ablation for ventricular tachycardia. For more information see our website.\n\n# Information for patients\n\nNICE has produced information on this procedure for patients and carers ('Understanding NICE guidance'). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.", 'About this guidance': 'NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland.\n\nThis guidance was developed using the NICE interventional procedure guidance process.\n\nWe have produced a summary of this guidance for patients and carers. Information about the evidence it is based on is also available.\n\nChanges since publication\n\nMay 2012: minor maintenance.\n\nYour responsibility\n\nThis guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.\n\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.\n\nCopyright\n\n© National Institute for Health and Clinical Excellence 2009. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.\n\nContact NICE\n\nNational Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT\n\nwww.nice.org.uk\n \n nice@nice.org.uk\n 0845 033 7780'}	https://www.nice.org.uk/guidance/ipg294
43c71908406da717806471a71ed2a005dffb5fdc	nice	Percutaneous (non-thoracoscopic) epicardial catheter radiofrequency ablation for ventricular tachycardia	Percutaneous (non-thoracoscopic) epicardial catheter radiofrequency ablation for ventricular tachycardia # Guidance The evidence on percutaneous (non-thoracoscopic) epicardial catheter radiofrequency ablation for ventricular tachycardia (VT) is limited to a small number of patients, but it shows that the procedure is efficacious in carefully selected individuals and raises no major safety issues, in the context of a condition which is potentially life-threatening. Therefore, the procedure may be used with normal arrangements for clinical governance, but with special arrangements for consent. During the consent process clinicians should ensure that patients understand the risks of potentially serious complications, including damage to the heart muscle. Patient selection and treatment should be carried out only by a team specialising in the treatment of cardiac arrhythmias that includes experts in electrophysiology and ablation. The procedure should only be carried out by interventional cardiologists with specific training in electrophysiology and in accessing the pericardial space and performing complex ablation procedures. The procedure should only be carried out in units with arrangements for emergency cardiac surgical support in case of complications. The NHS Information Centre for health and social care runs the UK Central Cardiac Audit Database, and clinicians should enter details about all patients undergoing percutaneous (non-thoracoscopic) epicardial catheter radiofrequency ablation for VT onto this database. NICE encourages further research into and publication of the outcomes and potential serious complications of percutaneous (non-thoracoscopic) epicardial catheter radiofrequency ablation for VT in larger numbers of patients.# The procedure # Indications and current treatments Ventricular tachycardia is caused by abnormal electrical circuits originating from diseased areas of the ventricular myocardium. It usually results in a rapid heartbeat, preventing effective ventricular refill and adequate cardiac output. Untreated VT is usually life-threatening. Depending on the type, VT may be managed by antiarrhythmic drugs. People who have recurrent VT episodes may need an implantable cardiac defibrillator (ICD) or endocardial catheter ablation to destroy diseased areas of the ventricular myocardium and interrupt the abnormal electrical circuits. # Outline of the procedure The procedure is carried out with the patient under sedation or general anaesthesia. The pericardial space is accessed by a subxiphoid needle puncture under fluoroscopic guidance. A guidewire is introduced through the needle and a sheath is advanced over the guidewire so that the tip is placed inside the pericardial sac. The sheath is aspirated to check for bleeding. A radiofrequency catheter is inserted into the sheath. After electrophysiological mapping to determine target sites for ablation, radiofrequency energy pulses are applied to the epicardium. During the procedure, catheter position is monitored with a three-dimensional mapping system to avoid collateral damage. Saline is placed in the pericardial space to reduce the risk of oesophageal injury, and steroids are administered to reduce the risk of pericarditis. Patients can have a combined procedure that includes electrophysiological mapping and ablation by both endocardial and epicardial approaches. Sections 2.3 and 2.4 describe efficacy and safety outcomes which were available in the published literature and which the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview. # Efficacy In a case series of 48 patients with VT, of whom 18 had epicardial ablation, the procedure eliminated VT-inducing circuits in 94% (17/18) of patients (mean follow-up 25 months). In a case series of 14 patients, an epicardial VT circuit was mapped in 7 patients and was successfully terminated with epicardial ablation in all patients (mean follow-up 14 months). In a case series of 10 patients, VT-inducing circuits were eliminated in 8 (there were no episodes of syncope at 18-month follow-up). The Specialist Advisers stated that key efficacy outcomes included termination of VT (acutely and making it non-inducible), lack of VT recurrence, and reduction in the need for ICDs. # Safety No deaths directly attributable to the procedure have been reported in the literature. There were three deaths because of progression of severe heart failure. One patient in a case series of 48 patients died from decompensated congestive heart failure several weeks after successful epicardial ablation. Two patients in a case series of 20 patients died because of progressive heart failure during follow-up (mean 12 months). In a case series of 20 patients, one patient developed arteriovenous fistula formation needing surgical repair. In the same study, another patient developed an atrioventricular block. In a case series of 10 patients, one patient developed haemopericardium needing drainage. In the same study three patients developed pericardial friction rub without haemopericardium. In a case series of 48 patients, three patients developed transient pericarditis that resolved within 1 week. In a second case series of 10 patients, two patients reported acute thoracic pain needing analgesia. In a case series of 10 patients, five patients were in heart failure during the procedure, and one of these needed urgent heart transplantation after the procedure. The Specialist Advisers considered that potential safety concerns included myocardial puncture; pericarditis; coronary artery damage; perforation of the right ventricle; damage to the oesophagus, bronchi and phrenic nerve; gastric puncture and damage to abdominal vessels and organs when accessing the pericardial space.# Further information The National Patient Safety Agency runs the National Reporting and Learning System (NRLS), and clinicians should report any serious adverse events relating to the use of this procedure to the NRLS. NICE has published interventional procedures guidance on percutaneous (non-thoracoscopic) epicardial catheter radiofrequency ablation for atrial fibrillation and technology appraisals guidance on implantable cardioverter defibrillators for the treatment of arrhythmias. # Information for patients NICE has produced information on this procedure for patients and carers ('Understanding NICE guidance'). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.# About this guidance NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland. This guidance was developed using the NICE interventional procedure guidance process. We have produced a summary of this guidance for patients and carers. Information about the evidence it is based on is also available. Changes since publication May: minor maintenance. Your responsibility This guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer. Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties. Copyright © National Institute for Health and Clinical Excellence 2009. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE. Contact NICE National Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT www.nice.org.uk nice@nice.org.uk	{'Guidance ': 'The evidence on percutaneous (non-thoracoscopic) epicardial catheter radiofrequency ablation for ventricular tachycardia (VT) is limited to a small number of patients, but it shows that the procedure is efficacious in carefully selected individuals and raises no major safety issues, in the context of a condition which is potentially life-threatening. Therefore, the procedure may be used with normal arrangements for clinical governance, but with special arrangements for consent.\n\nDuring the consent process clinicians should ensure that patients understand the risks of potentially serious complications, including damage to the heart muscle.\n\nPatient selection and treatment should be carried out only by a team specialising in the treatment of cardiac arrhythmias that includes experts in electrophysiology and ablation.\n\nThe procedure should only be carried out by interventional cardiologists with specific training in electrophysiology and in accessing the pericardial space and performing complex ablation procedures.\n\nThe procedure should only be carried out in units with arrangements for emergency cardiac surgical support in case of complications.\n\nThe NHS Information Centre for health and social care runs the UK Central Cardiac Audit Database, and clinicians should enter details about all patients undergoing percutaneous (non-thoracoscopic) epicardial catheter radiofrequency ablation for VT onto this database.\n\nNICE encourages further research into and publication of the outcomes and potential serious complications of percutaneous (non-thoracoscopic) epicardial catheter radiofrequency ablation for VT in larger numbers of patients.', 'The procedure': '# Indications and current treatments\n\nVentricular tachycardia is caused by abnormal electrical circuits originating from diseased areas of the ventricular myocardium. It usually results in a rapid heartbeat, preventing effective ventricular refill and adequate cardiac output. Untreated VT is usually life-threatening.\n\nDepending on the type, VT may be managed by antiarrhythmic drugs. People who have recurrent VT episodes may need an implantable cardiac defibrillator (ICD) or endocardial catheter ablation to destroy diseased areas of the ventricular myocardium and interrupt the abnormal electrical circuits.\n\n# Outline of the procedure\n\nThe procedure is carried out with the patient under sedation or general anaesthesia. The pericardial space is accessed by a subxiphoid needle puncture under fluoroscopic guidance. A guidewire is introduced through the needle and a sheath is advanced over the guidewire so that the tip is placed inside the pericardial sac. The sheath is aspirated to check for bleeding. A radiofrequency catheter is inserted into the sheath. After electrophysiological mapping to determine target sites for ablation, radiofrequency energy pulses are applied to the epicardium.\n\nDuring the procedure, catheter position is monitored with a three-dimensional mapping system to avoid collateral damage. Saline is placed in the pericardial space to reduce the risk of oesophageal injury, and steroids are administered to reduce the risk of pericarditis.\n\nPatients can have a combined procedure that includes electrophysiological mapping and ablation by both endocardial and epicardial approaches.\n\nSections 2.3 and 2.4 describe efficacy and safety outcomes which were available in the published literature and which the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview.\n\n# Efficacy\n\nIn a case series of 48 patients with VT, of whom 18 had epicardial ablation, the procedure eliminated VT-inducing circuits in 94% (17/18) of patients (mean follow-up 25 months). In a case series of 14 patients, an epicardial VT circuit was mapped in 7 patients and was successfully terminated with epicardial ablation in all patients (mean follow-up 14 months). In a case series of 10 patients, VT-inducing circuits were eliminated in 8 (there were no episodes of syncope at 18-month follow-up).\n\nThe Specialist Advisers stated that key efficacy outcomes included termination of VT (acutely and making it non-inducible), lack of VT recurrence, and reduction in the need for ICDs.\n\n# Safety\n\nNo deaths directly attributable to the procedure have been reported in the literature. There were three deaths because of progression of severe heart failure. One patient in a case series of 48 patients died from decompensated congestive heart failure several weeks after successful epicardial ablation. Two patients in a case series of 20 patients died because of progressive heart failure during follow-up (mean 12 months).\n\nIn a case series of 20 patients, one patient developed arteriovenous fistula formation needing surgical repair. In the same study, another patient developed an atrioventricular block.\n\nIn a case series of 10 patients, one patient developed haemopericardium needing drainage. In the same study three patients developed pericardial friction rub without haemopericardium.\n\nIn a case series of 48 patients, three patients developed transient pericarditis that resolved within 1 week. In a second case series of 10 patients, two patients reported acute thoracic pain needing analgesia.\n\nIn a case series of 10 patients, five patients were in heart failure during the procedure, and one of these needed urgent heart transplantation after the procedure.\n\nThe Specialist Advisers considered that potential safety concerns included myocardial puncture; pericarditis; coronary artery damage; perforation of the right ventricle; damage to the oesophagus, bronchi and phrenic nerve; gastric puncture and damage to abdominal vessels and organs when accessing the pericardial space.', 'Further information': "The National Patient Safety Agency runs the National Reporting and Learning System (NRLS), and clinicians should report any serious adverse events relating to the use of this procedure to the NRLS.\n\nNICE has published interventional procedures guidance on percutaneous (non-thoracoscopic) epicardial catheter radiofrequency ablation for atrial fibrillation and technology appraisals guidance on implantable cardioverter defibrillators for the treatment of arrhythmias.\n\n# Information for patients\n\nNICE has produced information on this procedure for patients and carers ('Understanding NICE guidance'). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.", 'About this guidance': 'NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland.\n\nThis guidance was developed using the NICE interventional procedure guidance process.\n\nWe have produced a summary of this guidance for patients and carers. Information about the evidence it is based on is also available.\n\nChanges since publication\n\nMay: minor maintenance.\n\nYour responsibility\n\nThis guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.\n\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.\n\nCopyright\n\n© National Institute for Health and Clinical Excellence 2009. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.\n\nContact NICE\n\nNational Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT\n\nwww.nice.org.uk\n \n nice@nice.org.uk\n 0845 033 7780'}	https://www.nice.org.uk/guidance/ipg295
9c09d26b4e51b49fe110f59ce0f69a1903ed521a	nice	Sunitinib for the first-line treatment of advanced and/or metastatic renal cell carcinoma	Sunitinib for the first-line treatment of advanced and/or metastatic renal cell carcinoma Evidence-based recommendations on sunitinib (Sutent) for untreated advanced or metastatic renal cell carcinoma in adults. # Guidance Sunitinib is recommended as a first-line treatment option for people with advanced and/or metastatic renal cell carcinoma who are suitable for immunotherapy and have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. When using ECOG performance status score, clinicians should be mindful of the need to secure equality of access to treatments for people with disabilities. Clinicians should bear in mind that people with disabilities may have difficulties with activities of daily living that are unrelated to the prognosis of renal cell carcinoma. In such cases clinicians should make appropriate judgements of performance status taking these considerations into account. People who are currently being treated with sunitinib for advanced and/or metastatic renal cell carcinoma but who do not meet the criteria in 1.1 should have the option to continue their therapy until they and their clinicians consider it appropriate to stop.# Clinical need and practice Renal cell carcinoma (RCC) is a type of kidney cancer that usually originates in the lining of the tubules of the kidney and contains many blood vessels. RCC accounts for 90% of kidney cancers and approximately 3% of all adult cancers. In England and Wales, kidney cancer is the 8th most common cancer in men and the 14th most common in women. In 2004, there were 5745 cases of newly diagnosed kidney cancer registered in England and Wales. The incidence of kidney cancer begins to rise after the age of 40 and is highest in people older than 65. In England and Wales the estimated overall 5-year survival rate for RCC is 44%, but there are large differences according to the stage of disease at the time of diagnosis. The worldwide incidence of kidney cancer among both men and women has been rising steadily since the 1970s. The American Joint Committee on Cancer (AJCC) tumour node metastases (TNM) system is used to grade RCC into stages I to IV. Advanced RCC, in which the tumour is either locally advanced and/or has spread to regional lymph nodes, is generally defined as stage III. Metastatic RCC, in which the tumour has spread beyond the regional lymph nodes to other parts of the body, is generally defined as stage IV. In 2006, of people presenting with RCC in England and Wales for whom staging information was available, an estimated 26% and 17% had stage III and stage IV disease, respectively. About half of those who have curative resection for earlier stages of the disease also go on to develop advanced and/or metastatic disease. The prognosis following a diagnosis of advanced and/or metastatic RCC is poor. The 5-year survival rate for metastatic RCC is approximately 10%. There are currently no treatments that reliably cure advanced and/or metastatic RCC. The primary objectives of medical intervention are relief of physical symptoms and maintenance of function. Metastatic RCC is largely resistant to chemotherapy, radiotherapy and hormonal therapy. People with advanced and/or metastatic RCC are usually treated with either interferon alfa-2a (IFN-α) or interleukin-2 immunotherapy or a combination of IFN-α and interleukin-2. IFN-α (Roferon-A, Roche Products) is the most commonly used immunotherapy in England and Wales and has a UK marketing authorisation for treatment of people with advanced RCC. For those people receiving immunotherapies for the treatment of advanced RCC it is suggested that median overall survival is 11.4 months compared with a median overall survival of 7.6 months for those receiving control treatments. Commonly experienced adverse effects of IFN-α include flu-like symptoms, tiredness and depression. There is no standard treatment for people with advanced and/or metastatic RCC whose condition does not respond to first-line immunotherapy, or for people who are unsuitable for immunotherapy.# The technology # Sunitinib Sunitinib (Sutent, Pfizer) is an inhibitor of a group of closely related tyrosine kinase receptors. It inhibits VEGF/PDGF receptors on cancer cells, vascular endothelial cells and pericytes, inhibiting the proliferation of tumour cells and the development of tumour blood vessels. Sunitinib has a UK marketing authorisation for the treatment of people with advanced and/or metastatic RCC. Sunitinib is contraindicated in people who have hypersensitivity to sunitinib malate or to any of the excipients. The summary of product characteristics (SPC) lists the following conditions that may be associated with sunitinib treatment: skin and tissue problems, gastrointestinal events, haemorrhage, hypertension, haematological problems, venous thromboembolic events, pulmonary embolism and hypothyroidism. For full details of side effects and contraindications, see the SPC. Sunitinib is administered orally. The recommended dosage is 50 mg once daily for four consecutive weeks with a 2-week rest period (that is, a complete treatment cycle of 6 weeks). The dose may be adjusted in steps of 12.5 mg according to tolerability (dose range 25–75 mg). The price for a pack of 50-mg capsules (30 capsules per pack) is £3363.00 (excluding VAT; BNF edition 55). The average daily cost of sunitinib is £74.74, with an average 6-week cycle costing £3139. The manufacturer of sunitinib (Pfizer) has agreed a patient access scheme with the Department of Health, in which the first treatment cycle of sunitinib is free to the NHS. The Department of Health considered that this patient access scheme does not constitute an excessive administrative burden on the NHS. Costs of subsequent treatment cycles may vary in different settings because of negotiated procurement discounts.# Evidence and interpretation The Appraisal Committee (appendix A) considered evidence from a number of sources (appendix B). The following sections are based on the evidence received for the appraisal of 'bevacizumab, sorafenib, sunitinib and temsirolimus for the treatment of advanced and/or metastatic renal cell carcinoma'. However, they only relate to sunitinib for the first-line treatment of advanced and/or metastatic RCC. # Clinical effectiveness The Assessment Group and manufacturer identified evidence on the clinical effectiveness of sunitinib as a first-line treatment within its licensed indications against relevant comparators. The following potential treatment strategies were investigated: first-line treatment for people suitable for immunotherapy (sunitinib compared with IFN-α) first-line treatment for people suitable for immunotherapy who have a poor prognosis (sunitinib compared with IFN-α) first-line treatment for people unsuitable for immunotherapy (sunitinib compared with best supportive care) first-line treatment for people with a poor prognosis unsuitable for immunotherapy (sunitinib compared with best supportive care). ## First-line treatment for people suitable for immunotherapy One randomised controlled trial (RCT) of 750 people assessed the effect of sunitinib (n = 375) compared with IFN-α alone (n = 375). The primary outcome was progression-free survival. Three interim analyses were scheduled and after the second analysis the study was unblinded and participants in the IFN-α group with progressive disease were allowed to cross over into the sunitinib group. This is at variance with the study protocol which stated that all treatment would be stopped when there was evidence of disease progression. The study was conducted in participants with a good performance status (ECOG status 0 or 1) with clear cell RCC. Most had undergone prior nephrectomy. Median overall survival had not been reached in either treatment arm at the time of the interim data analyses. The manufacturer of sunitinib (Pfizer) submitted updated data on the final intention-to-treat (ITT) population. The median final overall survival was 26.4 months in the sunitinib arm and 21.8 months in the IFN-α arm (HR 0.821, 95% CI 0.673 to 1.001, p = 0.051). There were 25 participants in the IFN-α arm who, during the course of the study, crossed over to receive sunitinib treatment after disease progression. Censoring the data for these 25 participants (that is, the data for these 25 people were only included up to the point at which they crossed over) gave a median overall survival of 26.4 months in the sunitinib arm and 20.0 months in the IFN-α arm (HR 0.808, 95% CI 0.661 to 0.987, p = 0.0362). The manufacturer of sunitinib also provided post hoc data pertaining to a group of participants who did not receive any systemic post-study treatments. In this analysis, the median overall survival was 28.1 months for the 193 participants in the sunitinib arm and 14.1 months for the 162 participants in the IFN-α arm (HR 0.647, 95% CI 0.483 to 0.870, p = 0.0033). Progression-free survival was defined as the time between randomisation and first documented disease progression or death from any cause. Pre-planned interim results (at 13 months) and unplanned updated results (at 25 months) were presented, but the latter contained crossover between treatment arms. Again, the manufacturer submitted final results based on the ITT population and the median final progression-free survival was 48 weeks (11 months) in the sunitinib arm and 22.3 weeks (5.1 months) in the IFN-α arm (HR 0.488, 95% CI 0.406 to 0.586, p < 0.000001). Analysis of the group of participants who received no systemic post-study treatments gave median progression-free survival of 50.1 weeks (11.5 months) in the sunitinib arm and 22.3 weeks (5.1 months) in the IFN-α arm (HR 0.52, 95% CI 0.39, 0.70). A few participants were included who had not had a prior nephrectomy: 9% in the sunitinib arm and 11% in the IFN-α arm. The subgroup analyses, based only on the interim study results, suggested that sunitinib significantly improved progression-free survival for those who had undergone prior nephrectomy compared with IFN-α (HR 0.38, 95% CI 0.30 to 0.53). The improvement in progression-free survival for those who had not undergone prior nephrectomy was less and the difference between groups not statistically significant (HR 0.58, 95% CI 0.24 to 1.03). Tumour response rate was measured as a partial or complete reduction in tumour size. Results for the interim analyses only showed that the partial tumour response rate in the sunitinib arm was 31% compared with 6% in the IFN-α arm (p < 0.001). No participant had a complete tumour response. Adverse events were taken from the 'safety population' (that is, people were assigned to treatments in the analysis based on what they actually received). Results for the period up to the interim analyses only showed no significant differences between the treatment and control arms. However, the Assessment Group stated that there are emerging concerns in the published literature about the frequency of cardiovascular events associated with sunitinib. In the trial, the most commonly reported 'any grade' adverse events for participants receiving sunitinib were hypertension, fatigue, diarrhoea and hand–foot syndrome. For the participants receiving IFN-α, these were fatigue and asthenia. A total of 8% of participants receiving sunitinib discontinued treatment because of adverse events compared with 13% in the IFN-α arm. At the time of the interim analyses, overall results for health-related quality of life (total score and all subscales using the functional assessment of cancer therapy – general and functional assessment of cancer therapy – kidney symptom index tools) were significantly better in the sunitinib arm compared with the IFN-α arm. ## First-line treatment for people suitable for immunotherapy with at least three of six factors indicating poor prognosis In the RCT described above (see section 4.1.2), 6.1% of participants receiving sunitinib and 6.7% of participants receiving IFN-α were classified as having a poor prognosis according to the Memorial Sloan-Kettering Cancer Centre risk classification. However, outcome data were not reported separately for this subgroup. ## First-line treatment for people unsuitable for immunotherapy The Assessment Group did not identify any full reports of RCTs assessing sunitinib as first-line treatment for people with advanced and/or metastatic RCC who were unsuitable for immunotherapy. ## First-line treatment for people with poor prognosis unsuitable for immunotherapy The Assessment Group did not identify any data on the clinical effectiveness of sunitinib as first-line treatment for people with advanced and/or metastatic RCC who had a poor prognosis and were unsuitable for immunotherapy. ## Summary of clinical effectiveness The Assessment Group concluded that for people who are suitable for immunotherapy sunitinib appears to offer benefits compared with IFN-α alone in terms of overall survival, progression-free survival and tumour response. For people with a poor prognosis and people who are unsuitable for immunotherapy, limited evidence was identified and thus no conclusions about the clinical effectiveness of sunitinib as a first-line treatment in these groups could be made. The frequency of adverse events associated with sunitinib is comparable to that associated with IFN-α monotherapy. # Cost effectiveness No published studies of the cost effectiveness of sunitinib were identified. The manufacturer of sunitinib submitted a cost-effectiveness model and the Assessment Group developed a model to estimate the cost effectiveness of sunitinib. ## Manufacturer's model The manufacturer of sunitinib (Pfizer) submitted a simple state-transition model with three health states: progression-free survival (PFS), progressed disease (PD) and death. The model compared sunitinib with IFN-α as a first-line treatment for people suitable for immunotherapy. Patient-level data were taken from the sunitinib trial described in section 4.1.2. Weibull survival curves were fitted to the overall and progression-free survival data from the IFN-α arm in the trial. Hazard ratios for sunitinib were then used to extrapolate overall and progression-free survival for sunitinib treatment. The following treatment and health-state specific utility data from the sunitinib trial were applied: sunitinib/PFS = 0.77; IFN-α/PFS = 0.79; sunitinib/PD = 0.72; IFN-α/PD = 0.69. Drug costs were adjusted according to RCT data on dose intensity; the first-line drug cost for sunitinib was weighted by 86.4%. A pricing strategy with the first cycle of sunitinib being free of charge to the NHS was applied. The original base cases submitted by the manufacturer of sunitinib used the interim effectiveness data which were superseded by the final ITT results. With discounting at 3.5% per annum, the comparison of sunitinib with IFN-α produced an ICER of £72,003 per QALY gained using the final ITT population and £71,760 per QALY gained using the final ITT population censored for crossover. One-way sensitivity analyses applied to the original base case demonstrated that the ICERs were most sensitive to the extrapolation method and choice of utility value for progressed disease. The manufacturer of sunitinib also submitted cost-effectiveness analyses using the data from the group of participants who received no systemic post-study treatments. The progression-free and overall survival curves for IFN-α were modelled using Weibull curves and the hazard ratios for sunitinib were then applied, as in the ITT analyses. Without any curve adjustments, the ICER for sunitinib compared with IFN-α was £41,472 per QALY gained. However, the manufacturer stated that the modelled IFN-α progression-free survival curve did not fit the observed progression-free survival data well, and adjusted the curve using fewer data points. Application of the trial hazard ratio to this curve then resulted in a progression-free survival curve that did not fit the empirical data from the sunitinib arm of the trial well. Therefore, the progression-free survival curve for sunitinib was also fitted independently. These adjustments resulted in an ICER of £35,245 per QALY gained for sunitinib compared with IFN-α. The manufacturer of sunitinib then adjusted the overall survival curve for the IFN-α arm using the same principles as for adjustments for the progression-free survival curve. However, unlike the curve fitting for progression-free survival, for overall survival the trial hazard ratio was applied to the fitted IFN-α curve to derive an overall survival curve for the sunitinib arm. These adjustments resulted in an extrapolated mean overall survival of 46.6 months for participants in the sunitinib arm and 27.5 months for participants in the IFN-α arm. These adjustments were associated with an ICER of £29,440 per QALY gained for sunitinib compared with IFN-α. Probabilistic sensitivity analyses of the final cost-effectiveness estimate demonstrated that at a willingness to pay threshold of £30,000 per QALY gained, sunitinib has a 51% probability of being a cost-effective treatment compared with IFN-α. ## Assessment Group model The Assessment Group model was developed in order to estimate the cost effectiveness of sunitinib, sorafenib, temsirolimus and bevacizumab plus IFN-α, against relevant comparators and according to the licensed indication of each drug. The Markov model used three distinct health states: progression-free survival, progressive disease and death. Baseline disease progression (IFN-α alone) in the original Assessment Group model was taken from a study comparing bevacizumab plus IFN-α with IFN-α alone. The Assessment Group stated that this data source was chosen for the IFN-α ITT population cost-effectiveness analyses because at the time of the original analysis the overall survival Kaplan–Meier curve from the sunitinib RCT had not been published and that these data were therefore immature. Data for progression-free survival and overall survival for people receiving IFN-α were read directly from reported Kaplan–Meier curves, and Weibull curves were then fitted for use in the model. The disease progression was estimated using the hazard ratios from the sunitinib trial. The health-state utilities used in the Assessment Group model were derived from trial data in the manufacturer submission and UK EQ–5D tariffs. Participants were assumed to be similar at baseline in terms of health-state value. Therefore treatment-specific health-state values were not applied. People who receive first-line treatments were assumed to have a utility of 0.78 when in the PFS state and 0.70 when in the PD state; these assumptions came from the manufacturer (Pfizer) submission. In the Assessment Group model, drug acquisition costs were modified according to dose intensities reported in the sunitinib RCT. Current list prices were taken from the BNF (edition 55), and the agreed patient access scheme of the first cycle of sunitinib being free to the NHS was applied. All other costs were inflated to 2007/08 values. It was assumed that 100% of IFN-α monotherapy was administered at home, with 75% being self-administered. Additional resource uses associated with outpatient monitoring, scans and tests were used in the model for people in the PFS health state on drug treatment. In the PFS state, the medical management cost per cycle was £223 for sunitinib treatment. In the PD state, the cost for best supportive care was £435 per cycle. A number of one-way and multi-way sensitivity analyses were performed to test the sensitivity of the cost-effectiveness analyses. The key sensitivity analyses investigated the assumptions that were made on clinical effectiveness, drug acquisition and administration costs, best supportive care and management costs and health-state utility values. In particular, the Assessment Group highlighted a paucity of data surrounding accurate health-state utility values and best supportive care costs. The Assessment Group performed sensitivity analyses on their own model by varying their own assumptions and also by incorporating the manufacturer's parameters. The Assessment Group also performed sensitivity analyses on the manufacturer's model by incorporating the Assessment Group parameters and assumptions. The original Assessment Group base case comparing sunitinib with IFN-α was superseded by analyses using the final ITT results. The comparison of sunitinib with IFN-α resulted in an ICER of £104,715 per QALY gained. The deterministic sensitivity analyses on the interim data demonstrated that estimates of treatment effectiveness, drug pricing (including dose intensity data) and health-state utility input parameters were the key drivers affecting the ICERs. The ICERs were particularly sensitive to variations in estimates of the hazard ratio for overall survival. The Assessment Group also undertook cost-effectiveness analyses using the data from the 'no post-study treatment' group in the sunitinib trial once these had been submitted by the manufacturer. Using a similar approach to the manufacturer, the empirical progression-free and overall survival data from the IFN-α 'no post-study treatment' arm were modelled using a Weibull curve. The hazard ratio for overall survival for sunitinib of 0.647 from the 'no post-study treatment' group and the hazard ratio for progression-free survival for sunitinib of 0.488 from the ITT population were then applied to derive survival curves for sunitinib treatment. For the 'no post-study treatment' group, the cost-effectiveness analysis resulted in an ICER of £62,365 per QALY gained for sunitinib compared with IFN-α. Both of the ICERs calculated by the Assessment Group included the agreed patient access scheme of the first cycle of sunitinib being free to the NHS. The manufacturer of sunitinib provided a late submission, which included details of the final ITT analysis and details of the 'no post-study treatment' group. The manufacturer also presented additional cost-effectiveness estimates based on the 'no post-study treatment' group. The Decision Support Unit (DSU) was asked to explore these data and the approach used in the manufacturer's model. In relation to the 'no-post study treatment' group, the DSU firstly noted that over half of the trial population did receive further treatments and were therefore excluded from the 'no post-study treatment' group analyses. The DSU highlighted that the wholesale exclusion of participants based on whether or not they had received further treatments could be considered as inappropriate. This is because the reason for exclusion from the analyses is most likely to be disease progression, which is linked to a number of outcomes (including survival). The DSU noted that a more appropriate strategy would have been to censor, rather than exclude, the participants at the point at which they received any further treatments. The DSU then appraised the approach taken by the manufacturer in modelling the cost effectiveness associated with the 'no post-study treatment' group. The DSU highlighted that, compared with the final ITT analyses submitted by the manufacturer, there was an increase in overall survival for the participants that received sunitinib when people who received any further systemic treatments were excluded. The DSU stated that this was counter-intuitive and suggested that randomisation had not been preserved. The DSU stated that this cast serious doubt on the validity of the approach used by the manufacturer for the 'no post study treatment' group cost-effectiveness analysis. The DSU were requested to use the following assumptions in the manufacturer's model: 1.06 (12.72 months) and 1.74 (20.88 months) progression-free years for the IFN-α and sunitinib arms, respectively; 2.29 (27.48 months) and 3.13 (37.56 months) life years overall survival for the IFN-α and sunitinib arms, respectively. All data were from the final ITT analysis except for overall survival data for the IFN-α arm, which were from the 'no post-study treatment' group. Using these data in the manufacturer's model resulted in an ICER of £49,304 per QALY gained for sunitinib compared with IFN-α. The Assessment Group was requested to use the same assumptions as the DSU in the Assessment Group model: progression-free survival 1.06 (12.72 months) and 1.75 (21 months) progression-free years for the IFN-α and sunitinib arms, respectively; overall survival 2.21 (26.5 months) life years and 3.07 (36.84 months) life years for the IFN-α and sunitinib arms, respectively. Again, all data were from the final ITT analysis except for overall survival data for the IFN-α arm, which were from the 'no post-study treatment' group. The inputs used by the Assessment Group differ slightly from those used by the DSU as the Assessment Group model assumes a 10-year time horizon, whereas the manufacturer's model assumes an infinite time horizon. This approach included the agreed pricing strategy of the first cycle of sunitinib being free to the NHS and resulted in an ICER of £54,366 per QALY gained for sunitinib compared with IFN−α. # Consideration of the evidence The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of sunitinib, having considered evidence on the nature of the condition and the value placed on the benefits of sunitinib by people with advanced and/or metastatic RCC, those who represent them, and clinical specialists. It was also mindful of the need to take account of the effective use of NHS resources. The Committee heard from clinical specialists and patient experts that there are limited treatment options for people with advanced and/or metastatic RCC. The Committee noted that the only current standard first-line treatment is immunotherapy and there are no current treatment options for people whose condition had failed to respond to immunotherapy or who were considered unsuitable for immunotherapy. Moreover there are no current standard second-line treatment options. The Committee heard from people with RCC and patient experts that immunotherapy is associated with limited effectiveness and high toxicity. The Committee also heard that RCC does not respond well to conventional chemotherapies and that sunitinib represents a substantial improvement in first-line treatment for advanced and/or metastatic RCC. The Committee noted the comments received that some individual patients experienced clinical benefit from this drug and that lives of people with RCC had been extended for a number of years following treatment with sunitinib. The Committee heard from people with RCC and patient experts that advanced and/or metastatic RCC is a relatively rare cancer and noted the views of both patient and clinical experts concerning the severity of the disease. The Committee also heard from clinical experts, the Assessment Group and the manufacturer that there is a paucity of data on the utility values associated with living with advanced and/or metastatic RCC. The Committee noted that it may be difficult to fully capture the effects of sunitinib on health-related quality of life. The Committee acknowledged the comments that were received from people with RCC and the public, and that were summarised in a report, stating that some people with RCC had experienced significant improvements in their quality of life as a result of using sunitinib. The Committee was aware of the supplementary advice from NICE that should be taken into account when appraising treatments which may extend the life of people with a short life expectancy and which are licensed for indications that affect small numbers of people with incurable illnesses. For this advice to be applied, all the following criteria must be met: The treatment is indicated for patients with a short life expectancy, normally less than 24 months. There is sufficient evidence to indicate that the treatment offers an extension to life, normally of at least an additional 3 months, compared with current NHS treatment. No alternative treatment with comparable benefits is available through the NHS. The treatment is licensed or otherwise indicated for small patient populations.In addition when taking these into account the Committee must be persuaded that the estimates of the extension to life are robust and the assumptions used in the reference case economic modelling are plausible, objective and robust. ## First-line treatment for people suitable for immunotherapy The Committee reviewed the evidence of clinical effectiveness from the ITT population analyses of the sunitinib RCT. The Committee noted that 25 out of 375 participants in the IFN-α arm had crossed over and received sunitinib after disease progression. The Committee noted that the ITT censored population analyses accounted for the crossover by censoring the participants who had crossed over from the IFN-α arm to receive sunitinib. The Committee noted that, in these analyses, sunitinib demonstrated significant gains in terms of progression-free and overall survival compared with IFN-α. The Committee noted that the sunitinib trial was only conducted with participants that had a good ECOG performance status of 0 or 1. Therefore the Committee concluded that sunitinib is a clinically effective first-line treatment for advanced and/or metastatic RCC for patients with an ECOG performance status of 0 or 1. The Committee then considered the estimates provided of the cost effectiveness of sunitinib. For the ITT population the manufacturer's and the Assessment Group's estimates were £72,000 and £105,000 per QALY, respectively. The Committee also noted the manufacturer's estimate of £71,800 per QALY gained for the ITT censored for crossover population. The Committee noted instructions from the Department of Health that all of the cost-effectiveness estimates should include the first cycle of sunitinib as free to the NHS. The Committee understood that in the sunitinib RCT not only had there been crossover after disease progression, but also participants had had second-line treatment after the study had ended. This could be expected to exaggerate overall survival estimates for people in the UK receiving IFN-α in the future, as the Committee accepted testimony from clinical experts that current UK practice is likely to preclude treatment with second-line therapies. The Committee therefore considered that the investigation of outcomes in the participants who received no 'post-study treatment' was appropriate. However, the Committee was concerned about the data and approach used by the manufacturer. The Committee was mindful that this group was not pre-specified and represented approximately half of the original trial population. The Committee noted that even though the baseline demographics of the group appeared similar to those of the whole trial population the findings were suggestive of an unbalanced comparison. In the ITT analysis the differences in progression-free survival and overall survival between treatment groups had been 8.2 and 6.2 months, respectively. For the 'no post-study treatment' group they were 6.5 and 19.1 months, respectively. The Committee agreed that this divergence made the argument that these groups were matched implausible. It could indicate that the 'no post-study treatment' group receiving sunitinib comprised people who had not experienced disease progression and thus had not needed any second-line treatments, whereas the IFN-α group might have included more people who had died before other treatments could be considered. The Committee further considered that the divergence might have been exacerbated by the curve fitting techniques used in the manufacturer's model. For the group with 'no post-study treatment' the progression-free survival curves for IFN-α and sunitinib were fitted independently, but the overall survival curve for sunitinib was estimated by applying the study hazard ratio to the IFN-α overall survival curve. The Committee then considered what cost-effectiveness inferences could be made from the 'no post-study treatment' data provided by the manufacturer. The Committee considered that it was reasonable to accept the reduced overall survival estimate that these data implied for the control (IFN-α) group. However, it agreed that it could not accept that not having a second-line treatment could increase the overall survival of participants receiving sunitinib. The Committee noted the decrease in survival in the sunitinib group when crossover was censored (but participants not excluded completely from the study). Furthermore, the Committee agreed that the best estimates for progression-free survival came from the whole-study ITT population rather than a population lacking over half of the trial participants. The Committee could not therefore accept the manufacturer's ICER of £29,400 for the 'no post-study treatment' group. The Committee proceeded to explore the cost-effectiveness estimates based on its preferred assumptions for the 'no post-study treatment' group. The Committee noted the DSU and Assessment Group analyses based on the Committee's preferred assumptions (see sections 4.2.12 and 4.2.13). These analyses used estimates for progression-free survival derived from the ITT population for both groups (approximately 13 months and 21 months for the IFN-α and sunitinib arms, respectively) and estimates for overall survival of the sunitinib group from the ITT population (approximately 37 months), but overall survival estimates for the IFN-α group from those with 'no post-study treatment' (approximately 27 months) applied to the manufacturer's model (performed by the DSU) and the Assessment Group model (performed by the Assessment Group). The Committee noted the DSU's resulting cost-effectiveness estimate of £49,300 per QALY gained. The Committee noted the DSU's comments that this was likely to be an underestimate and also noted the cost-effectiveness estimate of £54,400 per QALY gained from the same preferred Committee assumptions in the Assessment Group model. The Committee then considered the sensitivity analyses on utility values conducted by the Assessment Group. The Committee was aware that there was a paucity of data on quality of life and acknowledged consultation responses that the difference of 0.08 between the utility assigned to a progression-free health state and a progressed disease health state was too small. The Committee considered that the impact of sunitinib on quality of life may not have been adequately captured, particularly for the progressed disease state. Therefore the Committee agreed that an increased utility difference between the two health states was plausible and noted the Assessment Group's utility sensitivity analyses which suggested a lowering of the final ICER as the utility difference widened. Taking this into account and reflecting back to the proven benefit in median progression-free survival in the ITT sensitivity analyses, the Committee was persuaded that the ICER for sunitinib 'no post-study treatment group' could be less than £50,000 per QALY gained. The Committee next discussed whether sunitinib for advanced and/or metastatic RCC fulfilled the criteria for consideration as a life-extending, end-of-life treatment. It was aware that the total number of people with advanced and/or metastatic RCC in England and Wales was approximately 4000. Although the Committee noted that sunitinib was to be aimed at more patient groups than just people with RCC, such as people with gastrointestinal stromal tumours, this was the first indication for which it was being appraised. It therefore considered that for this appraisal, sunitinib should be regarded as meeting this criterion for an end-of-life treatment. The Committee noted from the clinical trials that the normal life expectancy with IFN-α treatment alone was unlikely to be greater than 24 months and was potentially as low as 12 months. The Committee also noted that evidence from the sunitinib trial suggested that sunitinib increased survival by more than 3 months in comparison with IFN-α alone. It was further persuaded that sunitinib provided a step-change in the first-line treatment of advanced and/or metastatic RCC and noted that more than 20% of the public and patients that responded in consultation highlighted this impressive benefit from sunitinib. In summary, the Committee was satisfied that sunitinib currently meets the criteria for being a life-extending end-of-life treatment, and that the evidence presented for this consideration was sufficiently robust. The Committee next considered the cost-effectiveness estimates of sunitinib, in light of the appraisal of a life-extending, end-of-life treatment. Firstly, it considered the ITT cost-effectiveness estimates (derived from the whole trial population) of £72,000 per QALY gained and £105,000 per QALY gained as calculated by the manufacturer of sunitinib and the DSU (using the Assessment Group model), respectively. It considered that the magnitude of additional weight that would need to be assigned to the original QALY benefits in this patient group for the cost effectiveness of the drug to fall within the current threshold range would be too great. The Committee then considered the most plausible cost-effectiveness estimate following the sensitivity analysis of the utility values of the group of people that had received no post-study treatments (see section 4.3.10), in light of the appraisal of a life-extending, end-of-life treatment. It considered the impact of giving a greater weight to QALYs achieved in the later stages of terminal diseases, using the assumption that the extended survival period is experienced at the full quality of life anticipated for a healthy person of the same age and the magnitude of additional weight that would need to be assigned to the original QALY benefits in this patient group for the cost effectiveness of the drug to fall within the current threshold range. The Committee concluded that although it might be at the upper end of any plausible valuation of such benefits, in this case there was a significant step-change in treating a disease for which there is only one current standard first-line treatment option. The Committee concluded that sunitinib as a first-line treatment for advanced and/or metastatic RCC could be recommended as a cost-effective use of NHS resources, if a patient has an ECOG performance status of 0 or 1 and there are no further treatment options recommended by NICE after first-line sunitinib treatment. The Committee also considered that, because of the additional weight assigned to the original QALY benefit, rigorous data collection investigating the benefits of sunitinib in this group of people should be conducted. ## First-line treatment for people suitable for immunotherapy with at least three of six factors indicating poor prognosis Very few data were presented to the Committee on the clinical or cost effectiveness of sunitinib compared with IFN-α as first-line treatments for people with a poor prognosis, suitable for immunotherapy. In the absence of robust data, the Committee concluded that sunitinib could not be considered a clinically effective first-line treatment for people with poor prognosis, suitable for immunotherapy with advanced and/or metastatic RCC. ## First-line treatment for people unsuitable for immunotherapy No data were presented to the Committee on the clinical or cost effectiveness of sunitinib compared with best supportive care as a first-line treatment for people who were unsuitable for immunotherapy. In the absence of robust data, the Committee concluded that sunitinib could not be considered a clinically effective first-line treatment for those unsuitable for immunotherapy with advanced and/or metastatic RCC. ## First-line treatment for people with poor prognosis unsuitable for immunotherapy No data were presented to the Committee on the clinical or cost effectiveness of sunitinib compared with best supportive care as a first-line treatment for people with a poor prognosis who were unsuitable for immunotherapy. In the absence of robust data, the Committee concluded that sunitinib could not be considered a clinically effective first-line treatment for people with a poor prognosis who are unsuitable for immunotherapy.# Recommendations for further research There are a number of ongoing trials that are actively recruiting participants and that are relevant to this appraisal. Some of these trials are investigating the optimum sequences of treatment. Full details of ongoing research can be found at the National Institute for Health Research Clinical Research Network, ClinicalTrials.gov and Current Controlled Trials. The Assessment Group considered that the following well-conducted RCTs reporting health-related utility values in accordance with the NICE methods guide could be of value: RCTs to investigate the effectiveness of sunitinib compared with best supportive care in people who are unsuitable or have contraindications for immunotherapy and who have a poor or intermediate prognosis. The Committee considered that rigorous data collection is needed on the life-extending benefits of sunitinib when no second-line treatments are given.# Related NICE guidance Percutaneous radiofrequency ablation of renal cancer. NICE interventional procedure guidance 91 (2004). Improving outcomes in urological cancers. NICE cancer service guidance (2002).# Review of guidance The review date for a technology appraisal refers to the month and year in which the Guidance Executive will consider whether the technology should be reviewed. This decision will be taken in the light of information gathered by NICE, and in consultation with consultees and commentators. The guidance on this technology was considered for review in March 2012. Details are available on the NICE website. Andrew DillonChief ExecutiveMarch 2009# Changes after publication February 2014: implementation section updated to clarify that sunitinib is recommended as an option for treating advanced and/or metastatic renal cell carcinoma. Additional minor maintenance update also carried out. March 2012: minor maintenance# About this guidance NICE technology appraisal guidance is about the use of new and existing medicines and treatments in the NHS in England and Wales. This guidance was developed using the NICE multiple technology appraisal process. We have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available. Your responsibility This guidance represents the views of NICE and was arrived at after careful consideration of the evidence available. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. However, the guidance does not override the individual responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or guardian or carer. Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties. Copyright © National Institute for Health and Clinical Excellence 2009. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.	{'Guidance': 'Sunitinib is recommended as a first-line treatment option for people with advanced and/or metastatic renal cell carcinoma who are suitable for immunotherapy and have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.\n\nWhen using ECOG performance status score, clinicians should be mindful of the need to secure equality of access to treatments for people with disabilities. Clinicians should bear in mind that people with disabilities may have difficulties with activities of daily living that are unrelated to the prognosis of renal cell carcinoma. In such cases clinicians should make appropriate judgements of performance status taking these considerations into account.\n\nPeople who are currently being treated with sunitinib for advanced and/or metastatic renal cell carcinoma but who do not meet the criteria in 1.1 should have the option to continue their therapy until they and their clinicians consider it appropriate to stop.', 'Clinical need and practice': 'Renal cell carcinoma (RCC) is a type of kidney cancer that usually originates in the lining of the tubules of the kidney and contains many blood vessels. RCC accounts for 90% of kidney cancers and approximately 3% of all adult cancers. In England and Wales, kidney cancer is the 8th most common cancer in men and the 14th most common in women. In 2004, there were 5745 cases of newly diagnosed kidney cancer registered in England and Wales. The incidence of kidney cancer begins to rise after the age of 40 and is highest in people older than 65. In England and Wales the estimated overall 5-year survival rate for RCC is 44%, but there are large differences according to the stage of disease at the time of diagnosis. The worldwide incidence of kidney cancer among both men and women has been rising steadily since the 1970s.\n\nThe American Joint Committee on Cancer (AJCC) tumour node metastases (TNM) system is used to grade RCC into stages I to IV. Advanced RCC, in which the tumour is either locally advanced and/or has spread to regional lymph nodes, is generally defined as stage III. Metastatic RCC, in which the tumour has spread beyond the regional lymph nodes to other parts of the body, is generally defined as stage IV.\n\nIn 2006, of people presenting with RCC in England and Wales for whom staging information was available, an estimated 26% and 17% had stage III and stage IV disease, respectively. About half of those who have curative resection for earlier stages of the disease also go on to develop advanced and/or metastatic disease. The prognosis following a diagnosis of advanced and/or metastatic RCC is poor. The 5-year survival rate for metastatic RCC is approximately 10%.\n\nThere are currently no treatments that reliably cure advanced and/or metastatic RCC. The primary objectives of medical intervention are relief of physical symptoms and maintenance of function. Metastatic RCC is largely resistant to chemotherapy, radiotherapy and hormonal therapy. People with advanced and/or metastatic RCC are usually treated with either interferon alfa-2a (IFN-α) or interleukin-2 immunotherapy or a combination of IFN-α and interleukin-2. IFN-α (Roferon-A, Roche Products) is the most commonly used immunotherapy in England and Wales and has a UK marketing authorisation for treatment of people with advanced RCC. For those people receiving immunotherapies for the treatment of advanced RCC it is suggested that median overall survival is 11.4 months compared with a median overall survival of 7.6 months for those receiving control treatments. Commonly experienced adverse effects of IFN-α include flu-like symptoms, tiredness and depression. There is no standard treatment for people with advanced and/or metastatic RCC whose condition does not respond to first-line immunotherapy, or for people who are unsuitable for immunotherapy.', 'The technology': '# Sunitinib\n\nSunitinib (Sutent, Pfizer) is an inhibitor of a group of closely related tyrosine kinase receptors. It inhibits VEGF/PDGF receptors on cancer cells, vascular endothelial cells and pericytes, inhibiting the proliferation of tumour cells and the development of tumour blood vessels. Sunitinib has a UK marketing authorisation for the treatment of people with advanced and/or metastatic RCC.\n\nSunitinib is contraindicated in people who have hypersensitivity to sunitinib malate or to any of the excipients. The summary of product characteristics (SPC) lists the following conditions that may be associated with sunitinib treatment: skin and tissue problems, gastrointestinal events, haemorrhage, hypertension, haematological problems, venous thromboembolic events, pulmonary embolism and hypothyroidism. For full details of side effects and contraindications, see the SPC.\n\nSunitinib is administered orally. The recommended dosage is 50\xa0mg once daily for four consecutive weeks with a 2-week rest period (that is, a complete treatment cycle of 6 weeks). The dose may be adjusted in steps of 12.5\xa0mg according to tolerability (dose range 25–75\xa0mg). The price for a pack of 50-mg capsules (30 capsules per pack) is £3363.00 (excluding VAT; BNF edition 55). The average daily cost of sunitinib is £74.74, with an average 6-week cycle costing £3139. The manufacturer of sunitinib (Pfizer) has agreed a patient access scheme with the Department of Health, in which the first treatment cycle of sunitinib is free to the NHS. The Department of Health considered that this patient access scheme does not constitute an excessive administrative burden on the NHS. Costs of subsequent treatment cycles may vary in different settings because of negotiated procurement discounts.', 'Evidence and interpretation': "The Appraisal Committee (appendix A) considered evidence from a number of sources (appendix B). The following sections are based on the evidence received for the appraisal of 'bevacizumab, sorafenib, sunitinib and temsirolimus for the treatment of advanced and/or metastatic renal cell carcinoma'. However, they only relate to sunitinib for the first-line treatment of advanced and/or metastatic RCC.\n\n# Clinical effectiveness\n\nThe Assessment Group and manufacturer identified evidence on the clinical effectiveness of sunitinib as a first-line treatment within its licensed indications against relevant comparators. The following potential treatment strategies were investigated:\n\nfirst-line treatment for people suitable for immunotherapy (sunitinib compared with IFN-α)\n\nfirst-line treatment for people suitable for immunotherapy who have a poor prognosis (sunitinib compared with IFN-α)\n\nfirst-line treatment for people unsuitable for immunotherapy (sunitinib compared with best supportive care)\n\nfirst-line treatment for people with a poor prognosis unsuitable for immunotherapy (sunitinib compared with best supportive care).\n\n## First-line treatment for people suitable for immunotherapy\n\nOne randomised controlled trial (RCT) of 750 people assessed the effect of sunitinib (n\xa0=\xa0375) compared with IFN-α alone (n\xa0=\xa0375). The primary outcome was progression-free survival. Three interim analyses were scheduled and after the second analysis the study was unblinded and participants in the IFN-α group with progressive disease were allowed to cross over into the sunitinib group. This is at variance with the study protocol which stated that all treatment would be stopped when there was evidence of disease progression. The study was conducted in participants with a good performance status (ECOG status 0 or 1) with clear cell RCC. Most had undergone prior nephrectomy.\n\nMedian overall survival had not been reached in either treatment arm at the time of the interim data analyses. The manufacturer of sunitinib (Pfizer) submitted updated data on the final intention-to-treat (ITT) population. The median final overall survival was 26.4\xa0months in the sunitinib arm and 21.8\xa0months in the IFN-α arm (HR 0.821, 95% CI 0.673 to 1.001, p\xa0=\xa00.051). There were 25 participants in the IFN-α arm who, during the course of the study, crossed over to receive sunitinib treatment after disease progression. Censoring the data for these 25 participants (that is, the data for these 25 people were only included up to the point at which they crossed over) gave a median overall survival of 26.4\xa0months in the sunitinib arm and 20.0\xa0months in the IFN-α arm (HR 0.808, 95% CI 0.661 to 0.987, p\xa0=\xa00.0362).\n\nThe manufacturer of sunitinib also provided post hoc data pertaining to a group of participants who did not receive any systemic post-study treatments. In this analysis, the median overall survival was 28.1 months for the 193 participants in the sunitinib arm and 14.1\xa0months for the 162 participants in the IFN-α arm (HR\xa00.647, 95% CI 0.483 to 0.870, p\xa0=\xa00.0033).\n\nProgression-free survival was defined as the time between randomisation and first documented disease progression or death from any cause. Pre-planned interim results (at 13\xa0months) and unplanned updated results (at 25\xa0months) were presented, but the latter contained crossover between treatment arms. Again, the manufacturer submitted final results based on the ITT population and the median final progression-free survival was 48\xa0weeks (11\xa0months) in the sunitinib arm and 22.3\xa0weeks (5.1\xa0months) in the IFN-α arm (HR 0.488, 95% CI 0.406 to 0.586, p\xa0<\xa00.000001). Analysis of the group of participants who received no systemic post-study treatments gave median progression-free survival of 50.1\xa0weeks (11.5\xa0months) in the sunitinib arm and 22.3\xa0weeks (5.1\xa0months) in the IFN-α arm (HR 0.52, 95% CI 0.39, 0.70).\n\nA few participants were included who had not had a prior nephrectomy: 9% in the sunitinib arm and 11% in the IFN-α arm. The subgroup analyses, based only on the interim study results, suggested that sunitinib significantly improved progression-free survival for those who had undergone prior nephrectomy compared with IFN-α (HR 0.38, 95% CI 0.30 to 0.53). The improvement in progression-free survival for those who had not undergone prior nephrectomy was less and the difference between groups not statistically significant (HR 0.58, 95% CI 0.24 to 1.03).\n\nTumour response rate was measured as a partial or complete reduction in tumour size. Results for the interim analyses only showed that the partial tumour response rate in the sunitinib arm was 31% compared with 6% in the IFN-α arm (p\xa0<\xa00.001). No participant had a complete tumour response.\n\nAdverse events were taken from the 'safety population' (that is, people were assigned to treatments in the analysis based on what they actually received). Results for the period up to the interim analyses only showed no significant differences between the treatment and control arms. However, the Assessment Group stated that there are emerging concerns in the published literature about the frequency of cardiovascular events associated with sunitinib. In the trial, the most commonly reported 'any grade' adverse events for participants receiving sunitinib were hypertension, fatigue, diarrhoea and hand–foot syndrome. For the participants receiving IFN-α, these were fatigue and asthenia. A total of 8% of participants receiving sunitinib discontinued treatment because of adverse events compared with 13% in the IFN-α arm. At the time of the interim analyses, overall results for health-related quality of life (total score and all subscales using the functional assessment of cancer therapy – general [FACT-G] and functional assessment of cancer therapy – kidney symptom index [FKSI] tools) were significantly better in the sunitinib arm compared with the IFN-α arm.\n\n## First-line treatment for people suitable for immunotherapy with at least three of six factors indicating poor prognosis\n\nIn the RCT described above (see section 4.1.2), 6.1% of participants receiving sunitinib and 6.7% of participants receiving IFN-α were classified as having a poor prognosis according to the Memorial Sloan-Kettering Cancer Centre risk classification. However, outcome data were not reported separately for this subgroup.\n\n## First-line treatment for people unsuitable for immunotherapy\n\nThe Assessment Group did not identify any full reports of RCTs assessing sunitinib as first-line treatment for people with advanced and/or metastatic RCC who were unsuitable for immunotherapy.\n\n## First-line treatment for people with poor prognosis unsuitable for immunotherapy\n\nThe Assessment Group did not identify any data on the clinical effectiveness of sunitinib as first-line treatment for people with advanced and/or metastatic RCC who had a poor prognosis and were unsuitable for immunotherapy.\n\n## Summary of clinical effectiveness\n\nThe Assessment Group concluded that for people who are suitable for immunotherapy sunitinib appears to offer benefits compared with IFN-α alone in terms of overall survival, progression-free survival and tumour response. For people with a poor prognosis and people who are unsuitable for immunotherapy, limited evidence was identified and thus no conclusions about the clinical effectiveness of sunitinib as a first-line treatment in these groups could be made. The frequency of adverse events associated with sunitinib is comparable to that associated with IFN-α monotherapy.\n\n# Cost effectiveness\n\nNo published studies of the cost effectiveness of sunitinib were identified. The manufacturer of sunitinib submitted a cost-effectiveness model and the Assessment Group developed a model to estimate the cost effectiveness of sunitinib.\n\n## Manufacturer's model\n\nThe manufacturer of sunitinib (Pfizer) submitted a simple state-transition model with three health states: progression-free survival (PFS), progressed disease (PD) and death. The model compared sunitinib with IFN-α as a first-line treatment for people suitable for immunotherapy. Patient-level data were taken from the sunitinib trial described in section 4.1.2. Weibull survival curves were fitted to the overall and progression-free survival data from the IFN-α arm in the trial. Hazard ratios for sunitinib were then used to extrapolate overall and progression-free survival for sunitinib treatment. The following treatment and health-state specific utility data from the sunitinib trial were applied: sunitinib/PFS\xa0=\xa00.77; IFN-α/PFS\xa0=\xa00.79; sunitinib/PD\xa0=\xa00.72; IFN-α/PD\xa0=\xa00.69. Drug costs were adjusted according to RCT data on dose intensity; the first-line drug cost for sunitinib was weighted by 86.4%. A pricing strategy with the first cycle of sunitinib being free of charge to the NHS was applied.\n\nThe original base cases submitted by the manufacturer of sunitinib used the interim effectiveness data which were superseded by the final ITT results. With discounting at 3.5% per annum, the comparison of sunitinib with IFN-α produced an ICER of £72,003 per QALY gained using the final ITT population and £71,760 per QALY gained using the final ITT population censored for crossover. One-way sensitivity analyses applied to the original base case demonstrated that the ICERs were most sensitive to the extrapolation method and choice of utility value for progressed disease.\n\nThe manufacturer of sunitinib also submitted cost-effectiveness analyses using the data from the group of participants who received no systemic post-study treatments. The progression-free and overall survival curves for IFN-α were modelled using Weibull curves and the hazard ratios for sunitinib were then applied, as in the ITT analyses. Without any curve adjustments, the ICER for sunitinib compared with IFN-α was £41,472 per QALY gained. However, the manufacturer stated that the modelled IFN-α progression-free survival curve did not fit the observed progression-free survival data well, and adjusted the curve using fewer data points. Application of the trial hazard ratio to this curve then resulted in a progression-free survival curve that did not fit the empirical data from the sunitinib arm of the trial well. Therefore, the progression-free survival curve for sunitinib was also fitted independently. These adjustments resulted in an ICER of £35,245 per QALY gained for sunitinib compared with IFN-α.\n\nThe manufacturer of sunitinib then adjusted the overall survival curve for the IFN-α arm using the same principles as for adjustments for the progression-free survival curve. However, unlike the curve fitting for progression-free survival, for overall survival the trial hazard ratio was applied to the fitted IFN-α curve to derive an overall survival curve for the sunitinib arm. These adjustments resulted in an extrapolated mean overall survival of 46.6\xa0months for participants in the sunitinib arm and 27.5\xa0months for participants in the IFN-α arm. These adjustments were associated with an ICER of £29,440 per QALY gained for sunitinib compared with IFN-α. Probabilistic sensitivity analyses of the final cost-effectiveness estimate demonstrated that at a willingness to pay threshold of £30,000 per QALY gained, sunitinib has a 51% probability of being a cost-effective treatment compared with IFN-α.\n\n## Assessment Group model\n\nThe Assessment Group model was developed in order to estimate the cost effectiveness of sunitinib, sorafenib, temsirolimus and bevacizumab plus IFN-α, against relevant comparators and according to the licensed indication of each drug. The Markov model used three distinct health states: progression-free survival, progressive disease and death. Baseline disease progression (IFN-α alone) in the original Assessment Group model was taken from a study comparing bevacizumab plus IFN-α with IFN-α alone. The Assessment Group stated that this data source was chosen for the IFN-α ITT population cost-effectiveness analyses because at the time of the original analysis the overall survival Kaplan–Meier curve from the sunitinib RCT had not been published and that these data were therefore immature. Data for progression-free survival and overall survival for people receiving IFN-α were read directly from reported Kaplan–Meier curves, and Weibull curves were then fitted for use in the model. The disease progression was estimated using the hazard ratios from the sunitinib trial.\n\nThe health-state utilities used in the Assessment Group model were derived from trial data in the manufacturer submission and UK EQ–5D tariffs. Participants were assumed to be similar at baseline in terms of health-state value. Therefore treatment-specific health-state values were not applied. People who receive first-line treatments were assumed to have a utility of 0.78 when in the PFS state and 0.70 when in the PD state; these assumptions came from the manufacturer (Pfizer) submission.\n\nIn the Assessment Group model, drug acquisition costs were modified according to dose intensities reported in the sunitinib RCT. Current list prices were taken from the BNF (edition 55), and the agreed patient access scheme of the first cycle of sunitinib being free to the NHS was applied. All other costs were inflated to 2007/08 values. It was assumed that 100% of IFN-α monotherapy was administered at home, with 75% being self-administered. Additional resource uses associated with outpatient monitoring, scans and tests were used in the model for people in the PFS health state on drug treatment. In the PFS state, the medical management cost per cycle was £223 for sunitinib treatment. In the PD state, the cost for best supportive care was £435 per cycle.\n\nA number of one-way and multi-way sensitivity analyses were performed to test the sensitivity of the cost-effectiveness analyses. The key sensitivity analyses investigated the assumptions that were made on clinical effectiveness, drug acquisition and administration costs, best supportive care and management costs and health-state utility values. In particular, the Assessment Group highlighted a paucity of data surrounding accurate health-state utility values and best supportive care costs. The Assessment Group performed sensitivity analyses on their own model by varying their own assumptions and also by incorporating the manufacturer's parameters. The Assessment Group also performed sensitivity analyses on the manufacturer's model by incorporating the Assessment Group parameters and assumptions.\n\nThe original Assessment Group base case comparing sunitinib with IFN-α was superseded by analyses using the final ITT results. The comparison of sunitinib with IFN-α resulted in an ICER of £104,715 per QALY gained. The deterministic sensitivity analyses on the interim data demonstrated that estimates of treatment effectiveness, drug pricing (including dose intensity data) and health-state utility input parameters were the key drivers affecting the ICERs. The ICERs were particularly sensitive to variations in estimates of the hazard ratio for overall survival. The Assessment Group also undertook cost-effectiveness analyses using the data from the 'no post-study treatment' group in the sunitinib trial once these had been submitted by the manufacturer. Using a similar approach to the manufacturer, the empirical progression-free and overall survival data from the IFN-α 'no post-study treatment' arm were modelled using a Weibull curve. The hazard ratio for overall survival for sunitinib of 0.647 from the 'no post-study treatment' group and the hazard ratio for progression-free survival for sunitinib of 0.488 from the ITT population were then applied to derive survival curves for sunitinib treatment. For the 'no post-study treatment' group, the cost-effectiveness analysis resulted in an ICER of £62,365 per QALY gained for sunitinib compared with IFN-α. Both of the ICERs calculated by the Assessment Group included the agreed patient access scheme of the first cycle of sunitinib being free to the NHS.\n\nThe manufacturer of sunitinib provided a late submission, which included details of the final ITT analysis and details of the 'no post-study treatment' group. The manufacturer also presented additional cost-effectiveness estimates based on the 'no post-study treatment' group. The Decision Support Unit (DSU) was asked to explore these data and the approach used in the manufacturer's model. In relation to the 'no-post study treatment' group, the DSU firstly noted that over half of the trial population did receive further treatments and were therefore excluded from the 'no post-study treatment' group analyses. The DSU highlighted that the wholesale exclusion of participants based on whether or not they had received further treatments could be considered as inappropriate. This is because the reason for exclusion from the analyses is most likely to be disease progression, which is linked to a number of outcomes (including survival). The DSU noted that a more appropriate strategy would have been to censor, rather than exclude, the participants at the point at which they received any further treatments. The DSU then appraised the approach taken by the manufacturer in modelling the cost effectiveness associated with the 'no post-study treatment' group. The DSU highlighted that, compared with the final ITT analyses submitted by the manufacturer, there was an increase in overall survival for the participants that received sunitinib when people who received any further systemic treatments were excluded. The DSU stated that this was counter-intuitive and suggested that randomisation had not been preserved. The DSU stated that this cast serious doubt on the validity of the approach used by the manufacturer for the 'no post study treatment' group cost-effectiveness analysis.\n\nThe DSU were requested to use the following assumptions in the manufacturer's model: 1.06 (12.72\xa0months) and 1.74 (20.88\xa0months) progression-free years for the IFN-α and sunitinib arms, respectively; 2.29 (27.48\xa0months) and 3.13 (37.56\xa0months) life years overall survival for the IFN-α and sunitinib arms, respectively. All data were from the final ITT analysis except for overall survival data for the IFN-α arm, which were from the 'no post-study treatment' group. Using these data in the manufacturer's model resulted in an ICER of £49,304 per QALY gained for sunitinib compared with IFN-α.\n\nThe Assessment Group was requested to use the same assumptions as the DSU in the Assessment Group model: progression-free survival 1.06 (12.72\xa0months) and 1.75 (21\xa0months) progression-free years for the IFN-α and sunitinib arms, respectively; overall survival 2.21 (26.5\xa0months) life years and 3.07 (36.84\xa0months) life years for the IFN-α and sunitinib arms, respectively. Again, all data were from the final ITT analysis except for overall survival data for the IFN-α arm, which were from the 'no post-study treatment' group. The inputs used by the Assessment Group differ slightly from those used by the DSU as the Assessment Group model assumes a 10-year time horizon, whereas the manufacturer's model assumes an infinite time horizon. This approach included the agreed pricing strategy of the first cycle of sunitinib being free to the NHS and resulted in an ICER of £54,366 per QALY gained for sunitinib compared with IFN−α.\n\n# Consideration of the evidence\n\nThe Appraisal Committee reviewed the data available on the clinical and cost effectiveness of sunitinib, having considered evidence on the nature of the condition and the value placed on the benefits of sunitinib by people with advanced and/or metastatic RCC, those who represent them, and clinical specialists. It was also mindful of the need to take account of the effective use of NHS resources.\n\nThe Committee heard from clinical specialists and patient experts that there are limited treatment options for people with advanced and/or metastatic RCC. The Committee noted that the only current standard first-line treatment is immunotherapy and there are no current treatment options for people whose condition had failed to respond to immunotherapy or who were considered unsuitable for immunotherapy. Moreover there are no current standard second-line treatment options. The Committee heard from people with RCC and patient experts that immunotherapy is associated with limited effectiveness and high toxicity. The Committee also heard that RCC does not respond well to conventional chemotherapies and that sunitinib represents a substantial improvement in first-line treatment for advanced and/or metastatic RCC. The Committee noted the comments received that some individual patients experienced clinical benefit from this drug and that lives of people with RCC had been extended for a number of years following treatment with sunitinib.\n\nThe Committee heard from people with RCC and patient experts that advanced and/or metastatic RCC is a relatively rare cancer and noted the views of both patient and clinical experts concerning the severity of the disease. The Committee also heard from clinical experts, the Assessment Group and the manufacturer that there is a paucity of data on the utility values associated with living with advanced and/or metastatic RCC. The Committee noted that it may be difficult to fully capture the effects of sunitinib on health-related quality of life. The Committee acknowledged the comments that were received from people with RCC and the public, and that were summarised in a report, stating that some people with RCC had experienced significant improvements in their quality of life as a result of using sunitinib.\n\nThe Committee was aware of the supplementary advice from NICE that should be taken into account when appraising treatments which may extend the life of people with a short life expectancy and which are licensed for indications that affect small numbers of people with incurable illnesses. For this advice to be applied, all the following criteria must be met:\n\nThe treatment is indicated for patients with a short life expectancy, normally less than 24 months.\n\nThere is sufficient evidence to indicate that the treatment offers an extension to life, normally of at least an additional 3\xa0months, compared with current NHS treatment.\n\nNo alternative treatment with comparable benefits is available through the NHS.\n\nThe treatment is licensed or otherwise indicated for small patient populations.In addition when taking these into account the Committee must be persuaded that the estimates of the extension to life are robust and the assumptions used in the reference case economic modelling are plausible, objective and robust.\n\n## First-line treatment for people suitable for immunotherapy\n\nThe Committee reviewed the evidence of clinical effectiveness from the ITT population analyses of the sunitinib RCT. The Committee noted that 25 out of 375 participants in the IFN-α arm had crossed over and received sunitinib after disease progression. The Committee noted that the ITT censored population analyses accounted for the crossover by censoring the participants who had crossed over from the IFN-α arm to receive sunitinib. The Committee noted that, in these analyses, sunitinib demonstrated significant gains in terms of progression-free and overall survival compared with IFN-α. The Committee noted that the sunitinib trial was only conducted with participants that had a good ECOG performance status of 0 or 1. Therefore the Committee concluded that sunitinib is a clinically effective first-line treatment for advanced and/or metastatic RCC for patients with an ECOG performance status of 0 or 1.\n\nThe Committee then considered the estimates provided of the cost effectiveness of sunitinib. For the ITT population the manufacturer's and the Assessment Group's estimates were £72,000 and £105,000 per QALY, respectively. The Committee also noted the manufacturer's estimate of £71,800 per QALY gained for the ITT censored for crossover population. The Committee noted instructions from the Department of Health that all of the cost-effectiveness estimates should include the first cycle of sunitinib as free to the NHS.\n\nThe Committee understood that in the sunitinib RCT not only had there been crossover after disease progression, but also participants had had second-line treatment after the study had ended. This could be expected to exaggerate overall survival estimates for people in the UK receiving IFN-α in the future, as the Committee accepted testimony from clinical experts that current UK practice is likely to preclude treatment with second-line therapies. The Committee therefore considered that the investigation of outcomes in the participants who received no 'post-study treatment' was appropriate. However, the Committee was concerned about the data and approach used by the manufacturer. The Committee was mindful that this group was not pre-specified and represented approximately half of the original trial population. The Committee noted that even though the baseline demographics of the group appeared similar to those of the whole trial population the findings were suggestive of an unbalanced comparison. In the ITT analysis the differences in progression-free survival and overall survival between treatment groups had been 8.2 and 6.2\xa0months, respectively. For the 'no post-study treatment' group they were 6.5 and 19.1\xa0months, respectively. The Committee agreed that this divergence made the argument that these groups were matched implausible. It could indicate that the 'no post-study treatment' group receiving sunitinib comprised people who had not experienced disease progression and thus had not needed any second-line treatments, whereas the IFN-α group might have included more people who had died before other treatments could be considered. The Committee further considered that the divergence might have been exacerbated by the curve fitting techniques used in the manufacturer's model. For the group with 'no post-study treatment' the progression-free survival curves for IFN-α and sunitinib were fitted independently, but the overall survival curve for sunitinib was estimated by applying the study hazard ratio to the IFN-α overall survival curve.\n\nThe Committee then considered what cost-effectiveness inferences could be made from the 'no post-study treatment' data provided by the manufacturer. The Committee considered that it was reasonable to accept the reduced overall survival estimate that these data implied for the control (IFN-α) group. However, it agreed that it could not accept that not having a second-line treatment could increase the overall survival of participants receiving sunitinib. The Committee noted the decrease in survival in the sunitinib group when crossover was censored (but participants not excluded completely from the study). Furthermore, the Committee agreed that the best estimates for progression-free survival came from the whole-study ITT population rather than a population lacking over half of the trial participants. The Committee could not therefore accept the manufacturer's ICER of £29,400 for the 'no post-study treatment' group. The Committee proceeded to explore the cost-effectiveness estimates based on its preferred assumptions for the 'no post-study treatment' group.\n\nThe Committee noted the DSU and Assessment Group analyses based on the Committee's preferred assumptions (see sections 4.2.12 and 4.2.13). These analyses used estimates for progression-free survival derived from the ITT population for both groups (approximately 13\xa0months and 21\xa0months for the IFN-α and sunitinib arms, respectively) and estimates for overall survival of the sunitinib group from the ITT population (approximately 37\xa0months), but overall survival estimates for the IFN-α group from those with 'no post-study treatment' (approximately 27\xa0months) applied to the manufacturer's model (performed by the DSU) and the Assessment Group model (performed by the Assessment Group). The Committee noted the DSU's resulting cost-effectiveness estimate of £49,300 per QALY gained. The Committee noted the DSU's comments that this was likely to be an underestimate and also noted the cost-effectiveness estimate of £54,400 per QALY gained from the same preferred Committee assumptions in the Assessment Group model.\n\nThe Committee then considered the sensitivity analyses on utility values conducted by the Assessment Group. The Committee was aware that there was a paucity of data on quality of life and acknowledged consultation responses that the difference of 0.08 between the utility assigned to a progression-free health state and a progressed disease health state was too small. The Committee considered that the impact of sunitinib on quality of life may not have been adequately captured, particularly for the progressed disease state. Therefore the Committee agreed that an increased utility difference between the two health states was plausible and noted the Assessment Group's utility sensitivity analyses which suggested a lowering of the final ICER as the utility difference widened. Taking this into account and reflecting back to the proven benefit in median progression-free survival in the ITT sensitivity analyses, the Committee was persuaded that the ICER for sunitinib 'no post-study treatment group' could be less than £50,000 per QALY gained.\n\nThe Committee next discussed whether sunitinib for advanced and/or metastatic RCC fulfilled the criteria for consideration as a life-extending, end-of-life treatment. It was aware that the total number of people with advanced and/or metastatic RCC in England and Wales was approximately 4000. Although the Committee noted that sunitinib was to be aimed at more patient groups than just people with RCC, such as people with gastrointestinal stromal tumours, this was the first indication for which it was being appraised. It therefore considered that for this appraisal, sunitinib should be regarded as meeting this criterion for an end-of-life treatment. The Committee noted from the clinical trials that the normal life expectancy with IFN-α treatment alone was unlikely to be greater than 24\xa0months and was potentially as low as 12\xa0months. The Committee also noted that evidence from the sunitinib trial suggested that sunitinib increased survival by more than 3\xa0months in comparison with IFN-α alone. It was further persuaded that sunitinib provided a step-change in the first-line treatment of advanced and/or metastatic RCC and noted that more than 20% of the public and patients that responded in consultation highlighted this impressive benefit from sunitinib. In summary, the Committee was satisfied that sunitinib currently meets the criteria for being a life-extending end-of-life treatment, and that the evidence presented for this consideration was sufficiently robust.\n\nThe Committee next considered the cost-effectiveness estimates of sunitinib, in light of the appraisal of a life-extending, end-of-life treatment. Firstly, it considered the ITT cost-effectiveness estimates (derived from the whole trial population) of £72,000 per QALY gained and £105,000 per QALY gained as calculated by the manufacturer of sunitinib and the DSU (using the Assessment Group model), respectively. It considered that the magnitude of additional weight that would need to be assigned to the original QALY benefits in this patient group for the cost effectiveness of the drug to fall within the current threshold range would be too great.\n\nThe Committee then considered the most plausible cost-effectiveness estimate following the sensitivity analysis of the utility values of the group of people that had received no post-study treatments (see section 4.3.10), in light of the appraisal of a life-extending, end-of-life treatment. It considered the impact of giving a greater weight to QALYs achieved in the later stages of terminal diseases, using the assumption that the extended survival period is experienced at the full quality of life anticipated for a healthy person of the same age and the magnitude of additional weight that would need to be assigned to the original QALY benefits in this patient group for the cost effectiveness of the drug to fall within the current threshold range. The Committee concluded that although it might be at the upper end of any plausible valuation of such benefits, in this case there was a significant step-change in treating a disease for which there is only one current standard first-line treatment option. The Committee concluded that sunitinib as a first-line treatment for advanced and/or metastatic RCC could be recommended as a cost-effective use of NHS resources, if a patient has an ECOG performance status of 0 or 1 and there are no further treatment options recommended by NICE after first-line sunitinib treatment. The Committee also considered that, because of the additional weight assigned to the original QALY benefit, rigorous data collection investigating the benefits of sunitinib in this group of people should be conducted.\n\n## First-line treatment for people suitable for immunotherapy with at least three of six factors indicating poor prognosis\n\nVery few data were presented to the Committee on the clinical or cost effectiveness of sunitinib compared with IFN-α as first-line treatments for people with a poor prognosis, suitable for immunotherapy. In the absence of robust data, the Committee concluded that sunitinib could not be considered a clinically effective first-line treatment for people with poor prognosis, suitable for immunotherapy with advanced and/or metastatic RCC.\n\n## First-line treatment for people unsuitable for immunotherapy\n\nNo data were presented to the Committee on the clinical or cost effectiveness of sunitinib compared with best supportive care as a first-line treatment for people who were unsuitable for immunotherapy. In the absence of robust data, the Committee concluded that sunitinib could not be considered a clinically effective first-line treatment for those unsuitable for immunotherapy with advanced and/or metastatic RCC.\n\n## First-line treatment for people with poor prognosis unsuitable for immunotherapy\n\nNo data were presented to the Committee on the clinical or cost effectiveness of sunitinib compared with best supportive care as a first-line treatment for people with a poor prognosis who were unsuitable for immunotherapy. In the absence of robust data, the Committee concluded that sunitinib could not be considered a clinically effective first-line treatment for people with a poor prognosis who are unsuitable for immunotherapy.", 'Recommendations for further research ': 'There are a number of ongoing trials that are actively recruiting participants and that are relevant to this appraisal. Some of these trials are investigating the optimum sequences of treatment. Full details of ongoing research can be found at the National Institute for Health Research Clinical Research Network, ClinicalTrials.gov and Current Controlled Trials.\n\nThe Assessment Group considered that the following well-conducted RCTs reporting health-related utility values in accordance with the NICE methods guide could be of value:\n\nRCTs to investigate the effectiveness of sunitinib compared with best supportive care in people who are unsuitable or have contraindications for immunotherapy and who have a poor or intermediate prognosis.\n\nThe Committee considered that rigorous data collection is needed on the life-extending benefits of sunitinib when no second-line treatments are given.', 'Related NICE guidance': 'Percutaneous radiofrequency ablation of renal cancer. NICE interventional procedure guidance 91 (2004). [Replaced by NICE interventional procedure guidance 353]\n\nImproving outcomes in urological cancers. NICE cancer service guidance (2002).', 'Review of guidance': 'The review date for a technology appraisal refers to the month and year in which the Guidance Executive will consider whether the technology should be reviewed. This decision will be taken in the light of information gathered by NICE, and in consultation with consultees and commentators.\n\nThe guidance on this technology was considered for review in March 2012. Details are available on the NICE website.\n\nAndrew DillonChief ExecutiveMarch 2009', 'Changes after publication': 'February 2014: implementation section updated to clarify that sunitinib is recommended as an option for treating advanced and/or metastatic renal cell carcinoma. Additional minor maintenance update also carried out.\n\nMarch 2012: minor maintenance', 'About this guidance': 'NICE technology appraisal guidance is about the use of new and existing medicines and treatments in the NHS in England and Wales.\n\nThis guidance was developed using the NICE multiple technology appraisal process.\n\nWe have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available.\n\nYour responsibility\n\nThis guidance represents the views of NICE and was arrived at after careful consideration of the evidence available. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. However, the guidance does not override the individual responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.\n\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.\n\nCopyright\n\n© National Institute for Health and Clinical Excellence 2009. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.'}	https://www.nice.org.uk/guidance/ta169	Evidence-based recommendations on sunitinib (Sutent) for untreated advanced or metastatic renal cell carcinoma in adults.
49901ad279399be666f95cf0ab00c42e47a63123	nice	Rehabilitation after critical illness in adults	Rehabilitation after critical illness in adults This guideline covers rehabilitation strategies for adults who have experienced a critical illness and stayed in critical care. It aims to improve physical, psychological and cognitive outcomes in people who have been discharged from critical care. # Introduction Approximately 110,000 people (estimated from the UK Intensive Care National Audit and Research Centre Case Mix Programme Summary Statistics) spend time in critical care units in England and Wales each year, the majority surviving to be discharged home. The general perception among patients, families and most healthcare professionals is that these people undergo a rapid convalescence and recover to their previous life, in terms of both quantity and quality. Until relatively recently, there was little understanding of what really happens to all of these people. In the United Kingdom, a handful of hospitals established specialist follow-up clinics, staffed initially by doctors and nurses who also worked in critical care, and who thus understood the context of the patients' clinical stories. Research on the longer-term consequences of critical illness has shown that significant numbers of patients surviving critical illness have important continuing problems. For many, discharge from critical care is the start of an uncertain journey to recovery characterised by, among other problems, weakness, loss of energy and physical difficulties, anxiety, depression, post-traumatic stress (PTS) phenomena and, for some, a loss of mental faculty (termed cognitive function). Family members become informal caregivers, and this itself can exert a secondary toll of ill-health; family relationships can become altered and financial security imperilled. Recovery from illness is highly individual, and few studies have been able to demonstrate a close relationship between features of the acute illness and longer-term impact. Logically, patients who have had prolonged episodes of critical illness are likely to have greater long-term difficulties, however patients with relatively short intensive care stays may also need substantial help. The optimisation of recovery as a therapeutic objective, rather than mere survival, has developed increasing prominence. Identified as an important area during the creation of NICE's guideline on acutely ill adults in hospital, the Department of Health charged NICE 'To develop a short clinical guideline on rehabilitation after a period of critical illness requiring a stay in an ITU', and this series of documents represents the result of the process. To the non-specialist, the terminology around critical illness can be confusing. Critical care is now used as a term that encompasses intensive care or intensive therapy; provided in intensive care units (ICUs) or intensive therapy units (ITUs), together with what used to be called high-dependency care provided in high-dependency units (HDUs). Intensive care, or level 3 care, generally involves the support of one or more failing organ system, usually including the lungs, whereas high dependency care, or level 2 care, supports one system. Recently the distinctions have become blurred, hence the increasing use of the term criticalcare. For simplicity, we have chosen to divide the potential consequences of critical illness into 'physical', and 'non-physical' domains, the latter to encompass all the non-physical symptoms one might envisage, such as anxiety, depression, post-traumatic stress disorder (PTSD), and cognitive dysfunction. There is no particular requirement for a specified period of mechanical ventilatory support as an entry criterion for this pathway. Comments from the initial stakeholder meeting drew attention to the numbers of trauma patients, who receive mechanical ventilatory support for brief periods of time and yet who have the potential to benefit greatly. The Guideline Development Group (GDG) also recognised the strain suffered by many families, and the commitment involved in helping the recovering patient. There is a tension between providing information to help families cope, and recognising that many patients may not wish specific information to be shared; patient autonomy must be respected. Many families suffer financial strain as well as strain on their health and emotional resources. It was recognised that information around social services and benefits is often difficult to obtain and understand by those who need it, and decisions made around this area occasionally seem arbitrary; however, although there is clear room for improvement, it was difficult to see how this could be incorporated into the guideline beyond generalities, given how often such guidance would need to be changed. For many patients the recovery after critical illness is relatively straightforward and it is important not to lose sight of this. What is clear is that tens of thousands of patients leave critical care to go home each year, and it is likely that poor-quality recovery represents a substantial problem. Given the individual impact on patients, and ripple effects on families and society in general, poor-quality rehabilitation and impaired recovery from severe illness should be regarded as a major public health issue. The GDG has made a series of specific research recommendations, which are detailed later in the document. Additionally, of particular strategic importance is the lack of detailed understanding of the pathophysiology of the muscle wasting that is a feature of critical illness, and this area needs to be addressed. Critical illness polyneuropathy and myopathy are related and important problems. Alongside this, a better understanding of the impact of critical illness on the brain, and its relationship to sedation, neuroinflammation, delirium and future cognitive impairment is a priority. There is scope here for interventional trials in the near future. A thorough understanding of the socioeconomic consequences of critical illness at both individual and society levels is also needed to inform broader policy. As the majority of the recommendations in this guideline are consensus based, this guideline should stimulate, rather than stifle, research, and the impact of the introduction of the recommendations, along with alternative approaches, should be thoroughly evaluated. From my perspective as GDG Chair, the development process has been a challenge. It is one thing to know that a problem exists, and quite another to translate knowledge of a problem into an evidence-based management guideline, that can be implemented in the NHS for the benefit of patients. The GDG and the technical team have worked extremely hard picking their way through a difficult and somewhat patchy evidence base; I am grateful for their commitment and effort. Our ambition is that this guideline will lead to substantial benefits for recovering patients and their families. We hope that when this guideline is reviewed, the evidence base for specific interventions and service delivery models is more substantial. Stephen BrettConsultant and Senior Lecturer in Intensive Care Medicine, Imperial College Healthcare NHS TrustGuideline Development Group Chair# Guidance People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care. Making decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding. The Guideline Development Group (GDG) used the following definitions in this guideline: Short clinical assessment: a brief clinical assessment to identify patients who may be at risk of developing physical and non-physical morbidity. Comprehensive clinical assessment: a more detailed assessment to determine the rehabilitation needs of patients who have been identified as being at risk of developing physical and non-physical morbidity. Functional assessment: an assessment to examine the patient's daily functional ability. Short-term rehabilitation goals: goals for the patient to reach before they are discharged from hospital. Medium-term rehabilitation goals: goals to help the patient return to their normal activities of daily living after they are discharged from hospital. Physical morbidity: problems such as muscle loss, muscle weakness, musculoskeletal problems including contractures, respiratory problems, sensory problems, pain, and swallowing and communication problems. Non-physical morbidity: psychological, emotional and psychiatric problems, and cognitive dysfunction. Multidisciplinary team: a team of healthcare professionals with the full spectrum of clinical skills needed to offer holistic care to patients with complex problems. The team may be a group of people who normally work together or who only work together intermittently. # Key principle of care To ensure continuity of care, healthcare professional(s) with the appropriate competencies should coordinate the patient's rehabilitation care pathway. Key elements of the coordination are as follows.The healthcare professional(s) may be intensive care professional(s) or, depending on local arrangements, any appropriately trained healthcare professional(s) from a service (including specialist rehabilitation medicine services) with access to referral pathways and medical support (if not medically qualified). Ensure the short-term and medium-term rehabilitation goals are reviewed, agreed and updated throughout the patient's rehabilitation care pathway. Ensure the delivery of the structured and supported self-directed rehabilitation manual, when applicable. Liaise with primary/community care for the functional reassessment at 2 to 3 months after the patient's discharge from critical care. Ensure information, including documentation, is communicated between hospitals and to other hospital-based or community rehabilitation services and primary care services. Give patients the contact details of the healthcare professional(s) on discharge from critical care, and again on discharge from hospital.See the NICE guideline on patient experience in adult NHS services. # During the critical care stay During the patient's critical care stay and as early as clinically possible, perform a short clinical assessment to determine the patient's risk of developing physical and non-physical morbidity (see table 1). For patients at risk of physical and non-physical morbidity, perform a comprehensive clinical assessment to identify their current rehabilitation needs. This should include assessments by healthcare professionals experienced in critical care and rehabilitation. For patients at risk, agree short-term and medium-term rehabilitation goals, based on the comprehensive clinical assessment. The patient's family and/or carer should also be involved.During the critical care stay, the patient may not gain full consciousness or may not have full capacity to give formal consent. Therefore, the involvement of the family and/or carer is important at this stage. The comprehensive clinical assessment and the rehabilitation goals should be collated and documented in the patient's clinical records. For patients at risk, start rehabilitation as early as clinically possible, based on the comprehensive clinical assessment and the rehabilitation goals. Rehabilitation should include: measures to prevent avoidable physical and non-physical morbidity, including a review of previous and current medication nutrition support, based on the recommendations in the NICE guideline on nutrition support for adults. an individualised, structured rehabilitation programme with frequent follow-up reviews. The details of the structured rehabilitation programme and the reviews should be collated and documented in the patient's clinical records. Give patients the following information during their critical care stay. Also give the information to their family and/or carer, unless the patient disagrees.During the critical care stay, the patient may not gain full consciousness or may not have full capacity to give formal consent. Therefore, the involvement of the family and/or carer is important at this stage. Information about the patient's critical illness, interventions and treatments. Information about the equipment used during the patient's critical care stay. If applicable, information about any possible short-term and/or long-term physical and non-physical problems which may require rehabilitation.Deliver all the above information more than once during the patient's critical care stay. # Before discharge from critical care For patients who were previously identified as being at low risk, perform a short clinical assessment before their discharge from critical care to determine their risk of developing physical and non‑physical morbidity (see table 1). For patients at risk, and patients who started the individualised, structured rehabilitation programme in critical care, perform a comprehensive clinical reassessment to identify their current rehabilitation needs. The comprehensive reassessment should pay particular attention to: physical, sensory and communication problems (see table 2) underlying factors, such as pre-existing psychological or psychiatric distress symptoms that have developed during the critical care stay, such as delusions, intrusive memories, anxiety, panic episodes, nightmares, flashback episodes or depression (see the NICE guideline on the prevention, diagnosis and management of delirium). For patients who were previously identified as being at risk during critical care, the outcomes of the comprehensive reassessment should inform the individualised, structured rehabilitation programme (recommendation 1.6). For patients at risk, agree or review and update the rehabilitation goals, based on the comprehensive reassessment. The family and/or carer should also be involved, unless the patient disagrees. Ensure that the transfer of patients and the formal structured handover of their care are in line with the NICE guideline on acutely ill patients in hospital. This should include the formal handover of the individualised, structured rehabilitation programme. Give patients the following information before, or as soon as possible after, their discharge from critical care. Also give the information to their family and/or carer, unless the patient disagrees. Information about the rehabilitation care pathway. Information about the differences between critical care and ward-based care. This should include information about the differences in the environment, and staffing and monitoring levels. Information about the transfer of clinical responsibility to a different medical team (this includes information about the formal structured handover of care recommended in the NICE guideline on acutely ill patients in hospital. If applicable, emphasise the information about possible short‑term and/or long-term physical and non-physical problems that may require rehabilitation. If applicable, information about sleeping problems, nightmares and hallucinations and the readjustment to ward-based care. # During ward-based care For patients who were previously identified as being at low risk before discharge from critical care, perform a short clinical assessment to determine their risk of physical and non‑physical morbidity (see table 1). For patients at risk, perform a comprehensive clinical reassessment (see recommendation 1.9) to identify their current rehabilitation needs. For patients at risk, offer an individualised, structured rehabilitation programme, based on the comprehensive clinical reassessment and the agreed or updated rehabilitation goals set before the patient was discharged from critical care. Comprehensive reassessments apply to both those before discharge from critical care and during ward-based care. The individualised, structured rehabilitation programme should be developed and delivered by members of a multidisciplinary team, and should include appropriate referrals, if applicable. Based on clinical judgement and the individual patient's rehabilitation needs, consider offering a structured and supported self-directed rehabilitation manual for at least 6 weeks after discharge from critical care, as part of the individualised, structured rehabilitation programme.The structured and supported self-directed rehabilitation manual (based on Jones et al. 2003) should be coordinated by an appropriately skilled healthcare professional throughout its duration. The optimal time for starting the structured and supported self-directed rehabilitation manual should be based on individual patients' physical and cognitive capacity at different stages of their illness and recovery. For patients with symptoms of stress related to traumatic incidents and/or memories, refer to the NICE guideline on the management of post-traumatic stress disorder (PTSD) and initiate appropriate preventative strategies. # Before discharge to home or community care Before discharging patients who were receiving the individualised structured rehabilitation programme during ward-based care (recommendation 1.15): perform a functional assessment which should include the following physical and non-physical dimensions (also see table 2 for possible examples): physical problems (physical dimension) sensory problems (physical dimension) communication problems (physical dimension) social care or equipment needs (physical dimension) anxiety (non-physical dimension) depression (non-physical dimension) post-traumatic stress-related symptoms (non-physical dimension) behavioural and cognitive problems (non-physical dimension) psychosocial problems (non-physical dimension). assess the impact of the outcomes from the functional assessment on the patient's activities of daily living and participation based on the functional assessment, review, update and agree the rehabilitation goals with the patient. The family and/or carer should be involved if the patient agrees.See also, the NICE guideline on the transition between inpatient hospital settings and community or care home settings for adults with social care needs. If continuing rehabilitation needs are identified from the functional assessment, ensure that before the patient is discharged: discharge arrangements, including appropriate referrals for the necessary ongoing care, are in place before completing the discharge all discharge documents are completed and forwarded to the appropriate post-discharge services and the patient the patient, and/or the family and/or carer as appropriate, is aware of the discharge arrangements and understands them (see the NICE guideline on intermediate care including reablement). Give patients the following information before their discharge to home or community care. Also give the information to their family and/or carer, if the patient agrees. Information about their physical recovery, based on the goals set during ward-based care if applicable. If applicable, information about diet and any other continuing treatments. Information about how to manage activities of daily living including self-care and re-engaging with everyday life. If applicable, information about driving, returning to work, housing and benefits. Information about local statutory and non-statutory support services, such as support groups. General guidance, especially for the family and/or carer, on what to expect and how to support the patient at home. This should take into account both the patient's needs and the family's/carer's needs. Give the patient their own copy of the critical care discharge summary. # –3 months after discharge from critical care Review patients with rehabilitation needs 2 to 3 months after their discharge from critical care. Carry out a functional reassessment of their health and social care needs, using the dimensions in recommendation 1.20. If appropriate, also enquire about sexual dysfunction. The functional reassessment should be face to face in the community or in hospital, performed by an appropriately-skilled healthcare professional(s) who is familiar with the patient's critical care problems and rehabilitation care pathway. Based on the functional reassessment. Refer the patient to the appropriate rehabilitation or specialist services if: the patient appears to be recovering at a slower rate than anticipated, according to their rehabilitation goals, or the patient has developed unanticipated physical and/or non‑physical morbidity that was not previously identified. Give support if the patient is not recovering as quickly as they anticipated. If anxiety or depression is suspected, follow the stepped care models recommended in the NICE guidelines on generalised anxiety disorder and panic disorder in adults and depression in adults. If PTSD is suspected or the patient has significant symptoms of PTS, refer to the NICE guideline on post-traumatic stress disorder. Physical Unable to get out of bed independently. Anticipated long duration of critical care stay. Obvious significant physical or neurological injury. Lack of cognitive functioning to continue exercise independently. Unable to self ventilate on 35% of oxygen or less. Presence of premorbid respiratory or mobility problems. Unable to mobilise independently over short distances. Non-physical Recurrent nightmares, particularly where patients report trying to stay awake to avoid nightmares. Intrusive memories of traumatic events which have occurred prior to admission (for example, road traffic accidents) or during their critical care stay (for example, delusion experiences or flashbacks). New and recurrent anxiety or panic attacks. Expressing the wish not to talk about their illness or changing the subject quickly off the topic. Note: this list is not exhaustive and healthcare professionals should use their clinical judgement Physical dimensions Physical problems Weakness, inability/partial ability to sit, rise to standing, or to walk, fatigue, pain, breathlessness, swallowing difficulties, incontinence, inability/partial ability to self-care. Sensory problems Changes in vision or hearing, pain, altered sensation. Communication problems Difficulties in speaking or using language to communicate, difficulties in writing. Social care or equipment needs Mobility aids, transport, housing, benefits, employment and leisure needs. Non-physical dimensions Anxiety, depression and PTS-related symptoms New or recurrent somatic symptoms including palpitations, irritability and sweating; symptoms of derealisation and depersonalisation; avoidance behaviour; depressive symptoms including tearfulness and withdrawal; nightmares, delusions, hallucinations and flashbacks. Behavioural and cognitive problems Loss of memory, attention deficits, sequencing problems, deficits in organisational skills, confusion, apathy, disinhibition, compromised insight. Other psychological or psychosocial problems Low-self-esteem, poor or low self-image and/or body image issues, relationship difficulties, including those with the family and/or carer.# Research recommendations What is the most effective way of identifying patients at risk of critical illness-associated physical morbidity, psychological morbidity and cognitive dysfunction and how can the disease progress and response to interventions monitored? In patients at high risk, which therapeutic strategies are the most clinically and cost effective at reducing the prevalence and severity of critical illness-associated physical morbidity, psychological morbidity and cognitive dysfunction? In patients with established morbidity, which specific therapeutic strategies are the most clinically and cost effective at reducing the magnitude of critical illness-associated physical morbidity, psychological morbidity and cognitive dysfunction? For patients at high risk of critical illness-associated morbidity, what is the clinical effectiveness and cost effectiveness of organised critical care rehabilitation versus usual care on physical and psychological functioning, participation and quality of life? For those patients not identified as at high risk of critical illness-associated morbidity, what is the clinical effectiveness and cost effectiveness of organised critical care rehabilitation versus usual care on physical, psychological functioning, participation and quality of life?	{'Introduction': "Approximately 110,000 people (estimated from the UK Intensive Care National Audit and Research Centre [ICNARC] Case Mix Programme [CMP] Summary Statistics) spend time in critical care units in England and Wales each year, the majority surviving to be discharged home. The general perception among patients, families and most healthcare professionals is that these people undergo a rapid convalescence and recover to their previous life, in terms of both quantity and\xa0quality.\n\nUntil relatively recently, there was little understanding of what really happens to all of these people. In the United Kingdom, a handful of hospitals established specialist follow-up clinics, staffed initially by doctors and nurses who also worked in critical care, and who thus understood the context of the patients' clinical stories. Research on the longer-term consequences of critical illness has shown that significant numbers of patients surviving critical illness have important continuing problems. For many, discharge from critical care is the start of an uncertain journey to recovery characterised by, among other problems, weakness, loss of energy and physical difficulties, anxiety, depression, post-traumatic stress (PTS) phenomena and, for some, a loss of mental faculty (termed cognitive function). Family members become informal caregivers, and this itself can exert a secondary toll of ill-health; family relationships can become altered and financial security imperilled. Recovery from illness is highly individual, and few studies have been able to demonstrate a close relationship between features of the acute illness and longer-term impact. Logically, patients who have had prolonged episodes of critical illness are likely to have greater long-term difficulties, however patients with relatively short intensive care stays may also need substantial help.\n\nThe optimisation of recovery as a therapeutic objective, rather than mere survival, has developed increasing prominence. Identified as an important area during the creation of NICE's guideline on acutely ill adults in hospital, the Department of Health charged NICE 'To develop a short clinical guideline on rehabilitation after a period of critical illness requiring a stay in an ITU', and this series of documents represents the result of the process.\n\nTo the non-specialist, the terminology around critical illness can be confusing. Critical care is now used as a term that encompasses intensive care or intensive therapy; provided in intensive care units (ICUs) or intensive therapy units (ITUs), together with what used to be called high-dependency care provided in high-dependency units (HDUs). Intensive care, or level 3 care, generally involves the support of one or more failing organ system, usually including the lungs, whereas high dependency care, or level 2 care, supports one system. Recently the distinctions have become blurred, hence the increasing use of the term criticalcare.\n\nFor simplicity, we have chosen to divide the potential consequences of critical illness into 'physical', and 'non-physical' domains, the latter to encompass all the non-physical symptoms one might envisage, such as anxiety, depression, post-traumatic stress disorder (PTSD), and cognitive dysfunction.\n\nThere is no particular requirement for a specified period of mechanical ventilatory support as an entry criterion for this pathway. Comments from the initial stakeholder meeting drew attention to the numbers of trauma patients, who receive mechanical ventilatory support for brief periods of time and yet who have the potential to benefit greatly.\n\nThe Guideline Development Group (GDG) also recognised the strain suffered by many families, and the commitment involved in helping the recovering patient. There is a tension between providing information to help families cope, and recognising that many patients may not wish specific information to be shared; patient autonomy must be respected.\n\nMany families suffer financial strain as well as strain on their health and emotional resources. It was recognised that information around social services and benefits is often difficult to obtain and understand by those who need it, and decisions made around this area occasionally seem arbitrary; however, although there is clear room for improvement, it was difficult to see how this could be incorporated into the guideline beyond generalities, given how often such guidance would need to be changed.\n\nFor many patients the recovery after critical illness is relatively straightforward and it is important not to lose sight of this. What is clear is that tens of thousands of patients leave critical care to go home each year, and it is likely that poor-quality recovery represents a substantial problem. Given the individual impact on patients, and ripple effects on families and society in general, poor-quality rehabilitation and impaired recovery from severe illness should be regarded as a major public health issue.\n\nThe GDG has made a series of specific research recommendations, which are detailed later in the document. Additionally, of particular strategic importance is the lack of detailed understanding of the pathophysiology of the muscle wasting that is a feature of critical illness, and this area needs to be addressed. Critical illness polyneuropathy and myopathy are related and important problems. Alongside this, a better understanding of the impact of critical illness on the brain, and its relationship to sedation, neuroinflammation, delirium and future cognitive impairment is a priority. There is scope here for interventional trials in the near future. A thorough understanding of the socioeconomic consequences of critical illness at both individual and society levels is also needed to inform broader policy. As the majority of the recommendations in this guideline are consensus based, this guideline should stimulate, rather than stifle, research, and the impact of the introduction of the recommendations, along with alternative approaches, should be thoroughly evaluated.\n\nFrom my perspective as GDG Chair, the development process has been a challenge. It is one thing to know that a problem exists, and quite another to translate knowledge of a problem into an evidence-based management guideline, that can be implemented in the NHS for the benefit of patients. The GDG and the technical team have worked extremely hard picking their way through a difficult and somewhat patchy evidence base; I am grateful for their commitment and effort. Our ambition is that this guideline will lead to substantial benefits for recovering patients and their families. We hope that when this guideline is reviewed, the evidence base for specific interventions and service delivery models is more substantial.\n\nStephen BrettConsultant and Senior Lecturer in Intensive Care Medicine, Imperial College Healthcare NHS TrustGuideline Development Group Chair", 'Guidance': "People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.\n\nMaking decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.\n\nThe Guideline Development Group (GDG) used the following definitions in this guideline:\n\nShort clinical assessment: a brief clinical assessment to identify patients who may be at risk of developing physical and non-physical morbidity.\n\nComprehensive clinical assessment: a more detailed assessment to determine the rehabilitation needs of patients who have been identified as being at risk of developing physical and non-physical morbidity.\n\nFunctional assessment: an assessment to examine the patient's daily functional ability.\n\nShort-term rehabilitation goals: goals for the patient to reach before they are discharged from hospital.\n\nMedium-term rehabilitation goals: goals to help the patient return to their normal activities of daily living after they are discharged from hospital.\n\nPhysical morbidity: problems such as muscle loss, muscle weakness, musculoskeletal problems including contractures, respiratory problems, sensory problems, pain, and swallowing and communication problems.\n\nNon-physical morbidity: psychological, emotional and psychiatric problems, and cognitive dysfunction.\n\nMultidisciplinary team: a team of healthcare professionals with the full spectrum of clinical skills needed to offer holistic care to patients with complex problems. The team may be a group of people who normally work together or who only work together intermittently.\n\n# Key principle of care\n\nTo ensure continuity of care, healthcare professional(s) with the appropriate competencies should coordinate the patient's rehabilitation care pathway. Key elements of the coordination are as follows.The healthcare professional(s) may be intensive care professional(s) or, depending on local arrangements, any appropriately trained healthcare professional(s) from a service (including specialist rehabilitation medicine services) with access to referral pathways and medical support (if not medically qualified).\n\nEnsure the short-term and medium-term rehabilitation goals are reviewed, agreed and updated throughout the patient's rehabilitation care pathway.\n\nEnsure the delivery of the structured and supported self-directed rehabilitation manual, when applicable.\n\nLiaise with primary/community care for the functional reassessment at 2 to 3\xa0months after the patient's discharge from critical care.\n\nEnsure information, including documentation, is communicated between hospitals and to other hospital-based or community rehabilitation services and primary care services.\n\nGive patients the contact details of the healthcare professional(s) on discharge from critical care, and again on discharge from hospital.See the NICE guideline on patient experience in adult NHS services.\n\n# During the critical care stay\n\nDuring the patient's critical care stay and as early as clinically possible, perform a short clinical assessment to determine the patient's risk of developing physical and non-physical morbidity (see table 1).\n\nFor patients at risk of physical and non-physical morbidity, perform a comprehensive clinical assessment to identify their current rehabilitation needs. This should include assessments by healthcare professionals experienced in critical care and\xa0rehabilitation.\n\nFor patients at risk, agree short-term and medium-term rehabilitation goals, based on the comprehensive clinical assessment. The patient's family and/or carer should also be involved.During the critical care stay, the patient may not gain full consciousness or may not have full capacity to give formal consent. Therefore, the involvement of the family and/or carer is important at this stage.\n\nThe comprehensive clinical assessment and the rehabilitation goals should be collated and documented in the patient's clinical records.\n\nFor patients at risk, start rehabilitation as early as clinically possible, based on the comprehensive clinical assessment and the rehabilitation goals. Rehabilitation should include:\n\nmeasures to prevent avoidable physical and non-physical morbidity, including a review of previous and current medication\n\nnutrition support, based on the recommendations in the NICE guideline on nutrition support for adults.\n\nan individualised, structured rehabilitation programme with frequent follow-up reviews. The details of the structured rehabilitation programme and the reviews should be collated and documented in the patient's clinical records.\n\nGive patients the following information during their critical care stay. Also give the information to their family and/or carer, unless the patient disagrees.During the critical care stay, the patient may not gain full consciousness or may not have full capacity to give formal consent. Therefore, the involvement of the family and/or carer is important at this stage.\n\nInformation about the patient's critical illness, interventions and\xa0treatments.\n\nInformation about the equipment used during the patient's critical care\xa0stay.\n\nIf applicable, information about any possible short-term and/or long-term physical and non-physical problems which may require rehabilitation.Deliver all the above information more than once during the patient's critical care stay.\n\n# Before discharge from critical care\n\nFor patients who were previously identified as being at low risk, perform a short clinical assessment before their discharge from critical care to determine their risk of developing physical and non‑physical morbidity (see table 1).\n\nFor patients at risk, and patients who started the individualised, structured rehabilitation programme in critical care, perform a comprehensive clinical reassessment to identify their current rehabilitation needs. The comprehensive reassessment should pay particular attention to:\n\nphysical, sensory and communication problems (see table 2)\n\nunderlying factors, such as pre-existing psychological or psychiatric distress\n\nsymptoms that have developed during the critical care stay, such as delusions, intrusive memories, anxiety, panic episodes, nightmares, flashback episodes or depression (see the NICE guideline on the prevention, diagnosis and management of delirium).\n\nFor patients who were previously identified as being at risk during critical care, the outcomes of the comprehensive reassessment should inform the individualised, structured rehabilitation programme (recommendation\xa01.6).\n\nFor patients at risk, agree or review and update the rehabilitation goals, based on the comprehensive reassessment. The family and/or carer should also be involved, unless the patient disagrees.\n\nEnsure that the transfer of patients and the formal structured handover of their care are in line with the NICE guideline on acutely ill patients in hospital. This should include the formal handover of the individualised, structured rehabilitation programme.\n\nGive patients the following information before, or as soon as possible after, their discharge from critical care. Also give the information to their family and/or carer, unless the patient disagrees.\n\nInformation about the rehabilitation care pathway.\n\nInformation about the differences between critical care and ward-based care. This should include information about the differences in the environment, and staffing and monitoring levels.\n\nInformation about the transfer of clinical responsibility to a different medical team (this includes information about the formal structured handover of care recommended in the NICE guideline on acutely ill patients in hospital.\n\nIf applicable, emphasise the information about possible short‑term and/or long-term physical and non-physical problems that may require rehabilitation.\n\nIf applicable, information about sleeping problems, nightmares and hallucinations and the readjustment to ward-based care.\n\n# During ward-based care\n\nFor patients who were previously identified as being at low risk before discharge from critical care, perform a short clinical assessment to determine their risk of physical and non‑physical morbidity (see table 1).\n\nFor patients at risk, perform a comprehensive clinical reassessment (see recommendation 1.9) to identify their current rehabilitation needs.\n\nFor patients at risk, offer an individualised, structured rehabilitation programme, based on the comprehensive clinical reassessment and the agreed or updated rehabilitation goals set before the patient was discharged from critical care. Comprehensive reassessments apply to both those before discharge from critical care and during ward-based care.\n\nThe individualised, structured rehabilitation programme should be developed and delivered by members of a multidisciplinary team, and should include appropriate referrals, if applicable.\n\nBased on clinical judgement and the individual patient's rehabilitation needs, consider offering a structured and supported self-directed rehabilitation manual for at least 6\xa0weeks after discharge from critical care, as part of the individualised, structured rehabilitation programme.The structured and supported self-directed rehabilitation manual (based on Jones et al. 2003) should be coordinated by an appropriately skilled healthcare professional throughout its duration. The optimal time for starting the structured and supported self-directed rehabilitation manual should be based on individual patients' physical and cognitive capacity at different stages of their illness and recovery.\n\nFor patients with symptoms of stress related to traumatic incidents and/or memories, refer to the NICE guideline on the management of post-traumatic stress disorder (PTSD) and initiate appropriate preventative strategies.\n\n# Before discharge to home or community care\n\nBefore discharging patients who were receiving the individualised structured rehabilitation programme during ward-based care (recommendation 1.15):\n\nperform a functional assessment which should include the following physical and non-physical dimensions (also see table 2 for possible examples):\n\n\n\nphysical problems (physical dimension)\n\nsensory problems (physical dimension)\n\ncommunication problems (physical dimension)\n\nsocial care or equipment needs (physical dimension)\n\nanxiety (non-physical dimension)\n\ndepression (non-physical dimension)\n\npost-traumatic stress-related symptoms (non-physical dimension)\n\nbehavioural and cognitive problems (non-physical dimension)\n\npsychosocial problems (non-physical dimension).\n\n\n\nassess the impact of the outcomes from the functional assessment on the patient's activities of daily living and participation\n\nbased on the functional assessment, review, update and agree the rehabilitation goals with the patient. The family and/or carer should be involved if the patient agrees.See also, the NICE guideline on the transition between inpatient hospital settings and community or care home settings for adults with social care needs.\n\nIf continuing rehabilitation needs are identified from the functional assessment, ensure that before the patient is discharged:\n\ndischarge arrangements, including appropriate referrals for the necessary ongoing care, are in place before completing the\xa0discharge\n\nall discharge documents are completed and forwarded to the appropriate post-discharge services and the patient\n\nthe patient, and/or the family and/or carer as appropriate, is aware of the discharge arrangements and understands them (see the NICE guideline on intermediate care including reablement).\n\nGive patients the following information before their discharge to home or community care. Also give the information to their family and/or carer, if the patient agrees.\n\nInformation about their physical recovery, based on the goals set during ward-based care if applicable.\n\nIf applicable, information about diet and any other continuing\xa0treatments.\n\nInformation about how to manage activities of daily living including self-care and re-engaging with everyday life.\n\nIf applicable, information about driving, returning to work, housing and benefits.\n\nInformation about local statutory and non-statutory support services, such as support groups.\n\nGeneral guidance, especially for the family and/or carer, on what to expect and how to support the patient at home. This should take into account both the patient's needs and the family's/carer's needs.\n\nGive the patient their own copy of the critical care discharge summary.\n\n# –3 months after discharge from critical care\n\nReview patients with rehabilitation needs 2 to 3 months after their discharge from critical care. Carry out a functional reassessment of their health and social care needs, using the dimensions in recommendation 1.20. If appropriate, also enquire about sexual\xa0dysfunction.\n\nThe functional reassessment should be face to face in the community or in hospital, performed by an appropriately-skilled healthcare professional(s) who is familiar with the patient's critical care problems and rehabilitation care pathway.\n\nBased on the functional reassessment.\n\nRefer the patient to the appropriate rehabilitation or specialist services if:\n\n\n\nthe patient appears to be recovering at a slower rate than anticipated, according to their rehabilitation goals, or\n\nthe patient has developed unanticipated physical and/or non‑physical morbidity that was not previously identified.\n\n\n\nGive support if the patient is not recovering as quickly as they\xa0anticipated.\n\nIf anxiety or depression is suspected, follow the stepped care models recommended in the NICE guidelines on generalised anxiety disorder and panic disorder in adults and depression in adults.\n\nIf PTSD is suspected or the patient has significant symptoms of PTS, refer to the NICE guideline on post-traumatic stress disorder.\n\n\n\nPhysical\n\nUnable to get out of bed independently.\n\nAnticipated long duration of critical care stay.\n\nObvious significant physical or neurological injury.\n\nLack of cognitive functioning to continue exercise independently.\n\nUnable to self ventilate on 35% of oxygen or less.\n\nPresence of premorbid respiratory or mobility problems.\n\nUnable to mobilise independently over short distances.\n\nNon-physical\n\nRecurrent nightmares, particularly where patients report trying to stay awake to avoid nightmares.\n\nIntrusive memories of traumatic events which have occurred prior to admission (for example, road traffic accidents) or during their critical care stay (for example, delusion experiences or flashbacks).\n\nNew and recurrent anxiety or panic attacks.\n\nExpressing the wish not to talk about their illness or changing the subject quickly off the topic.\n\nNote: this list is not exhaustive and healthcare professionals should use their clinical judgement\n\nPhysical dimensions\n\n-\n\nPhysical problems\n\nWeakness, inability/partial ability to sit, rise to standing, or to walk, fatigue, pain, breathlessness, swallowing difficulties, incontinence, inability/partial ability to self-care.\n\nSensory problems\n\nChanges in vision or hearing, pain, altered sensation.\n\nCommunication problems\n\nDifficulties in speaking or using language to communicate, difficulties in writing.\n\nSocial care or equipment needs\n\nMobility aids, transport, housing, benefits, employment and leisure needs.\n\nNon-physical dimensions\n\n-\n\nAnxiety, depression and PTS-related symptoms\n\nNew or recurrent somatic symptoms including palpitations, irritability and sweating; symptoms of derealisation and depersonalisation; avoidance behaviour; depressive symptoms including tearfulness and withdrawal; nightmares, delusions, hallucinations and flashbacks.\n\nBehavioural and cognitive problems\n\nLoss of memory, attention deficits, sequencing problems, deficits in organisational skills, confusion, apathy, disinhibition, compromised insight.\n\nOther psychological or psychosocial problems\n\nLow-self-esteem, poor or low self-image and/or body image issues, relationship difficulties, including those with the family and/or carer.", 'Research recommendations': 'What is the most effective way of identifying patients at risk of critical illness-associated physical morbidity, psychological morbidity and cognitive dysfunction and how can the disease progress and response to interventions monitored?\n\nIn patients at high risk, which therapeutic strategies are the most clinically and cost effective at reducing the prevalence and severity of critical illness-associated physical morbidity, psychological morbidity and cognitive dysfunction?\n\nIn patients with established morbidity, which specific therapeutic strategies are the most clinically and cost effective at reducing the magnitude of critical illness-associated physical morbidity, psychological morbidity and cognitive dysfunction?\n\nFor patients at high risk of critical illness-associated morbidity, what is the clinical effectiveness and cost effectiveness of organised critical care rehabilitation versus usual care on physical and psychological functioning, participation and quality of life?\n\nFor those patients not identified as at high risk of critical illness-associated morbidity, what is the clinical effectiveness and cost effectiveness of organised critical care rehabilitation versus usual care on physical, psychological functioning, participation and quality of life?'}	https://www.nice.org.uk/guidance/cg83	This guideline covers rehabilitation strategies for adults who have experienced a critical illness and stayed in critical care. It aims to improve physical, psychological and cognitive outcomes in people who have been discharged from critical care.
b83c4c8e67633074b741e1926386e5d38cc568a0	nice	Photodynamic therapy for brain tumours	Photodynamic therapy for brain tumours # Guidance Current evidence on the safety and efficacy of photodynamic therapy (PDT) for brain tumours is limited in both quality and quantity. Therefore, this procedure should only be used in the context of randomised controlled trials with well-defined inclusion criteria (specifying the tumour type for inclusion in the trial) and treatment protocols, and with collection of both survival and quality of life outcomes.# The procedure # Indications and current treatments Brain tumours may be primary tumours or metastases from tumours elsewhere in the body. Primary brain tumours are graded using a World Health Organization (WHO) classification from I (least aggressive) to IV (most aggressive). Patients with high-grade tumours often have a poor prognosis. The symptoms of a brain tumour are determined by its location and size. Depending on its location in the brain, a tumour can cause limb weakness or speech disturbance. Any brain swelling caused by a tumour can result in raised intracranial pressure, which can lead to headache, vomiting and reduced consciousness. Some patients can be treated by surgical resection, with the aim of reducing symptoms and improving prognosis. Non-surgical treatment options include chemotherapy and radiotherapy. A combination of these treatments may be used, or surgery may be followed by chemotherapy and radiotherapy. # Outline of the procedure Photodynamic therapy is usually carried out with the patient under general anaesthesia, at the same operation as surgical resection, when as much of the tumour has been removed as possible. A photosensitising agent is injected, usually intravenously, although direct injection into the tumour is also possible. The photosensitising agent is activated by illuminating the selected area with a laser source. The photosensitising agent absorbs the light and forms high-energy oxygen molecules that interact with the brain tissue to cause tumour necrosis through a photochemical effect. Occasionally, repeated PDT sessions are performed after surgery via access maintained through the skull. To minimise the risks associated with skin photosensitivity, patients are advised to avoid exposure to bright light and direct sunlight for several weeks after the procedure. This guidance refers to the therapeutic use of PDT and not to PDT-guided resection. Various devices and photosensitising agents can be used for this procedure. Sections 2.3 and 2.4 describe efficacy and safety outcomes which were available in the published literature and which the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview. # Efficacy A randomised controlled trial (RCT) of 27 patients with newly diagnosed glioblastoma and a Karnofsky score of 60 or greater (on a scale where 100 is 'perfect health' and 0 is 'death') reported an increase in mean survival in 13 patients who received PDT after surgery compared with 14 patients treated by surgical resection alone (52.8 weeks and 24.1 weeks respectively; p = 0.001). A case series of 112 patients treated by PDT following surgical resection reported median survival of 30 weeks in patients with gliomas and 24 weeks in patients with metastatic carcinoma (follow-up not stated). A case series of 136 patients treated by PDT following surgical resection reported that median survival from initial diagnosis was 76.5 months for patients with primary anaplastic astrocytoma and 14.3 months for patients with glioblastoma multiforme (p = 0.001), with a minimum follow-up of 3 years. Duration of survival was not associated with the location of the tumours in the brain (p = 0.54). A case series of 26 patients with recurrent glioblastoma (WHO grade IV) treated by PDT following surgical resection reported median survival of 8.5 months. The case series of 26 patients reported that median time to disease progression was 6 months. The RCT of 27 patients reported an improvement in mean Karnofsky score from 60 to 80 points in the PDT after surgery group but no change from 70 points in the surgical resection group (follow-up not stated; p < 0.05). The Specialist Advisers considered key efficacy outcomes to include overall and progression-free survival, completeness of resection and quality of life. # Safety In the case series of 112 patients, 3% (3/112) died after the operation, 1 of pulmonary embolism and 2 of tumour cavity haemorrhage. Deep vein thrombosis occurred in 4% (4/112), infection (not otherwise specified) in 4% (4/112), and cerebrospinal fluid leak in 1% (1/112) of patients (no further details stated). The case series of 26 patients reported transient oedema of the treated area in 4% (1/26) of patients. Across three case series, sunburn due to light exposure occurred at a rate of between 2% (2/112, 2/136) and 8% (2/26). The Specialist Advisers considered adverse events associated with PDT for brain tumours to include cerebral oedema, raised intracranial pressure, hypersensitivity reactions and skin photosensitisation. They stated that additional theoretical adverse events include damage to the normal brain and cerebral blood vessels, stroke, and compromising of further treatments by increasing the sensitivity of the brain to their toxic side effects.# Further information NICE has published technology appraisal guidance on temozolomide for the treatment of recurrent malignant glioma (brain cancer) and carmustine implants and temozolomide for the treatment of newly diagnosed high grade glioma, and service guidance for improving outcomes for people with brain and other central nervous system tumours. # Information for patients NICE has produced information on this procedure for patients and carers ('Understanding NICE guidance'). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.# About this guidance NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland. This guidance was developed using the NICE interventional procedure guidance process. We have produced a summary of this guidance for patients and carers. Information about the evidence it is based on is also available. Changes since publication January 2012: minor maintenance. Your responsibility This guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer. Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties. Copyright © National Institute for Health and Clinical Excellence 2009. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE. Contact NICE National Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT www.nice.org.uk nice@nice.org.uk	{'Guidance ': 'Current evidence on the safety and efficacy of photodynamic therapy (PDT) for brain tumours is limited in both quality and quantity. Therefore, this procedure should only be used in the context of randomised controlled trials with well-defined inclusion criteria (specifying the tumour type for inclusion in the trial) and treatment protocols, and with collection of both survival and quality of life outcomes.', 'The procedure': "# Indications and current treatments\n\nBrain tumours may be primary tumours or metastases from tumours elsewhere in the body. Primary brain tumours are graded using a World Health Organization (WHO) classification from I (least aggressive) to IV (most aggressive). Patients with high-grade tumours often have a poor prognosis.\n\nThe symptoms of a brain tumour are determined by its location and size. Depending on its location in the brain, a tumour can cause limb weakness or speech disturbance. Any brain swelling caused by a tumour can result in raised intracranial pressure, which can lead to headache, vomiting and reduced consciousness.\n\nSome patients can be treated by surgical resection, with the aim of reducing symptoms and improving prognosis. Non-surgical treatment options include chemotherapy and radiotherapy. A combination of these treatments may be used, or surgery may be followed by chemotherapy and radiotherapy.\n\n# Outline of the procedure\n\nPhotodynamic therapy is usually carried out with the patient under general anaesthesia, at the same operation as surgical resection, when as much of the tumour has been removed as possible. A photosensitising agent is injected, usually intravenously, although direct injection into the tumour is also possible. The photosensitising agent is activated by illuminating the selected area with a laser source. The photosensitising agent absorbs the light and forms high-energy oxygen molecules that interact with the brain tissue to cause tumour necrosis through a photochemical effect. Occasionally, repeated PDT sessions are performed after surgery via access maintained through the skull. To minimise the risks associated with skin photosensitivity, patients are advised to avoid exposure to bright light and direct sunlight for several weeks after the procedure.\n\nThis guidance refers to the therapeutic use of PDT and not to PDT-guided resection.\n\nVarious devices and photosensitising agents can be used for this procedure.\n\nSections 2.3 and 2.4 describe efficacy and safety outcomes which were available in the published literature and which the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview.\n\n# Efficacy\n\nA randomised controlled trial (RCT) of 27 patients with newly diagnosed glioblastoma and a Karnofsky score of 60 or greater (on a scale where 100 is 'perfect health' and 0 is 'death') reported an increase in mean survival in 13 patients who received PDT after surgery compared with 14 patients treated by surgical resection alone (52.8 weeks and 24.1 weeks respectively; p = 0.001). A case series of 112 patients treated by PDT following surgical resection reported median survival of 30 weeks in patients with gliomas and 24 weeks in patients with metastatic carcinoma (follow-up not stated). A case series of 136 patients treated by PDT following surgical resection reported that median survival from initial diagnosis was 76.5 months for patients with primary anaplastic astrocytoma and 14.3 months for patients with glioblastoma multiforme (p = 0.001), with a minimum follow-up of 3 years. Duration of survival was not associated with the location of the tumours in the brain (p = 0.54). A case series of 26 patients with recurrent glioblastoma (WHO grade IV) treated by PDT following surgical resection reported median survival of 8.5 months.\n\nThe case series of 26 patients reported that median time to disease progression was 6 months.\n\nThe RCT of 27 patients reported an improvement in mean Karnofsky score from 60 to 80 points in the PDT after surgery group but no change from 70 points in the surgical resection group (follow-up not stated; p < 0.05).\n\nThe Specialist Advisers considered key efficacy outcomes to include overall and progression-free survival, completeness of resection and quality of life.\n\n# Safety\n\nIn the case series of 112 patients, 3% (3/112) died after the operation, 1 of pulmonary embolism and 2 of tumour cavity haemorrhage. Deep vein thrombosis occurred in 4% (4/112), infection (not otherwise specified) in 4% (4/112), and cerebrospinal fluid leak in 1% (1/112) of patients (no further details stated).\n\nThe case series of 26 patients reported transient oedema of the treated area in 4% (1/26) of patients.\n\nAcross three case series, sunburn due to light exposure occurred at a rate of between 2% (2/112, 2/136) and 8% (2/26).\n\nThe Specialist Advisers considered adverse events associated with PDT for brain tumours to include cerebral oedema, raised intracranial pressure, hypersensitivity reactions and skin photosensitisation. They stated that additional theoretical adverse events include damage to the normal brain and cerebral blood vessels, stroke, and compromising of further treatments by increasing the sensitivity of the brain to their toxic side effects.", 'Further information': "NICE has published technology appraisal guidance on temozolomide for the treatment of recurrent malignant glioma (brain cancer) and carmustine implants and temozolomide for the treatment of newly diagnosed high grade glioma, and service guidance for improving outcomes for people with brain and other central nervous system tumours.\n\n# Information for patients\n\nNICE has produced information on this procedure for patients and carers ('Understanding NICE guidance'). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.", 'About this guidance': 'NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland.\n\nThis guidance was developed using the NICE interventional procedure guidance process.\n\nWe have produced a summary of this guidance for patients and carers. Information about the evidence it is based on is also available.\n\nChanges since publication\n\nJanuary 2012: minor maintenance.\n\nYour responsibility\n\nThis guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.\n\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.\n\nCopyright\n\n© National Institute for Health and Clinical Excellence 2009. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.\n\nContact NICE\n\nNational Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT\n\nwww.nice.org.uk\n \n nice@nice.org.uk\n 0845 033 7780'}	https://www.nice.org.uk/guidance/ipg290
5601b3b5385c2960dc302d2f49c8a95bfaf68ee8	nice	Implantation of an opaque intraocular lens for intractable double vision	Implantation of an opaque intraocular lens for intractable double vision # Guidance Implantation of an opaque intraocular lens (IOL) for intractable double vision is technically similar to standard cataract surgery. It is indicated only in highly selected patients. In this context the evidence on safety and efficacy, which is limited to a small number of patients, appears adequate for the procedure to be used provided that normal arrangements are in place for clinical governance and audit. During the consent process clinicians wishing to undertake implantation of an opaque IOL for intractable double vision should take the following actions. Ensure that patients and their carers understand that the removal of the natural lens required for this procedure is irreversible. If removal of the implanted opaque IOL were ever required, then damage to ocular structures would be a risk. They should provide them with clear information. In addition, the use of NICE's information for patients ('Understanding NICE guidance') is recommended. Patients should only be offered implantation of an opaque IOL when all alternative treatment options for their double vision have proved inadequate.# The procedure # Indications and current treatments Double vision (also known as diplopia) occurs when a person sees two images of a single object instead of one. It most commonly results from the eyes pointing in different directions. Binocular double vision may be caused by disorders affecting the eye muscles or other conditions such as brain tumours, diabetes, thyroid disease or severe head injury. This form of double vision may stop if either eye is covered. Occasionally, people may have monocular double vision (one eye only), which is usually caused by a type of cataract. The procedure described in this guidance is not used for monocular double vision. Treatment of binocular double vision depends on its underlying cause and prognosis. It may include wearing a patch over one eye, use of filters on spectacles, use of an opaque contact lens in one eye, eye muscle botulinum toxin injection or eye muscle surgery. Some patients, particularly children, may be able to ignore the double vision. # Outline of the procedure Implantation of an opaque lens for intractable double vision is carried out with the patient under local or general anaesthesia. Two different techniques can be used. One technique involves removal of the natural lens by phacoemulsification or extracapsular surgery (to extract the lens in fragments or in one piece, respectively, similar to standard cataract surgery). An opaque IOL is then inserted through the corneal incision and placed in the capsular bag or sulcus (cleft). In the alternative technique, a specially manufactured tinted IOL, called an iris claw lens, is surgically attached to the iris in the anterior chamber of the eye. The lens has a claw-like mechanism that attaches to the iris tissue by pinching it. Using this technique, the eye's natural lens is kept in place. Sections 2.3 and 2.4 describe efficacy and safety outcomes which were available in the published literature and which the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview. # Efficacy In a case series of 12 patients, the mean visual function score after implantation of an opaque IOL was 92 (measured by the 14-item Visual Function scale ) at a mean follow-up of 21 months (preoperative score not measured). One patient in the case series of 12 patients reported persistence of double vision that resolved with medical treatment. Case reports of six patients, including two patients with intractable double vision, stated that all patients had improved symptoms (not otherwise stated) after opaque IOL implantation at a mean follow-up of 14 months. Case reports of two patients described improvement in double vision in both patients after implantation of an opaque IOL (duration of follow-up not stated). In a case report of one patient, double vision resolved completely after implantation of an opaque IOL and a good result was reported to be maintained at 14-year follow-up. The case series of 12 patients reported that mean patient satisfaction score following the procedure was 3.4 (on a scale ranging from 0 to 4 ). The Specialist Advisers considered the key efficacy outcomes to be eradication of or improvement in symptoms of diplopia without discomfort to the eye. They stated that there were no concerns about the efficacy of the procedure. # Safety In the case series of 12 patients, one IOL broke during insertion; another IOL was successfully implanted into the eye 6 months later (mean follow-up 21 months). The case series of six patients reported mild IOL subluxation (partial dislocation of the lens) in one patient with leukocoria (time of occurrence not stated). However, this did not adversely affect patient satisfaction. The Specialist Advisers stated that there is concern about the blocking of vision in a functioning eye, since development of a sight-threatening condition in the other eye would leave the patient with impaired vision, and it is difficult to reverse the procedure. They considered theoretical adverse events to include failure to recognise pathology (such as a malignant tumour) in the implanted eye because the fundus is obscured from examination by the opaque lens, dislocation of the opaque lens and raised intraocular pressure. They considered that an iris claw IOL presents a theoretical risk of damage to the natural lens of the eye.# Further information NICE has published interventional procedures guidance on implantation of accommodating IOLs during cataract surgery. # Information for patients NICE has produced information on this procedure for patients and carers ('Understanding NICE guidance'). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.# About this guidance NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland. This guidance was developed using the NICE interventional procedure guidance process. We have produced a summary of this guidance for patients and carers. Information about the evidence it is based on is also available. Changes since publication January 2012: minor maintenance. Your responsibility This guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer. Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties. Copyright © National Institute for Health and Clinical Excellence 2009. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE. Contact NICE National Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT www.nice.org.uk nice@nice.org.uk	{'Guidance ': "Implantation of an opaque intraocular lens (IOL) for intractable double vision is technically similar to standard cataract surgery. It is indicated only in highly selected patients. In this context the evidence on safety and efficacy, which is limited to a small number of patients, appears adequate for the procedure to be used provided that normal arrangements are in place for clinical governance and audit.\n\nDuring the consent process clinicians wishing to undertake implantation of an opaque IOL for intractable double vision should take the following actions.\n\nEnsure that patients and their carers understand that the removal of the natural lens required for this procedure is irreversible. If removal of the implanted opaque IOL were ever required, then damage to ocular structures would be a risk. They should provide them with clear information. In addition, the use of NICE's information for patients ('Understanding NICE guidance') is recommended.\n\nPatients should only be offered implantation of an opaque IOL when all alternative treatment options for their double vision have proved inadequate.", 'The procedure': "# Indications and current treatments\n\nDouble vision (also known as diplopia) occurs when a person sees two images of a single object instead of one. It most commonly results from the eyes pointing in different directions. Binocular double vision may be caused by disorders affecting the eye muscles or other conditions such as brain tumours, diabetes, thyroid disease or severe head injury. This form of double vision may stop if either eye is covered. Occasionally, people may have monocular double vision (one eye only), which is usually caused by a type of cataract. The procedure described in this guidance is not used for monocular double vision.\n\nTreatment of binocular double vision depends on its underlying cause and prognosis. It may include wearing a patch over one eye, use of filters on spectacles, use of an opaque contact lens in one eye, eye muscle botulinum toxin injection or eye muscle surgery. Some patients, particularly children, may be able to ignore the double vision.\n\n# Outline of the procedure\n\nImplantation of an opaque lens for intractable double vision is carried out with the patient under local or general anaesthesia. Two different techniques can be used. One technique involves removal of the natural lens by phacoemulsification or extracapsular surgery (to extract the lens in fragments or in one piece, respectively, similar to standard cataract surgery). An opaque IOL is then inserted through the corneal incision and placed in the capsular bag or sulcus (cleft). In the alternative technique, a specially manufactured tinted IOL, called an iris claw lens, is surgically attached to the iris in the anterior chamber of the eye. The lens has a claw-like mechanism that attaches to the iris tissue by pinching it. Using this technique, the eye's natural lens is kept in place.\n\nSections 2.3 and 2.4 describe efficacy and safety outcomes which were available in the published literature and which the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview.\n\n# Efficacy\n\nIn a case series of 12 patients, the mean visual function score after implantation of an opaque IOL was 92 (measured by the 14-item Visual Function scale [0–100 from maximum disability to no disability]) at a mean follow-up of 21 months (preoperative score not measured). One patient in the case series of 12 patients reported persistence of double vision that resolved with medical treatment. Case reports of six patients, including two patients with intractable double vision, stated that all patients had improved symptoms (not otherwise stated) after opaque IOL implantation at a mean follow-up of 14 months. Case reports of two patients described improvement in double vision in both patients after implantation of an opaque IOL (duration of follow-up not stated). In a case report of one patient, double vision resolved completely after implantation of an opaque IOL and a good result was reported to be maintained at 14-year follow-up.\n\nThe case series of 12 patients reported that mean patient satisfaction score following the procedure was 3.4 (on a scale ranging from 0 [unhappy] to 4 [very satisfied]).\n\nThe Specialist Advisers considered the key efficacy outcomes to be eradication of or improvement in symptoms of diplopia without discomfort to the eye. They stated that there were no concerns about the efficacy of the procedure.\n\n# Safety\n\nIn the case series of 12 patients, one IOL broke during insertion; another IOL was successfully implanted into the eye 6 months later (mean follow-up 21 months).\n\nThe case series of six patients reported mild IOL subluxation (partial dislocation of the lens) in one patient with leukocoria (time of occurrence not stated). However, this did not adversely affect patient satisfaction.\n\nThe Specialist Advisers stated that there is concern about the blocking of vision in a functioning eye, since development of a sight-threatening condition in the other eye would leave the patient with impaired vision, and it is difficult to reverse the procedure. They considered theoretical adverse events to include failure to recognise pathology (such as a malignant tumour) in the implanted eye because the fundus is obscured from examination by the opaque lens, dislocation of the opaque lens and raised intraocular pressure. They considered that an iris claw IOL presents a theoretical risk of damage to the natural lens of the eye.", 'Further information': "NICE has published interventional procedures guidance on implantation of accommodating IOLs during cataract surgery.\n\n# Information for patients\n\nNICE has produced information on this procedure for patients and carers ('Understanding NICE guidance'). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.", 'About this guidance': 'NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland.\n\nThis guidance was developed using the NICE interventional procedure guidance process.\n\nWe have produced a summary of this guidance for patients and carers. Information about the evidence it is based on is also available.\n\nChanges since publication\n\nJanuary 2012: minor maintenance.\n\nYour responsibility\n\nThis guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.\n\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.\n\nCopyright\n\n© National Institute for Health and Clinical Excellence 2009. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.\n\nContact NICE\n\nNational Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT\n\nwww.nice.org.uk\n \n nice@nice.org.uk\n 0845 033 7780'}	https://www.nice.org.uk/guidance/ipg293
5a05d9b76160ba986f30ecd75a2f3547b5b7b8f8	nice	Amantadine, oseltamivir and zanamivir for the treatment of influenza	Amantadine, oseltamivir and zanamivir for the treatment of influenza Evidence-based recommendations on amantadine (Lysovir), oseltamivir (Tamiflu) and zanamivir (Relenza) for treating influenza in children and adults. # Guidance This guidance replaces 'Flu treatment – zanamivir (review) amantadine and oseltamivir' (NICE technology appraisal 58). For details, see 'About this guidance'. This guidance does not cover the circumstances of a pandemic, impending pandemic, or a widespread epidemic of a new strain of influenza to which there is little or no community resistance. Oseltamivir and zanamivir are recommended, within their marketing authorisations, for the treatment of influenza in adults and children if all the following circumstances apply: national surveillance schemes indicate that influenza virus A or B is circulating the person is in an 'at-risk' group as defined in 1.2 the person presents with an influenza-like illness and can start treatment within 48 hours (or within 36 hours for zanamivir treatment in children) of the onset of symptoms as per licensed indications. For the purpose of this guidance, people 'at risk' are defined as those who have one of more of the following: chronic respiratory disease (including asthma and chronic obstructive pulmonary disease) chronic heart disease chronic renal disease chronic liver disease chronic neurological conditions diabetes mellitus.People who are aged 65 years or older and people who might be immunosuppressed are also defined as 'at-risk' for the purpose of this guidance. The choice of either oseltamivir or zanamivir in the circumstances described in 1.1 should be made after consultation between the healthcare professional, the patient and carers. The decision should take into account the patient's preferences regarding drug delivery and potential adverse effects and contraindications. If all other considerations are equal, the drug with the lowest acquisition cost should be offered. During localised outbreaks of influenza-like illness (outside the periods when national surveillance indicates that influenza virus is circulating in the community), oseltamivir and zanamivir may be offered for the treatment of influenza in 'at-risk' people who live in long-term residential or nursing homes. However, these treatments should be offered only if there is a high level of certainty that the causative agent in a localised outbreak is influenza (usually based on virological evidence of influenza infection in the initial case). Amantadine is not recommended for the treatment of influenza. The Health Protection Agency in England (and the equivalent bodies in Wales and Northern Ireland) uses information from a range of clinical, virological and epidemiological influenza surveillance schemes to identify periods when there is a substantial likelihood that people presenting with an influenza-like illness are infected with influenza virus.# Clinical need and practice Influenza is an acute infection of the respiratory tract caused by the influenza A and B viruses. The symptoms of influenza include fever, cough, sore throat, myalgia and headache. These symptoms are not specific to influenza, and can be caused by other viruses (such as respiratory syncytial virus) which can present as an 'influenza-like illness'. Diagnosis of influenza can only be confirmed by laboratory testing, although the probability that an influenza-like illness is caused by influenza is higher if influenza is known to be circulating and if a person has a high fever. The symptoms of influenza-like illness can be different in infants and children and may include fatigue, irritability, diarrhoea and vomiting. Influenza infection is usually self-limiting and lasts for 3–4 days, with some symptoms persisting for 1–2 weeks. The severity of the illness can vary from asymptomatic infection to life-threatening complications. The most common complications are secondary bacterial infections such as otitis media, pneumonia and bronchitis. In the UK, the average number of deaths attributed directly to influenza is approximately 600 in non-epidemic years and between 12,000 and 13,800 deaths in epidemic years. Influenza occurs in a seasonal pattern with epidemics in the winter months, typically between December and March. The illness is highly contagious and is spread from person to person by droplets of respiratory secretions produced by sneezing and coughing. Influenza activity is monitored through surveillance schemes, which record the number of new GP consultations for influenza-like illness per week per 100,000 population. In 1997, normal seasonal activity in England was defined as 30–200 consultations, with greater than 200 defined as an epidemic. In Wales, the corresponding figures are 25–100, and greater than 400. In addition, there are virological monitoring schemes based on the isolation of the virus from clinical specimens. 'Normal seasonal activity', as measured by these surveillance schemes, corresponds to the term 'circulating' in 'Guidance on the use of zanamivir, oseltamivir and amantadine for the treatment of influenza' (NICE technology appraisal guidance 58). Accurate monitoring of influenza activity requires analysis of clinical, virological and epidemiological information. The management of influenza is supportive and consists of relieving symptoms while awaiting recovery. Complications require specific management, and antibiotics are used for secondary bacterial infections. Vaccination has been established as the first-line intervention to prevent influenza and its complications. In the UK, the Department of Health currently recommends that people who are at risk of influenza infection or complications are vaccinated at the beginning of each winter. These include people with chronic respiratory, heart, renal, liver or neurological disease, people with diabetes, people who are immunosuppressed, people aged 65 and older, people who work or live in residential care facilities, carers of 'at-risk' people, healthcare and other essential workers and poultry workers. Antiviral drugs are also used for the prevention of influenza. They may be given to people who have been in contact with a person with influenza-like illness (post-exposure prophylaxis) and may be given in the absence of known contact when it is known that influenza is circulating in the community (seasonal prophylaxis). When antiviral drugs are given for seasonal prophylaxis, they are used for longer periods to cover the duration of the influenza season. Seasonal prophylaxis may be considered in exceptional situations such as an antigenic mismatch between circulating strains of the influenza virus and that used for vaccination, which would mean that 'at-risk' people are not effectively protected by vaccination. Prophylaxis may also be used to control outbreaks of influenza within a residential community. A review on the use of antiviral drugs for the prophylaxis of influenza (NICE technology appraisal guidance 158) recommends oseltamivir and zanamivir for post-exposure prophylaxis only.# The technologies # Amantadine Amantadine (Lysovir, Symmetrel, Alliance Pharmaceuticals) acts against influenza A virus by blocking viral replication. It has a UK marketing authorisation for the treatment of people who have signs and symptoms of infection caused by influenza A virus. The summary of product characteristics (SPC) states that treatment should be started as early as possible, and within 48 hours of symptom onset. The recommended dosage of amantadine is 100 mg daily for 4–5 days. Amantadine is administered orally as syrup (Symmetrel) or 100-mg capsules (Lysovir) for the treatment of influenza. The adverse effects associated with amantadine are often mild and transient. The most commonly reported effects are gastrointestinal disturbances such as anorexia and nausea, and central nervous system effects such as loss of concentration, dizziness, agitation, nervousness, depression, insomnia, fatigue, weakness and myalgia. Central nervous system effects are most common in older people. For full details of adverse effects and contraindications, see the SPC. Amantadine costs £2.40 for five capsules (100 mg each), £4.80 for 14 capsules and £5.55 for 150 ml syrup (50 mg/5 ml) (excluding VAT; 'British national formulary' edition 55). Costs may vary in different settings because of negotiated procurement discounts. # Oseltamivir Oseltamivir (Tamiflu, Roche Products) is a neuraminidase inhibitor that is active against influenza A and B viruses. It prevents viral release from infected cells and subsequent infection of adjacent cells. It has a UK marketing authorisation for the treatment of influenza in people 1 year of age or older who present with symptoms typical of influenza, when influenza virus is circulating in the community. The SPC states that treatment should be started as soon as possible within the first 48 hours of the onset of influenza symptoms. The recommended dosage of oseltamivir for adolescents (13–17 years of age) and adults is 75 mg twice daily for 5 days. For infants older than 1 year and children 2–12 years of age, the recommended dose of oseltamivir is adjusted according to body weight. Oseltamivir is given orally as syrup or capsules. Adverse effects associated with oseltamivir include gastrointestinal symptoms, bronchitis and cough, dizziness and fatigue and neurological symptoms such as headache, insomnia and vertigo. Skin rashes and allergic reactions and, rarely, disorders of the hepatobiliary system have been reported. Convulsions and neuropsychiatric disorders, mainly in children and adolescents, have also been reported but a causal link has not been established. For full details of adverse effects and contraindications, see the SPC. Oseltamivir costs £16.36 for a 5-day course for an adult (excluding VAT; BNF edition 55). Costs may vary in different settings because of negotiated procurement discounts. # Zanamivir Zanamivir (Relenza, GlaxoSmithKline) is a neuraminidase inhibitor that is active against influenza A and B viruses. It prevents viral release from infected cells and subsequent infection of adjacent cells. It has a UK marketing authorisation for the treatment of influenza in people older than 5 years who present with symptoms typical of influenza, when influenza is circulating in the community. The SPC states that treatment should begin as soon as possible, within 48 hours of symptom onset for adults and within 36 hours of symptom onset for children. The recommended dosage of zanamivir for people older than 5 years is 10 mg twice daily for 5 days. Zanamivir is taken by oral inhalation, using a Diskhaler device. Adverse effects associated with zanamivir are rare. They include bronchospasm and allergic phenomena. For full details of adverse effects and contraindications, see the SPC. The price of zanamivir was reduced during the course of the appraisal from £24.55 (excluding VAT; BNF edition 55) to £16.36 (excluding VAT; BNF edition 56) for a 5-day course. Costs may vary in different settings because of negotiated procurement discounts.# Evidence and interpretation The Appraisal Committee (appendix A) considered evidence from a number of sources (appendix B). # Clinical effectiveness The Assessment Group performed a systematic review to identify randomised controlled trials (RCTs) evaluating the clinical effectiveness of amantadine, oseltamivir and zanamivir compared with each other, placebo or with best symptomatic care. Studies included were conducted in people who presented with symptoms typical of influenza, whether influenza was reported as circulating in the community or not. The population was divided into the following categories: otherwise healthy adults; 'at-risk'; older people; children; and 'mixed' populations. Twenty-nine RCTs were identified by the systematic review. There was no new evidence on the clinical effectiveness of amantadine published after the review of the evidence for TA 58. No RCTs that directly compared zanamivir and oseltamivir were included; a Bayesian indirect comparison using placebo as a common comparator was conducted. The trials generally compared zanamivir or oseltamivir with placebo. The background circulating levels of influenza and the influenza vaccination rate in the trials were often not reported clearly. Levels of viral resistance were often not measured, but when reported were low. In most RCTs, the effectiveness of the antiviral drugs was measured in terms of time to alleviation of symptoms (a composite outcome) and time to return to normal activities. Adverse events and complications were also reported, the latter generally in terms of reductions in antibiotic usage. Analyses were reported for the ITT population (intention to treat; representative of the entire population recruited in the trials) and ITTI population (intention to treat, confirmed as being influenza positive) wherever possible. Evidence was submitted by consultees that there has been a decline in the rates of GP consultations for acute respiratory illnesses over the past 25 years. This has resulted in the lowering of the threshold levels of the surveillance schemes. In addition, it was stated that the influenza season as defined by the surveillance schemes does not correspond exactly to the period during which the virus is circulating in the community as indicated by virological monitoring. It was also apparent that outbreaks of influenza occur within localised areas, especially in residential care settings, outside of the influenza season. ## Oseltamivir The Assessment Group's systematic review identified 16 RCTs. Eight of these had been considered for TA 58 and eight were new studies that had been published since the review of evidence for TA 58. Two of the included studies recruited mixed populations, seven recruited only healthy adults, two recruited from general 'at-risk' populations, two recruited only children and three recruited only older people. Follow-up periods ranged from 10 to 28 days. Most of the included studies reported time to alleviation of symptoms and the Assessment Group conducted meta-analyses by population subgroup and by whole population. Overall, oseltamivir reduced the median time to alleviation of symptoms by 0.68 days (95% confidence interval 0.41 to 0.95) and 0.95 days (95% CI 0.50 to 1.39) in the ITT (n = 5036) and ITTI (n = 2541) analyses, respectively. The reduction in median time to alleviation of symptoms associated with oseltamivir treatment ranged from 0.41 days (older people) to 0.88 days (healthy and 'at-risk' children) in the ITT analyses and from 0.43 days ('at-risk' children) to 1.50 days (healthy children) in the ITTI analyses. Most of the included studies also reported time to return to normal activity and the Assessment Group conducted meta-analyses by population subgroup and by whole population. Overall, oseltamivir reduced the median time to return to normal activity by 1.32 days (95% CI 0.91 to 1.73) and 1.51 days (95% CI 1.01 to 2.02) in the ITT (n = 2754) and ITTI (n = 3013) analyses, respectively. The reduction in median time to return to normal activity associated with oseltamivir treatment ranged from 1.25 days (healthy children) to 4.09 days (older people) in the ITT analyses and from 0.50 days ('at-risk' children) to 3.07 days (older people) in the ITTI analyses. Alleviation of fever was reported in a few studies. Because the studies that reported alleviation of fever were generally conducted in healthy or mixed populations, meta-analyses were not presented by population category. All of the trials showed a reduction in the time to alleviation of fever. Overall, oseltamivir reduced the median time to alleviation of fever by 18.7 hours in the ITT population (95% CI 9.70 to 27.8, n = 1177) and 24.4 hours in the ITTI population (95% CI 17.2 to 31.6, n = 1720). The data on complications were sparse and only the use of antibiotics was significantly reduced for those who received oseltamivir compared with placebo (ITTI population, odds ratio 0.62, 95% CI 0.46 to 0.83 for antibiotic use, n = 2175). Across all trials, there was no evidence of a difference in the incidence of overall, serious or drug-related adverse effects between oseltamivir and placebo. Among the nine trials that reported mortality, there was a single death in the placebo arm of a trial in an 'at-risk' population; it was not clear whether this death was associated with influenza. ## Zanamivir The Assessment Group's systematic review identified 13 RCTs. Seven of these had been considered for TA 58 and six were new studies that had been published since the review of evidence for TA 58. Five of the studies recruited a mixed population (for which data on symptoms for healthy and 'at-risk' adults were available separately), three recruited only healthy adults, two recruited from general 'at-risk' populations, two recruited only children and one recruited only older people. The follow-up period ranged from 5 to 29 days. Most of the included studies reported time to alleviation of symptoms and the Assessment Group conducted meta-analyses by population subgroup and by whole population. Overall, zanamivir reduced the median time to alleviation of symptoms by 0.71 days (95% CI 0.41 to 1.01) and 1.07 days (95% CI 0.74 to 1.39) in the ITT (n = 4538) and ITTI (n = 2865) analyses, respectively. The reduction in the median time to alleviation of symptoms associated with zanamivir treatment ranged from 0.57 days (healthy adults) to 2.00 days ('at-risk' children) in the ITT analyses and from 0.96 days (healthy adults) to 3.75 days ('at-risk' children) in the ITTI analyses. Most of the included studies also reported time to return to normal activity and the Assessment Group conducted meta-analyses by population subgroup and by whole population. Overall, zanamivir reduced the median time to return to normal activity by 0.44 days (95% CI 0.05 to 0.84) and 0.71 days (95% CI 0.19 to 1.24) in the ITT (n = 4053) and ITTI (n = 2877) analyses, respectively. The reduction in median time to return to normal activity associated with zanamivir treatment ranged from 0.37 days (healthy adults) to 1.07 days ('at-risk' adults) in the ITT analyses and from 0.39 days (healthy adults) to 2.50 days ('at-risk' children) in the ITTI analyses. Alleviation of fever was reported in four studies but only one reported any measure of variance, so meta-analyses could not be conducted. Across the studies that reported this outcome (n = 1539), the median time to alleviation of fever was reduced by between 0.0 and 0.5 days for zanamivir compared with placebo. Although the data on complications were sparse, the incidence of overall complications and the use of antibiotics were significantly reduced for those who received zanamivir compared with placebo (ITTI populations, n = 2629, OR 0.77, 95% CI 0.65 to 0.92, p = 0.004 for overall complications; OR 0.79, 95% CI 0.63 to 0.99, p = 0.04 for antibiotic use). Across all trials, treatment with zanamivir significantly reduced the incidence of overall adverse events compared with placebo (OR 0.85, 95% CI 0.75 to 0.96, p = 0.007, n = 5430) but there was no evidence of a difference in the incidence of drug-related adverse events. Very few serious adverse events were reported and there were no deaths in any of the seven zanamivir trials that reported mortality. ## Indirect comparison of oseltamivir and zanamivir The Assessment Group identified one direct comparison of zanamivir and oseltamivir but excluded this trial because it did not report usable outcome data. Therefore, the Assessment Group performed an indirect comparison of zanamivir and oseltamivir using a multi-parameter Bayesian approach. The probabilities that each treatment was 'best' were calculated for the following population subgroups: otherwise healthy adults; otherwise healthy children; and an 'at-risk' group that combined 'at-risk' children, 'at-risk' adults and older people (owing to few data). All analyses were presented with associated 95% credibility intervals (CrI). A 95% Bayesian credibility interval means that, given the data, there is a 95% probability that the random variable lies within the interval. Across all analyses, point estimates suggested that either oseltamivir or zanamivir was more effective than placebo, but not all analyses were statistically significant. There was variation across population subgroups as to whether zanamivir or oseltamivir had a higher probability of being most effective. In all of the analyses, the median time to alleviation of symptoms and return to normal activity was shorter in the ITTI analyses than the ITT analyses. In the ITTI analyses, zanamivir treatment compared with placebo reduced the days to alleviation of symptoms by 1.3 (95% CrI 0.30 to 2.96) and 4.7 (95% CrI 1.98 to 9.44) for healthy adults and the 'at-risk' group, respectively. Similar analyses for oseltamivir treatment compared with placebo gave reductions of 2.08 (95% CrI 0.73 to 4.34) and 2.63 (95% CrI 0.38 to 6.53) days for healthy adults and healthy children, respectively. The ITTI analyses for zanamivir compared with placebo for healthy children gave a reduction of 1.77 days (95% CrI –0.41 to 5.10) and for oseltamivir compared with placebo in the 'at-risk' group gave a reduction of 1.56 days (95% CrI –0.78 to 4.66), but in both cases the credibility intervals included zero. In ITTI analyses for days to return to normal activities, zanamivir treatment compared with placebo gave reductions of 1.65, 5.97 and 2.25 for healthy adults, the 'at-risk' group and healthy children, respectively. In the ITTI analyses, compared with placebo oseltamivir treatment reduced the days to return to normal activity by 2.64, 1.98 and 3.34 for healthy adults, the 'at-risk' group and healthy children, respectively. # Cost effectiveness The Assessment Group identified 21 cost-effectiveness studies that assessed amantadine, oseltamivir or zanamivir for the treatment of influenza. The manufacturer of oseltamivir (Roche Products) also provided a de novo economic model. No cost-effectiveness analyses were submitted by the manufacturers of amantadine or zanamivir. Seven of the identified cost-effectiveness studies were conducted from the perspective of the NHS (including the assessment for the original appraisal TA 58 and the current submission from Roche Products). The decision-tree model developed by the Assessment Group for TA 58 was designed to compare amantadine, oseltamivir and zanamivir with usual care for the treatment and prophylaxis of influenza. The following four separate groups were considered: otherwise healthy adults; high-risk ('at-risk') adults; children; and older people in residential care. For each of the population groups, amantadine compared with usual care had the lowest incremental cost-effectiveness ratios (ICERs), which ranged from £4535 to £6190 per quality-adjusted life-year (QALY) gained. However, the Appraisal Committee for the original appraisal TA 58 was unable to accept that the clinical effectiveness of amantadine was sufficiently proven and so it did not recommend amantadine for the treatment of influenza A. The ICERs for oseltamivir compared with usual care ranged from £19,015 to £22,502 per QALY gained. The ICERs for zanamivir compared with usual care ranged from £16,819 to £31,529 per QALY gained. Of the five other studies conducted from the UK NHS perspective, two compared zanamivir with usual care in both healthy and 'at-risk' adults, two compared oseltamivir with usual care in healthy children and healthy adults, and one compared oseltamivir, zanamivir and usual care in healthy adults. The estimated ICERs for zanamivir compared with usual care ranged from £7490 to £54,000 per QALY gained for 'at-risk' adults and £65,000 per QALY gained for otherwise healthy adults. The estimated ICERs for oseltamivir compared with usual care ranged from oseltamivir being dominant to £11,173 per QALY gained for healthy children, and £225 to £5600 for adults per QALY gained. In the only comparison of oseltamivir with zanamivir (in healthy adults), zanamivir was dominated (that is, zanamivir was estimated to be more costly and less effective than oseltamivir). ## Manufacturer's model The current submission from the manufacturer of oseltamivir (Roche Products) included a decision-tree economic model that estimated the cost effectiveness of oseltamivir compared with zanamivir and usual care for the treatment of influenza, using separate pairwise comparisons. The model considered the following population subgroups separately: otherwise healthy adults; 'at-risk' adults (including older adults); otherwise healthy children aged 1–12 years; and otherwise healthy children aged 1–5 years. The model started when a patient presented to a GP with an influenza-like illness when influenza was reported to be circulating in the community. The probability that the illness was influenza was assumed to be 31% in all populations modelled. For the comparison of oseltamivir with zanamivir it was assumed that the drugs are equally effective. A cost-minimisation approach was used and the total cost of a course of zanamivir was assumed to be £0.19 higher than that of oseltamivir. The health state utility for influenza-like illness without complication was assumed to be 0.840; this was taken from Harvard utility scores and was assumed not to differ between populations. Zanamivir and oseltamivir treatment was assumed to be associated with an improved utility of 0.937; this improved utility was derived from the oseltamivir clinical trials. The resource-use data cover costs associated with GP visits, diagnostic tests, antibiotic treatments and hospital visits. The comparison of oseltamivir with usual care for the treatment of influenza produced base-case ICERs of £5452 per QALY gained for healthy adults, £5992 per QALY gained for healthy children aged between 1 and 12 years, £4687 per QALY gained for healthy children aged between 1 and 5 years and £652 for 'at-risk' adults. For all populations, zanamivir was dominated by oseltamivir (that is, oseltamivir was less costly and more effective than zanamivir). The model was sensitive to the changes in assumptions of the probability that an influenza-like illness was true influenza and the probability that patients presented to a GP within 48 hours. ## Assessment Group model The Assessment Group conducted an independent economic assessment. The model was used to develop incremental estimates of the cost effectiveness of oseltamivir and zanamivir for the treatment of influenza compared with usual care without antiviral treatment. The Assessment Group did not develop estimates of the cost effectiveness of amantadine for the treatment of influenza because it is not widely used and was not recommended for use in TA 58. The decision-tree model evaluated costs from an NHS and personal social services perspective. A single influenza season was modelled; however, a lifetime horizon was used to account for any reductions in life expectancy. The model started when a patient presented to a healthcare professional with an influenza-like illness and was considered suitable for treatment with either oseltamivir or zanamivir (according to the respective UK marketing authorisations of each antiviral drug). Cost-effectiveness estimates for influenza treatment were presented for the following population groups: otherwise healthy children (aged 1–14 years); 'at-risk' children (aged 1–14 years); otherwise healthy adults (aged 15–64 years); 'at-risk' adults (aged 15–64 years) and the 'elderly' (defined as adults older than 65 years). The model assumed that oseltamivir and zanamivir would be prescribed only when influenza was known to be circulating in the community, based on national surveillance schemes (this was assumed to be defined as 30 new GP consultations for influenza-like illness per 100,000 population). The probability that an influenza-like illness is true influenza was derived from national surveillance data provided by the Royal College of General Practitioners. The average probability that influenza-like illness was influenza was 0.495. However, calculating this for the separate age groups resulted in a probability of 0.56 (CrI 0.26 to 0.79) in people younger than 15 years and 0.41 (CrI 0.21 to 0.66) in people aged 15 years and over. The effectiveness of oseltamivir and zanamivir was derived from the overall duration of symptoms (that is, based on time to alleviation of symptoms) for the different subgroups in the model. These were taken directly from the mean ITTI results from the indirect Bayesian multi-parameter evidence synthesis model. The same mean duration of symptoms was applied to each of the separate 'at-risk' populations considered in the economic model. The relative effectiveness estimates from the ITTI populations were assumed to be independent of previous vaccination or prophylactic use of antivirals. The relative effectiveness of oseltamivir and zanamivir was assumed to be the same for both influenza type A and B. Both treatments were considered to be effective only in people with true influenza. The Assessment Group used the duration of symptoms as the basis for estimating the potential QALY gains associated with the reduction in symptom duration reported for oseltamivir and zanamivir compared with usual care. A systematic search of the literature was undertaken to identify suitable health-related quality of life data. Although the Assessment Group identified some studies, none presented comparable estimates for different risk groups and there were limitations in the methods used. Therefore, the utility values were based on those applied in TA 58. The data used in TA 58 were derived from the transformation of visual analogue scale (VAS) data reported in some of the oseltamivir trials into time trade-off utilities over a 21-day period. These data were then augmented with symptom duration estimates from the full range of RCTs identified in the current clinical effectiveness review. Separate values were reported for otherwise healthy adults and 'at-risk' adult populations. In the base-case analyses, the average quality of life decrement over the duration of influenza illness applied to healthy populations was between 0.4 and 0.5. The corresponding figure for 'at risk' populations was between 0.5 and 0.6. The Assessment Group also noted that if treatment of influenza shortens the duration of symptoms by reducing them at the end rather than the beginning of the illness, then the overall average decrement would be reduced to between 0.22 and 0.23 for healthy populations and 0.45 for 'at risk' populations. Adverse effects from oseltamivir and zanamivir were assumed to be mild and self-limiting and were assumed not to impact on a person's health-related quality of life. The model then assumed that all people with influenza-like illness (whether influenza or not) had a probability of developing a complication. Estimates of the baseline probabilities of developing each complication (and subsequent mortality) were derived separately for each subgroup from data reported in a large UK population-based study and ranged from 7.55% (healthy adults) to 17.59% ('at-risk' children). In the model, it was possible for a person to experience more than one complication; the probability of this was estimated for each person in each subgroup. Estimates of how effective the different treatments were at reducing the incidence of complications were based on the relative risk of antibiotic use. The relative risks for complications with zanamivir compared with placebo were 0.71 (95% CI 0.34 to 1.45), 0.74 (95% CI 0.35 to 1.57) and 0.78 (95% CI 0.45 to 1.35) for healthy adults, the 'at-risk' group and children, respectively. The relative risks for complications with oseltamivir compared with placebo were 0.57 (95% CI 0.24 to 1.35), 0.69 (95% CI 0.50 to 0.93) and 0.56 (95% CI 0.36 to 0.87) for the healthy adults, the 'at-risk' group and children, respectively. The quality of life estimates were decreased according to type of complication. Likelihood of hospitalisation as a result of each type of complication was also included in the model; however, only complicated cases were assumed to lead to hospitalisation and death. Premature death as a result of influenza was assumed to occur only following a secondary complication (irrespective of whether a person was hospitalised). Given limitations in the evidence base, it was assumed that hospitalisation occurred only as a result of respiratory tract infections. The model assumed that all people who develop a complication face a subsequent probability of mortality that varies only by population subgroup, not by treatment strategy or previous hospitalisation. Mortality was assumed to have no cost implication, but resulted in loss of potential QALYs. In each population age group (children, adults and older people), the expected age of death from complications related to an influenza-like illness was derived from data from national statistics reporting influenza deaths by age group. The acquisition cost of oseltamivir (£16.36) was based on the BNF (edition 55) list price, with identical estimates applied for zanamivir based on the revised price (see section 3.9). The costs associated with people developing complications as a result of influenza or influenza-like illness were also included. These costs included visits to a healthcare provider for treatment, antibiotics and hospitalisation. A total of 12 scenario analyses were investigated by the Assessment Group. These analyses included investigation of assumptions such as those made about complications, the probability that an influenza-like illness was true influenza and the relative efficacy of oseltamivir and zanamivir. In base-case results, for each population the ICER for both oseltamivir and zanamivir (relative to usual care) was less than £20,000 per QALY gained, and across the separate populations ranged from £562 to £7035 per QALY gained. In healthy children and healthy adults oseltamivir dominated zanamivir, with ICERs of £7035 and £5521 per QALY gained, respectively. In 'at-risk' children, 'at-risk' adults and older people zanamivir extendedly dominated oseltamivir (that is, the ICER for oseltamivir treatment is higher than that of zanamivir and usual care and is therefore ruled out on the basis of extended dominance). The ICERs were £1752 per QALY gained for 'at-risk' children, £2270 for 'at-risk' adults and £562 for older people. At a willingness to pay threshold of £20,000 per QALY gained, the probability that zanamivir was cost effective ranged from 23% (healthy children) to 90% ('at-risk' adults) and the probability that oseltamivir was cost effective ranged from 10% ('at-risk' adults) to 77% (healthy adults). The probability that usual care was cost effective at the same threshold was 0% (healthy adults, 'at-risk' adults, older people) to 4% (healthy children). Across the 12 scenario analyses performed by the Assessment Group, the overall conclusions and ICERs in the 'at-risk' populations were generally consistent. The ICERs appeared more sensitive in the otherwise healthy populations. The base-case estimates of the ICERs of oseltamivir and zanamivir compared with usual care in the healthy populations were sensitive to the following key assumptions: the exclusion of hospitalisation and mortality benefits with antiviral treatment (these were included in the base case and ICERs in the scenario analyses ranged up to £13,985 per QALY gained); a reduction in the probability that an influenza-like illness is true influenza (this was 0.41 for adults and 0.56 for children in the base case and the ICERs in the scenario analyses ranged up to £47,573 per QALY gained, and up to £48,390 per QALY gained if hospitalisation and mortality benefits were excluded); increases in consultations with healthcare providers combined with decreases in the probability that an influenza-like illness is influenza (ICERs in the scenario analyses ranged up to £13,959 per QALY gained, and up to £28,950 per QALY gained if hospitalisations and mortality benefits were excluded); and reductions in the decrements in quality of life associated with influenza (ICERs in the scenario analyses ranged up to £29,115 per QALY gained, and up to £59,684 per QALY gained if hospitalisation and mortality benefits were excluded). The Assessment Group conducted additional scenario analyses for healthy children and healthy adults, which combined the following parameters: exclusion of hospitalisation and mortality benefits an increase in GP consultations (between 5 and 15%) a decrease in the probability that an influenza-like illness is true influenza (between 5 and 15%) a smaller decrement in quality of life associated with influenza of 0.2 (this value reflects the estimate detailed in section 4.2.9 corresponding to reduction in the duration of symptoms being at the end of the illness. The sensitivity analyses of quality of life decrements were explored in increments of 0.1). These scenario analyses resulted in ICERs that ranged from £21,003 to £31,491 per QALY gained for healthy children and from £39,862 to £65,607 per QALY gained for healthy adults. # Consideration of the evidence The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of amantadine, oseltamivir and zanamivir, having considered evidence on the nature of the condition and the value placed on the benefits of amantadine, oseltamivir and zanamivir by people with influenza, those who represent them, and clinical specialists. It was also mindful of the need to take account of the effective use of NHS resources. The Committee understood that influenza causes a wide spectrum of respiratory illness of varying severity, and can lead to a number of potentially serious complications, especially in certain 'at-risk' groups. The Committee discussed the definition of 'at-risk' groups for whom treatment might be particularly suitable and decided that they would be best defined in the same way as for the current recommendations for vaccination. From the outset the Committee was of the view that vaccination has been established as the first-line intervention to prevent influenza and its complications, and was mindful that the use of antiviral treatments should not in any way detract from efforts to ensure that all eligible people are vaccinated at the beginning of each influenza season. The Committee noted that the surveillance scheme used in the NHS to determine levels of influenza activity in the community was based on clinical consultations, but that influenza activity as defined by the threshold levels of these consultation rates did not always coincide with laboratory-based virological evidence. The Committee understood that the Health Protection Agency in England and similar organisations in Wales and Northern Ireland use information from a range of clinical, virological and epidemiological influenza surveillance schemes to identify when influenza is circulating in the community. The Committee heard from clinical specialists that the threshold levels are not suitable for defining when antiviral treatments would be most efficacious because they do not accurately identify periods when influenza, as opposed to influenza-like illness, is circulating. The Committee considered the evidence for effectiveness of amantadine and noted that no new evidence on either the clinical or cost effectiveness of amantadine for the treatment of influenza had been published since the review of the evidence for TA 58. The Committee concluded that it had no basis on which to change the recommendations on the use of amantadine from the original appraisal (TA 58). Therefore amantadine is not recommended for the treatment of influenza. The Committee then reviewed the evidence on the clinical effectiveness of oseltamivir and zanamivir for the treatment of influenza. The Committee noted that in all of the population subgroups, treatment with either antiviral drug was associated with reductions in the average duration of symptoms compared with placebo, although the difference was not statistically significant in all subgroups. The Committee acknowledged that the reduction in duration of symptoms was generally greater for the 'at-risk' population compared with healthy populations. The Committee heard from clinical experts that this increased reduction in duration of symptoms for the 'at-risk' group was plausible for a number of reasons. It is likely that people in 'at-risk' groups would have a longer duration of illness, and would therefore be more likely to benefit from antiviral treatment. There is also clinical rationale to suggest that people in 'at-risk' groups could also suffer from exacerbations of underlying conditions as a result of influenza. This could increase the duration and severity of influenza symptoms, which would mean an increased potential benefit from antiviral treatments. These exacerbations might also lead to a person not recovering completely, and future influenza infections and subsequent exacerbations being more frequent. The Committee concluded that there is evidence indicating clinical effectiveness of antiviral drugs in a wide range of clinical settings, but that their use is of greatest clinical importance for people in 'at-risk' groups. The Committee noted that the probabilities for each antiviral drug being the 'best' treatment also differed according to population subgroup. The Committee discussed these results with clinical experts. The Committee was not persuaded that there was any plausible biological explanation for these observed differences. The Committee considered that the data were too sparse and uncertain to allow for any clear distinctions between the antiviral treatments to be made on the basis of clinical efficacy between different populations. The Committee concluded that oseltamivir and zanamivir are both clinically effective treatments for influenza, particularly for those people in 'at-risk' groups. The Committee considered the evidence on adverse events associated with oseltamivir and zanamivir. The Committee was aware that very sparse adverse event data were reported in the included RCTs. However, it noted that no significant differences between the antiviral treatments compared with placebo were reported. The Committee considered the structure of the economic models used to generate cost-effectiveness estimates for oseltamivir and zanamivir for the treatment of influenza. The Committee was aware that the models submitted by the manufacturer and the Assessment Group were not dynamic models. That is, the models did not account for effects of influenza treatment in reducing transmission of infection, the development of 'herd immunity', the potential for the development of drug resistance and the effect of treatment of influenza-like illness on attack rates. The Committee appreciated that some aspects of this approach to modelling additional benefits could improve the cost effectiveness of the antiviral agents but that there were potential disadvantages that would make treatment less cost effective. The Committee was also aware that dynamic models were technically complicated and that the current evidence would not have been sufficient to support this modelling approach. The Committee concluded that the evidence available from the submitted models was an appropriate basis on which to make a decision and that on balance an alternative dynamic modelling approach would not change its overall conclusions. The Committee then reviewed the cost-effectiveness estimates of oseltamivir and zanamivir as submitted by the manufacturer of oseltamivir and the Assessment Group. In particular, the Committee considered the key inputs in the models were the probability that an influenza-like illness is true influenza and complication rates following influenza infection and subsequent related hospitalisation and mortality. The Committee first considered the different estimates of the probability that an influenza-like illness is true influenza. The Committee noted that the probability used in the manufacturer's model was lower than that used in the Assessment Group model (for which different probabilities were used according to age group). The Committee was aware that the confidence intervals surrounding the probability estimates for different population subgroups used in the Assessment Group model were wide and overlapped with one another. The Committee heard from clinical experts that the probability of an influenza-like illness being true influenza in children was likely to be lower than that assumed in the Assessment Group model because of increased difficulties in diagnosis in children and the probability of other conditions such as respiratory syncytial virus, which can present as influenza-like illness. The Committee thought that this was particularly likely for otherwise healthy children and concluded that the estimate of 56% (influenza-like illness is true influenza) was too high and should be more closely aligned to that of adults (that is, 41%). The Committee considered whether the vaccination status would affect the probability that a person presenting with an influenza-like illness would have true influenza. The Committee considered that this would depend on a number of factors, including whether the vaccine was appropriately matched to the currently circulating strain of influenza virus and whether sufficient time had elapsed since vaccination to ensure it was effective. The Committee noted that there were insufficient data on which to inform differential considerations on the basis of vaccination status. Therefore the Committee concluded that any recommendation on the use of antiviral drugs would not distinguish between vaccinated and non-vaccinated people. The Committee then discussed whether increases in GP consultation rates (for example, as a result of a positive recommendation for the use of antiviral drugs) could result in more people presenting to a healthcare provider with an influenza-like illness that was not true influenza. The Committee heard from clinical experts that this was plausible. The Committee was also aware that current surveillance schemes are based in part on the number of GP consultations, and increases in consultation rates could lead to an apparent increase in influenza prevalence and thus reduction in the positive predictive value of influenza diagnoses. The Committee considered that such a scenario was more probable in healthy populations. The Committee concluded that for healthy populations increases in GP consultation rates would lead to decreases in the probabilities that an influenza-like illness was true influenza. The Committee was also aware that there would be extra costs associated with an increase in GP consultation rates. Therefore the Committee concluded that the base-case ICERs for these groups would be underestimates if a positive recommendation were given. The Committee considered the effects of oseltamivir and zanamivir treatment on complication rates associated with influenza. The Committee noted that the economic model provided by the Assessment Group included complication rates based only on reductions in antibiotic use in the absence of more direct data. The Committee was aware that there may be additional, alternative, approaches to measuring complication rates and that there were wide confidence intervals and uncertainty in the relative reduction rates in antibiotic use, particularly for healthy adults and children. The Committee also considered that the lower severity and duration of influenza symptoms, as may occur in healthy populations compared with 'at-risk' populations as discussed in section 4.3.5, could lead to a lower incidence of complications and subsequent hospitalisations. The Committee considered the effects of influenza on health-related quality of life. In the Assessment Group base case, an average quality of life decrement had been applied across the duration of an episode of influenza illness. The Committee noted that influenza is generally associated with worse disutility at the beginning rather than at the end of the illness. The Committee considered that it is more plausible that a reduction in symptoms arising from treatment would occur at the end of the illness. This would result in a lower impact on health-related quality of life, with an overall lower average quality of life decrement, compared with a reduction in symptoms at the beginning of the illness. The Committee noted that the Assessment Group estimated that in such a circumstance the average decrement in quality of life should be reduced to between 0.22 and 0.23 for healthy populations. The Committee considered that people in the 'at risk' population would be expected to have more severe symptoms for a longer period and that it is plausible that having to visit their GP to obtain treatment in the early phase of the illness might in itself cause additional impact on health-related quality of life. Therefore, taking all of these factors into account, the Committee accepted the average base-case decrement in quality of life for 'at risk' populations used in the Assessment Group base case (that is, between 0.5 and 0.6). The Committee then considered the cost-effectiveness estimates for oseltamivir and zanamivir treatment in otherwise healthy populations. It considered that the most plausible presented ICERs in this group were from the scenarios exploring the combined effect of excluding hospitalisation and mortality benefits, increased GP consultation rates with a subsequent reduction in the probability that an influenza-like illness is true influenza and a reduced decrement in quality of life of 0.2. The point estimate ICERs resulting from these scenarios ranged from £21,000 to £31,500 per QALY gained in healthy children and from £39,900 to £65,600 per QALY gained for healthy adults. The Committee was also mindful of its conclusion that in children 56% is an overestimate of the probability that influenza-like illness is influenza, and that the estimate should be more closely aligned with that for adults (that is, 41%). Hence it considered that the ICERs of £21,000 to £31,500 per QALY gained in healthy children were underestimates of the true ICERs within the preferred set of assumptions accepted by the Committee. The Committee was also aware that the ICERs presented assumed treatment with oseltamivir in all cases, because oseltamivir dominated zanamivir in healthy populations. The Committee was mindful that if both oseltamivir and zanamivir were recommended, then the true ICERs for healthy populations would be higher. Therefore, the Committee concluded that oseltamivir and zanamivir for the treatment of influenza in otherwise healthy children and adults would not be a cost-effective use of NHS resources. The Committee further considered the cost-effectiveness estimates of oseltamivir and zanamivir in 'at-risk' populations. Having reviewed a number of the key parameters from the economic models, the Committee concluded that for 'at-risk' populations the economic estimates submitted by the Assessment Group and the manufacturer of oseltamivir were plausible. The Committee concluded that because the base-case estimates were all less than £20,000 per QALY gained for these population subgroups, then oseltamivir and zanamivir, within their licensed indications, could be recommended as cost-effective uses of NHS resources. The Committee then discussed whether both oseltamivir and zanamivir should be recommended for the treatment of influenza. The Committee was aware of the limitations in the evidence base for comparative efficacy of the two drugs and it was not persuaded that there was evidence of differential effectiveness. However, the Committee noted that the drugs were administered differently and that zanamivir was not licensed for children aged 5 years or younger. The Committee concluded that it was therefore preferable not to give specific recommendations for oseltamivir or zanamivir, and that the decision as to which to prescribe should be made after consultation between the healthcare professional, the patient and carers on a case-by-case basis, taking into account the patient's preferences regarding drug delivery and potential adverse effects and contraindications. However, the Committee considered that if all other considerations are equal, the choice should be based on the less costly option within the marketing authorisations of the products. The Committee considered the need for managing outbreaks that occur outside the influenza season as defined by the surveillance threshold. It noted that such outbreaks often occurred in residential care establishments and were frequently associated with poor outcomes and complications in vulnerable populations. The Committee noted that the population in residential care was most likely to be older people or people otherwise at risk of influenza complications. It was mindful that, because oseltamivir and zanamivir are effective only against true influenza, the cost effectiveness of treatment in such situations would depend on the probability that the influenza-like illness was influenza. The Committee noted that this probability was low in the absence of wider circulation of influenza. Therefore, the Committee considered it important that in such situations there should be firmer evidence that the influenza-like illness was influenza. Such evidence could be supplied by virological testing. The Committee considered other people who lived together in a residential setting, such as a prison or boarding school. It noted that such populations would comprise mostly healthy people for whom the consequences of influenza infection would be minor. The Committee agreed that such populations would not be exceptions and treatment during outbreaks outside the influenza season would not be cost effective unless people in those populations were in an 'at-risk' group. Therefore the Committee recommended that outside the periods when national surveillance indicates that influenza virus is circulating, oseltamivir and zanamivir could be recommended for treatment of influenza in 'at-risk' people living in long-term residential or nursing homes, but only if there is a high level of certainty that a localised outbreak is occurring, usually based on virological evidence of infection with influenza in the incident case or cases.# Recommendations for further research The Committee recommended that a UK observational database is established to monitor the effectiveness of influenza treatment with the antiviral drugs oseltamivir and zanamivir. The Committee also recommended that cases of antiviral resistance to oseltamivir and zanamivir are monitored via the observational database. The Committee recommended that further research is conducted into the probability that an influenza-like illness is true influenza.# Related NICE guidance Respiratory tract infections – antibiotic prescribing. Prescribing of antibiotics for self-limiting respiratory tract infections in adults and children in primary care. NICE clinical guideline 69 (2008). Oseltamivir, amantadine (review) and zanamivir for the prophylaxis of influenza. NICE technology appraisal guidance 158 (2008).# Review of guidance The review date for a technology appraisal refers to the month and year in which the Guidance Executive will consider whether the technology should be reviewed. This decision will be taken in the light of information gathered by the Institute, and in consultation with consultees and commentators. The guidance on this technology will be considered for review in November 2013. Andrew DillonChief ExecutiveFebruary 2009# Changes after publication February 2014: minor maintenance March 2012: minor maintenance# About this guidance NICE technology appraisal guidance is about the use of new and existing medicines and treatments in the NHS in England and Wales. This guidance was developed using the NICE multiple technology appraisal process. It replaces 'Flu treatment – zanamivir (review), amantadine and oseltamivir' (NICE technology appraisal 58). The review and re-appraisal of amantadine, oseltamivir and zanamivir for the treatment of influenza has resulted in a change in the guidance. Specifically: people with chronic neurological conditions and people with chronic liver disease are now considered 'at risk' zanamivir is now recommended as a treatment option for children between the ages of 5 and 12 years in 'at-risk' groups if influenza is circulating and they can start treatment within 36 hours of first symptoms -seltamivir and zanamivir are now recommended as treatment options for 'at-risk' people in long-term and residential nursing homes during localised outbreaks (when influenza is not circulating), if there is a high level of certainty that the causative agent is influenza. This guidance has been prepared in the expectation that vaccination against influenza is undertaken in accordance with national guidelines. Vaccination has been established as the first-line intervention to prevent influenza and its complications, and the use of drugs described in this guidance should not in any way detract from efforts to ensure that all eligible people receive vaccination. We have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available. Your responsibility This guidance represents the views of NICE and was arrived at after careful consideration of the evidence available. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. However, the guidance does not override the individual responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or guardian or carer. Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties. Copyright © National Institute for Health and Clinical Excellence 2009. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.	{'Guidance': "This guidance replaces 'Flu treatment – zanamivir (review) amantadine and oseltamivir' (NICE technology appraisal 58).\n\nFor details, see 'About this guidance'.\n\nThis guidance does not cover the circumstances of a pandemic, impending pandemic, or a widespread epidemic of a new strain of influenza to which there is little or no community resistance.\n\nOseltamivir and zanamivir are recommended, within their marketing authorisations, for the treatment of influenza in adults and children if all the following circumstances apply:\n\nnational surveillance schemes indicate that influenza virus A or B is circulating\n\nthe person is in an 'at-risk' group as defined in 1.2\n\nthe person presents with an influenza-like illness and can start treatment within 48\xa0hours (or within 36\xa0hours for zanamivir treatment in children) of the onset of symptoms as per licensed indications.\n\nFor the purpose of this guidance, people 'at risk' are defined as those who have one of more of the following:\n\nchronic respiratory disease (including asthma and chronic obstructive pulmonary disease)\n\nchronic heart disease\n\nchronic renal disease\n\nchronic liver disease\n\nchronic neurological conditions\n\ndiabetes mellitus.People who are aged 65 years or older and people who might be immunosuppressed are also defined as 'at-risk' for the purpose of this guidance.\n\nThe choice of either oseltamivir or zanamivir in the circumstances described in 1.1 should be made after consultation between the healthcare professional, the patient and carers. The decision should take into account the patient's preferences regarding drug delivery and potential adverse effects and contraindications. If all other considerations are equal, the drug with the lowest acquisition cost should be offered.\n\nDuring localised outbreaks of influenza-like illness (outside the periods when national surveillance indicates that influenza virus is circulating in the community), oseltamivir and zanamivir may be offered for the treatment of influenza in 'at-risk' people who live in long-term residential or nursing homes. However, these treatments should be offered only if there is a high level of certainty that the causative agent in a localised outbreak is influenza (usually based on virological evidence of influenza infection in the initial case).\n\nAmantadine is not recommended for the treatment of influenza.\n\n The Health Protection Agency in England (and the equivalent bodies in Wales and Northern Ireland) uses information from a range of clinical, virological and epidemiological influenza surveillance schemes to identify periods when there is a substantial likelihood that people presenting with an influenza-like illness are infected with influenza virus.", 'Clinical need and practice': "Influenza is an acute infection of the respiratory tract caused by the influenza A and B viruses. The symptoms of influenza include fever, cough, sore throat, myalgia and headache. These symptoms are not specific to influenza, and can be caused by other viruses (such as respiratory syncytial virus) which can present as an 'influenza-like illness'. Diagnosis of influenza can only be confirmed by laboratory testing, although the probability that an influenza-like illness is caused by influenza is higher if influenza is known to be circulating and if a person has a high fever. The symptoms of influenza-like illness can be different in infants and children and may include fatigue, irritability, diarrhoea and vomiting. Influenza infection is usually self-limiting and lasts for 3–4\xa0days, with some symptoms persisting for 1–2\xa0weeks. The severity of the illness can vary from asymptomatic infection to life-threatening complications. The most common complications are secondary bacterial infections such as otitis media, pneumonia and bronchitis. In the UK, the average number of deaths attributed directly to influenza is approximately 600 in non-epidemic years and between 12,000 and 13,800 deaths in epidemic years.\n\nInfluenza occurs in a seasonal pattern with epidemics in the winter months, typically between December and March. The illness is highly contagious and is spread from person to person by droplets of respiratory secretions produced by sneezing and coughing. Influenza activity is monitored through surveillance schemes, which record the number of new GP consultations for influenza-like illness per week per 100,000 population. In 1997, normal seasonal activity in England was defined as 30–200 consultations, with greater than 200 defined as an epidemic. In Wales, the corresponding figures are 25–100, and greater than 400. In addition, there are virological monitoring schemes based on the isolation of the virus from clinical specimens. 'Normal seasonal activity', as measured by these surveillance schemes, corresponds to the term 'circulating' in 'Guidance on the use of zanamivir, oseltamivir and amantadine for the treatment of influenza' (NICE technology appraisal guidance 58). Accurate monitoring of influenza activity requires analysis of clinical, virological and epidemiological information.\n\nThe management of influenza is supportive and consists of relieving symptoms while awaiting recovery. Complications require specific management, and antibiotics are used for secondary bacterial infections. Vaccination has been established as the first-line intervention to prevent influenza and its complications. In the UK, the Department of Health currently recommends that people who are at risk of influenza infection or complications are vaccinated at the beginning of each winter. These include people with chronic respiratory, heart, renal, liver or neurological disease, people with diabetes, people who are immunosuppressed, people aged 65 and older, people who work or live in residential care facilities, carers of 'at-risk' people, healthcare and other essential workers and poultry workers.\n\nAntiviral drugs are also used for the prevention of influenza. They may be given to people who have been in contact with a person with influenza-like illness (post-exposure prophylaxis) and may be given in the absence of known contact when it is known that influenza is circulating in the community (seasonal prophylaxis). When antiviral drugs are given for seasonal prophylaxis, they are used for longer periods to cover the duration of the influenza season. Seasonal prophylaxis may be considered in exceptional situations such as an antigenic mismatch between circulating strains of the influenza virus and that used for vaccination, which would mean that 'at-risk' people are not effectively protected by vaccination. Prophylaxis may also be used to control outbreaks of influenza within a residential community. A review on the use of antiviral drugs for the prophylaxis of influenza (NICE technology appraisal guidance 158) recommends oseltamivir and zanamivir for post-exposure prophylaxis only.", 'The technologies ': "# Amantadine\n\nAmantadine (Lysovir, Symmetrel, Alliance Pharmaceuticals) acts against influenza A virus by blocking viral replication. It has a UK marketing authorisation for the treatment of people who have signs and symptoms of infection caused by influenza A virus. The summary of product characteristics (SPC) states that treatment should be started as early as possible, and within 48\xa0hours of symptom onset. The recommended dosage of amantadine is 100\xa0mg daily for 4–5\xa0days. Amantadine is administered orally as syrup (Symmetrel) or 100-mg capsules (Lysovir) for the treatment of influenza.\n\nThe adverse effects associated with amantadine are often mild and transient. The most commonly reported effects are gastrointestinal disturbances such as anorexia and nausea, and central nervous system effects such as loss of concentration, dizziness, agitation, nervousness, depression, insomnia, fatigue, weakness and myalgia. Central nervous system effects are most common in older people. For full details of adverse effects and contraindications, see the SPC.\n\nAmantadine costs £2.40 for five capsules (100\xa0mg each), £4.80 for 14 capsules and £5.55 for 150\xa0ml syrup (50\xa0mg/5\xa0ml) (excluding VAT; 'British national formulary' [BNF] edition 55). Costs may vary in different settings because of negotiated procurement discounts.\n\n# Oseltamivir\n\nOseltamivir (Tamiflu, Roche Products) is a neuraminidase inhibitor that is active against influenza A and B viruses. It prevents viral release from infected cells and subsequent infection of adjacent cells. It has a UK marketing authorisation for the treatment of influenza in people 1\xa0year of age or older who present with symptoms typical of influenza, when influenza virus is circulating in the community. The SPC states that treatment should be started as soon as possible within the first 48\xa0hours of the onset of influenza symptoms. The recommended dosage of oseltamivir for adolescents (13–17\xa0years of age) and adults is 75\xa0mg twice daily for 5\xa0days. For infants older than 1\xa0year and children 2–12\xa0years of age, the recommended dose of oseltamivir is adjusted according to body weight. Oseltamivir is given orally as syrup or capsules.\n\nAdverse effects associated with oseltamivir include gastrointestinal symptoms, bronchitis and cough, dizziness and fatigue and neurological symptoms such as headache, insomnia and vertigo. Skin rashes and allergic reactions and, rarely, disorders of the hepatobiliary system have been reported. Convulsions and neuropsychiatric disorders, mainly in children and adolescents, have also been reported but a causal link has not been established. For full details of adverse effects and contraindications, see the SPC.\n\nOseltamivir costs £16.36 for a 5-day course for an adult (excluding VAT; BNF edition 55). Costs may vary in different settings because of negotiated procurement discounts.\n\n# Zanamivir\n\nZanamivir (Relenza, GlaxoSmithKline) is a neuraminidase inhibitor that is active against influenza A and B viruses. It prevents viral release from infected cells and subsequent infection of adjacent cells. It has a UK marketing authorisation for the treatment of influenza in people older than 5\xa0years who present with symptoms typical of influenza, when influenza is circulating in the community. The SPC states that treatment should begin as soon as possible, within 48\xa0hours of symptom onset for adults and within 36\xa0hours of symptom onset for children. The recommended dosage of zanamivir for people older than 5\xa0years is 10\xa0mg twice daily for 5\xa0days. Zanamivir is taken by oral inhalation, using a Diskhaler device.\n\nAdverse effects associated with zanamivir are rare. They include bronchospasm and allergic phenomena. For full details of adverse effects and contraindications, see the SPC.\n\nThe price of zanamivir was reduced during the course of the appraisal from £24.55 (excluding VAT; BNF edition 55) to £16.36 (excluding VAT; BNF edition 56) for a 5-day course. Costs may vary in different settings because of negotiated procurement discounts.", 'Evidence and interpretation': "The Appraisal Committee (appendix A) considered evidence from a number of sources (appendix B).\n\n# Clinical effectiveness\n\nThe Assessment Group performed a systematic review to identify randomised controlled trials (RCTs) evaluating the clinical effectiveness of amantadine, oseltamivir and zanamivir compared with each other, placebo or with best symptomatic care. Studies included were conducted in people who presented with symptoms typical of influenza, whether influenza was reported as circulating in the community or not. The population was divided into the following categories: otherwise healthy adults; 'at-risk'; older people; children; and 'mixed' populations. Twenty-nine RCTs were identified by the systematic review. There was no new evidence on the clinical effectiveness of amantadine published after the review of the evidence for TA\xa058. No RCTs that directly compared zanamivir and oseltamivir were included; a Bayesian indirect comparison using placebo as a common comparator was conducted. The trials generally compared zanamivir or oseltamivir with placebo. The background circulating levels of influenza and the influenza vaccination rate in the trials were often not reported clearly. Levels of viral resistance were often not measured, but when reported were low.\n\nIn most RCTs, the effectiveness of the antiviral drugs was measured in terms of time to alleviation of symptoms (a composite outcome) and time to return to normal activities. Adverse events and complications were also reported, the latter generally in terms of reductions in antibiotic usage. Analyses were reported for the ITT population (intention to treat; representative of the entire population recruited in the trials) and ITTI population (intention to treat, confirmed as being influenza positive) wherever possible.\n\nEvidence was submitted by consultees that there has been a decline in the rates of GP consultations for acute respiratory illnesses over the past 25\xa0years. This has resulted in the lowering of the threshold levels of the surveillance schemes. In addition, it was stated that the influenza season as defined by the surveillance schemes does not correspond exactly to the period during which the virus is circulating in the community as indicated by virological monitoring. It was also apparent that outbreaks of influenza occur within localised areas, especially in residential care settings, outside of the influenza season.\n\n## Oseltamivir\n\nThe Assessment Group's systematic review identified 16 RCTs. Eight of these had been considered for TA\xa058 and eight were new studies that had been published since the review of evidence for TA\xa058. Two of the included studies recruited mixed populations, seven recruited only healthy adults, two recruited from general 'at-risk' populations, two recruited only children and three recruited only older people. Follow-up periods ranged from 10 to 28\xa0days.\n\nMost of the included studies reported time to alleviation of symptoms and the Assessment Group conducted meta-analyses by population subgroup and by whole population. Overall, oseltamivir reduced the median time to alleviation of symptoms by 0.68\xa0days (95% confidence interval [CI] 0.41 to 0.95) and 0.95\xa0days (95% CI 0.50 to 1.39) in the ITT (n\xa0=\xa05036) and ITTI (n\xa0=\xa02541) analyses, respectively. The reduction in median time to alleviation of symptoms associated with oseltamivir treatment ranged from 0.41\xa0days (older people) to 0.88\xa0days (healthy and 'at-risk' children) in the ITT analyses and from 0.43\xa0days ('at-risk' children) to 1.50\xa0days (healthy children) in the ITTI analyses.\n\nMost of the included studies also reported time to return to normal activity and the Assessment Group conducted meta-analyses by population subgroup and by whole population. Overall, oseltamivir reduced the median time to return to normal activity by 1.32\xa0days (95% CI 0.91 to 1.73) and 1.51\xa0days (95% CI 1.01 to 2.02) in the ITT (n\xa0=\xa02754) and ITTI (n\xa0=\xa03013) analyses, respectively. The reduction in median time to return to normal activity associated with oseltamivir treatment ranged from 1.25\xa0days (healthy children) to 4.09\xa0days (older people) in the ITT analyses and from 0.50\xa0days ('at-risk' children) to 3.07\xa0days (older people) in the ITTI analyses.\n\nAlleviation of fever was reported in a few studies. Because the studies that reported alleviation of fever were generally conducted in healthy or mixed populations, meta-analyses were not presented by population category. All of the trials showed a reduction in the time to alleviation of fever. Overall, oseltamivir reduced the median time to alleviation of fever by 18.7\xa0hours in the ITT population (95%\xa0CI 9.70 to 27.8, n\xa0=\xa01177) and 24.4\xa0hours in the ITTI population (95% CI 17.2 to 31.6, n\xa0=\xa01720).\n\nThe data on complications were sparse and only the use of antibiotics was significantly reduced for those who received oseltamivir compared with placebo (ITTI population, odds ratio [OR] 0.62, 95% CI 0.46 to 0.83 for antibiotic use, n\xa0=\xa02175). Across all trials, there was no evidence of a difference in the incidence of overall, serious or drug-related adverse effects between oseltamivir and placebo. Among the nine trials that reported mortality, there was a single death in the placebo arm of a trial in an 'at-risk' population; it was not clear whether this death was associated with influenza.\n\n## Zanamivir\n\nThe Assessment Group's systematic review identified 13 RCTs. Seven of these had been considered for TA\xa058 and six were new studies that had been published since the review of evidence for TA\xa058. Five of the studies recruited a mixed population (for which data on symptoms for healthy and 'at-risk' adults were available separately), three recruited only healthy adults, two recruited from general 'at-risk' populations, two recruited only children and one recruited only older people. The follow-up period ranged from 5 to 29\xa0days.\n\nMost of the included studies reported time to alleviation of symptoms and the Assessment Group conducted meta-analyses by population subgroup and by whole population. Overall, zanamivir reduced the median time to alleviation of symptoms by 0.71\xa0days (95% CI 0.41 to 1.01) and 1.07\xa0days (95% CI 0.74 to 1.39) in the ITT (n\xa0=\xa04538) and ITTI (n\xa0=\xa02865) analyses, respectively. The reduction in the median time to alleviation of symptoms associated with zanamivir treatment ranged from 0.57\xa0days (healthy adults) to 2.00\xa0days ('at-risk' children) in the ITT analyses and from 0.96\xa0days (healthy adults) to 3.75\xa0days ('at-risk' children) in the ITTI analyses.\n\nMost of the included studies also reported time to return to normal activity and the Assessment Group conducted meta-analyses by population subgroup and by whole population. Overall, zanamivir reduced the median time to return to normal activity by 0.44\xa0days (95% CI 0.05 to 0.84) and 0.71\xa0days (95% CI 0.19 to 1.24) in the ITT (n\xa0=\xa04053) and ITTI (n\xa0=\xa02877) analyses, respectively. The reduction in median time to return to normal activity associated with zanamivir treatment ranged from 0.37\xa0days (healthy adults) to 1.07\xa0days ('at-risk' adults) in the ITT analyses and from 0.39\xa0days (healthy adults) to 2.50\xa0days ('at-risk' children) in the ITTI analyses.\n\nAlleviation of fever was reported in four studies but only one reported any measure of variance, so meta-analyses could not be conducted. Across the studies that reported this outcome (n\xa0=\xa01539), the median time to alleviation of fever was reduced by between 0.0 and 0.5\xa0days for zanamivir compared with placebo.\n\nAlthough the data on complications were sparse, the incidence of overall complications and the use of antibiotics were significantly reduced for those who received zanamivir compared with placebo (ITTI populations, n\xa0=\xa02629, OR 0.77, 95% CI 0.65 to 0.92, p\xa0=\xa00.004 for overall complications; OR 0.79, 95% CI 0.63 to 0.99, p\xa0=\xa00.04 for antibiotic use). Across all trials, treatment with zanamivir significantly reduced the incidence of overall adverse events compared with placebo (OR 0.85, 95% CI 0.75 to 0.96, p\xa0=\xa00.007, n\xa0=\xa05430) but there was no evidence of a difference in the incidence of drug-related adverse events. Very few serious adverse events were reported and there were no deaths in any of the seven zanamivir trials that reported mortality.\n\n## Indirect comparison of oseltamivir and zanamivir\n\nThe Assessment Group identified one direct comparison of zanamivir and oseltamivir but excluded this trial because it did not report usable outcome data. Therefore, the Assessment Group performed an indirect comparison of zanamivir and oseltamivir using a multi-parameter Bayesian approach. The probabilities that each treatment was 'best' were calculated for the following population subgroups: otherwise healthy adults; otherwise healthy children; and an 'at-risk' group that combined 'at-risk' children, 'at-risk' adults and older people (owing to few data). All analyses were presented with associated 95% credibility intervals (CrI). A 95% Bayesian credibility interval means that, given the data, there is a 95% probability that the random variable lies within the interval.\n\nAcross all analyses, point estimates suggested that either oseltamivir or zanamivir was more effective than placebo, but not all analyses were statistically significant. There was variation across population subgroups as to whether zanamivir or oseltamivir had a higher probability of being most effective. In all of the analyses, the median time to alleviation of symptoms and return to normal activity was shorter in the ITTI analyses than the ITT analyses. In the ITTI analyses, zanamivir treatment compared with placebo reduced the days to alleviation of symptoms by 1.3 (95% CrI 0.30 to 2.96) and 4.7 (95% CrI 1.98 to 9.44) for healthy adults and the 'at-risk' group, respectively. Similar analyses for oseltamivir treatment compared with placebo gave reductions of 2.08 (95% CrI 0.73 to 4.34) and 2.63 (95% CrI 0.38 to 6.53) days for healthy adults and healthy children, respectively. The ITTI analyses for zanamivir compared with placebo for healthy children gave a reduction of 1.77 days (95% CrI –0.41 to 5.10) and for oseltamivir compared with placebo in the 'at-risk' group gave a reduction of 1.56 days (95% CrI –0.78 to 4.66), but in both cases the credibility intervals included zero. In ITTI analyses for days to return to normal activities, zanamivir treatment compared with placebo gave reductions of 1.65, 5.97 and 2.25 for healthy adults, the 'at-risk' group and healthy children, respectively. In the ITTI analyses, compared with placebo oseltamivir treatment reduced the days to return to normal activity by 2.64, 1.98 and 3.34 for healthy adults, the 'at-risk' group and healthy children, respectively.\n\n# Cost effectiveness\n\nThe Assessment Group identified 21 cost-effectiveness studies that assessed amantadine, oseltamivir or zanamivir for the treatment of influenza. The manufacturer of oseltamivir (Roche Products) also provided a de novo economic model. No cost-effectiveness analyses were submitted by the manufacturers of amantadine or zanamivir. Seven of the identified cost-effectiveness studies were conducted from the perspective of the NHS (including the assessment for the original appraisal TA\xa058 and the current submission from Roche Products).\n\nThe decision-tree model developed by the Assessment Group for TA\xa058 was designed to compare amantadine, oseltamivir and zanamivir with usual care for the treatment and prophylaxis of influenza. The following four separate groups were considered: otherwise healthy adults; high-risk ('at-risk') adults; children; and older people in residential care. For each of the population groups, amantadine compared with usual care had the lowest incremental cost-effectiveness ratios (ICERs), which ranged from £4535 to £6190 per quality-adjusted life-year (QALY) gained. However, the Appraisal Committee for the original appraisal TA\xa058 was unable to accept that the clinical effectiveness of amantadine was sufficiently proven and so it did not recommend amantadine for the treatment of influenza A. The ICERs for oseltamivir compared with usual care ranged from £19,015 to £22,502 per QALY gained. The ICERs for zanamivir compared with usual care ranged from £16,819 to £31,529 per QALY gained.\n\nOf the five other studies conducted from the UK NHS perspective, two compared zanamivir with usual care in both healthy and 'at-risk' adults, two compared oseltamivir with usual care in healthy children and healthy adults, and one compared oseltamivir, zanamivir and usual care in healthy adults. The estimated ICERs for zanamivir compared with usual care ranged from £7490 to £54,000 per QALY gained for 'at-risk' adults and £65,000 per QALY gained for otherwise healthy adults. The estimated ICERs for oseltamivir compared with usual care ranged from oseltamivir being dominant to £11,173 per QALY gained for healthy children, and £225 to £5600 for adults per QALY gained. In the only comparison of oseltamivir with zanamivir (in healthy adults), zanamivir was dominated (that is, zanamivir was estimated to be more costly and less effective than oseltamivir).\n\n## Manufacturer's model\n\nThe current submission from the manufacturer of oseltamivir (Roche Products) included a decision-tree economic model that estimated the cost effectiveness of oseltamivir compared with zanamivir and usual care for the treatment of influenza, using separate pairwise comparisons. The model considered the following population subgroups separately: otherwise healthy adults; 'at-risk' adults (including older adults); otherwise healthy children aged 1–12\xa0years; and otherwise healthy children aged 1–5\xa0years. The model started when a patient presented to a GP with an influenza-like illness when influenza was reported to be circulating in the community. The probability that the illness was influenza was assumed to be 31% in all populations modelled. For the comparison of oseltamivir with zanamivir it was assumed that the drugs are equally effective. A cost-minimisation approach was used and the total cost of a course of zanamivir was assumed to be £0.19 higher than that of oseltamivir. The health state utility for influenza-like illness without complication was assumed to be 0.840; this was taken from Harvard utility scores and was assumed not to differ between populations. Zanamivir and oseltamivir treatment was assumed to be associated with an improved utility of 0.937; this improved utility was derived from the oseltamivir clinical trials. The resource-use data cover costs associated with GP visits, diagnostic tests, antibiotic treatments and hospital visits.\n\nThe comparison of oseltamivir with usual care for the treatment of influenza produced base-case ICERs of £5452 per QALY gained for healthy adults, £5992 per QALY gained for healthy children aged between 1 and 12\xa0years, £4687 per QALY gained for healthy children aged between 1 and 5\xa0years and £652 for 'at-risk' adults. For all populations, zanamivir was dominated by oseltamivir (that is, oseltamivir was less costly and more effective than zanamivir). The model was sensitive to the changes in assumptions of the probability that an influenza-like illness was true influenza and the probability that patients presented to a GP within 48\xa0hours.\n\n## Assessment Group model\n\nThe Assessment Group conducted an independent economic assessment. The model was used to develop incremental estimates of the cost effectiveness of oseltamivir and zanamivir for the treatment of influenza compared with usual care without antiviral treatment. The Assessment Group did not develop estimates of the cost effectiveness of amantadine for the treatment of influenza because it is not widely used and was not recommended for use in TA\xa058. The decision-tree model evaluated costs from an NHS and personal social services perspective. A single influenza season was modelled; however, a lifetime horizon was used to account for any reductions in life expectancy. The model started when a patient presented to a healthcare professional with an influenza-like illness and was considered suitable for treatment with either oseltamivir or zanamivir (according to the respective UK marketing authorisations of each antiviral drug). Cost-effectiveness estimates for influenza treatment were presented for the following population groups: otherwise healthy children (aged 1–14\xa0years); 'at-risk' children (aged 1–14\xa0years); otherwise healthy adults (aged 15–64\xa0years); 'at-risk' adults (aged 15–64 years) and the 'elderly' (defined as adults older than 65\xa0years). The model assumed that oseltamivir and zanamivir would be prescribed only when influenza was known to be circulating in the community, based on national surveillance schemes (this was assumed to be defined as 30 new GP consultations for influenza-like illness per 100,000 population).\n\nThe probability that an influenza-like illness is true influenza was derived from national surveillance data provided by the Royal College of General Practitioners. The average probability that influenza-like illness was influenza was 0.495. However, calculating this for the separate age groups resulted in a probability of 0.56 (CrI 0.26 to 0.79) in people younger than 15 years and 0.41 (CrI 0.21 to 0.66) in people aged 15 years and over.\n\nThe effectiveness of oseltamivir and zanamivir was derived from the overall duration of symptoms (that is, based on time to alleviation of symptoms) for the different subgroups in the model. These were taken directly from the mean ITTI results from the indirect Bayesian multi-parameter evidence synthesis model. The same mean duration of symptoms was applied to each of the separate 'at-risk' populations considered in the economic model. The relative effectiveness estimates from the ITTI populations were assumed to be independent of previous vaccination or prophylactic use of antivirals. The relative effectiveness of oseltamivir and zanamivir was assumed to be the same for both influenza type A and B. Both treatments were considered to be effective only in people with true influenza.\n\nThe Assessment Group used the duration of symptoms as the basis for estimating the potential QALY gains associated with the reduction in symptom duration reported for oseltamivir and zanamivir compared with usual care. A systematic search of the literature was undertaken to identify suitable health-related quality of life data. Although the Assessment Group identified some studies, none presented comparable estimates for different risk groups and there were limitations in the methods used. Therefore, the utility values were based on those applied in TA\xa058. The data used in TA\xa058 were derived from the transformation of visual analogue scale (VAS) data reported in some of the oseltamivir trials into time trade-off utilities over a 21-day period. These data were then augmented with symptom duration estimates from the full range of RCTs identified in the current clinical effectiveness review. Separate values were reported for otherwise healthy adults and 'at-risk' adult populations. In the base-case analyses, the average quality of life decrement over the duration of influenza illness applied to healthy populations was between 0.4 and 0.5. The corresponding figure for 'at risk' populations was between 0.5 and 0.6. The Assessment Group also noted that if treatment of influenza shortens the duration of symptoms by reducing them at the end rather than the beginning of the illness, then the overall average decrement would be reduced to between 0.22 and 0.23 for healthy populations and 0.45 for 'at risk' populations. Adverse effects from oseltamivir and zanamivir were assumed to be mild and self-limiting and were assumed not to impact on a person's health-related quality of life.\n\nThe model then assumed that all people with influenza-like illness (whether influenza or not) had a probability of developing a complication. Estimates of the baseline probabilities of developing each complication (and subsequent mortality) were derived separately for each subgroup from data reported in a large UK population-based study and ranged from 7.55% (healthy adults) to 17.59% ('at-risk' children). In the model, it was possible for a person to experience more than one complication; the probability of this was estimated for each person in each subgroup. Estimates of how effective the different treatments were at reducing the incidence of complications were based on the relative risk of antibiotic use. The relative risks for complications with zanamivir compared with placebo were 0.71 (95% CI 0.34 to 1.45), 0.74 (95% CI 0.35 to 1.57) and 0.78 (95% CI 0.45 to 1.35) for healthy adults, the 'at-risk' group and children, respectively. The relative risks for complications with oseltamivir compared with placebo were 0.57 (95% CI 0.24 to 1.35), 0.69 (95% CI 0.50 to 0.93) and 0.56 (95% CI 0.36 to 0.87) for the healthy adults, the 'at-risk' group and children, respectively. The quality of life estimates were decreased according to type of complication.\n\nLikelihood of hospitalisation as a result of each type of complication was also included in the model; however, only complicated cases were assumed to lead to hospitalisation and death. Premature death as a result of influenza was assumed to occur only following a secondary complication (irrespective of whether a person was hospitalised). Given limitations in the evidence base, it was assumed that hospitalisation occurred only as a result of respiratory tract infections. The model assumed that all people who develop a complication face a subsequent probability of mortality that varies only by population subgroup, not by treatment strategy or previous hospitalisation. Mortality was assumed to have no cost implication, but resulted in loss of potential QALYs. In each population age group (children, adults and older people), the expected age of death from complications related to an influenza-like illness was derived from data from national statistics reporting influenza deaths by age group.\n\nThe acquisition cost of oseltamivir (£16.36) was based on the BNF (edition 55) list price, with identical estimates applied for zanamivir based on the revised price (see section 3.9). The costs associated with people developing complications as a result of influenza or influenza-like illness were also included. These costs included visits to a healthcare provider for treatment, antibiotics and hospitalisation.\n\nA total of 12 scenario analyses were investigated by the Assessment Group. These analyses included investigation of assumptions such as those made about complications, the probability that an influenza-like illness was true influenza and the relative efficacy of oseltamivir and zanamivir.\n\nIn base-case results, for each population the ICER for both oseltamivir and zanamivir (relative to usual care) was less than £20,000 per QALY gained, and across the separate populations ranged from £562 to £7035 per QALY gained. In healthy children and healthy adults oseltamivir dominated zanamivir, with ICERs of £7035 and £5521 per QALY gained, respectively. In 'at-risk' children, 'at-risk' adults and older people zanamivir extendedly dominated oseltamivir (that is, the ICER for oseltamivir treatment is higher than that of zanamivir and usual care and is therefore ruled out on the basis of extended dominance). The ICERs were £1752 per QALY gained for 'at-risk' children, £2270 for 'at-risk' adults and £562 for older people. At a willingness to pay threshold of £20,000 per QALY gained, the probability that zanamivir was cost effective ranged from 23% (healthy children) to 90% ('at-risk' adults) and the probability that oseltamivir was cost effective ranged from 10% ('at-risk' adults) to 77% (healthy adults). The probability that usual care was cost effective at the same threshold was 0% (healthy adults, 'at-risk' adults, older people) to 4% (healthy children).\n\nAcross the 12 scenario analyses performed by the Assessment Group, the overall conclusions and ICERs in the 'at-risk' populations were generally consistent. The ICERs appeared more sensitive in the otherwise healthy populations. The base-case estimates of the ICERs of oseltamivir and zanamivir compared with usual care in the healthy populations were sensitive to the following key assumptions: the exclusion of hospitalisation and mortality benefits with antiviral treatment (these were included in the base case and ICERs in the scenario analyses ranged up to £13,985 per QALY gained); a reduction in the probability that an influenza-like illness is true influenza (this was 0.41 for adults and 0.56 for children in the base case and the ICERs in the scenario analyses ranged up to £47,573 per QALY gained, and up to £48,390 per QALY gained if hospitalisation and mortality benefits were excluded); increases in consultations with healthcare providers combined with decreases in the probability that an influenza-like illness is influenza (ICERs in the scenario analyses ranged up to £13,959 per QALY gained, and up to £28,950 per QALY gained if hospitalisations and mortality benefits were excluded); and reductions in the decrements in quality of life associated with influenza (ICERs in the scenario analyses ranged up to £29,115 per QALY gained, and up to £59,684 per QALY gained if hospitalisation and mortality benefits were excluded).\n\nThe Assessment Group conducted additional scenario analyses for healthy children and healthy adults, which combined the following parameters:\n\nexclusion of hospitalisation and mortality benefits\n\nan increase in GP consultations (between 5 and 15%)\n\na decrease in the probability that an influenza-like illness is true influenza (between 5 and 15%)\n\na smaller decrement in quality of life associated with influenza of 0.2 (this value reflects the estimate detailed in section 4.2.9 corresponding to reduction in the duration of symptoms being at the end of the illness. The sensitivity analyses of quality of life decrements were explored in increments of 0.1). These scenario analyses resulted in ICERs that ranged from £21,003 to £31,491 per QALY gained for healthy children and from £39,862 to £65,607 per QALY gained for healthy adults.\n\n# Consideration of the evidence\n\nThe Appraisal Committee reviewed the data available on the clinical and cost effectiveness of amantadine, oseltamivir and zanamivir, having considered evidence on the nature of the condition and the value placed on the benefits of amantadine, oseltamivir and zanamivir by people with influenza, those who represent them, and clinical specialists. It was also mindful of the need to take account of the effective use of NHS resources.\n\nThe Committee understood that influenza causes a wide spectrum of respiratory illness of varying severity, and can lead to a number of potentially serious complications, especially in certain 'at-risk' groups. The Committee discussed the definition of 'at-risk' groups for whom treatment might be particularly suitable and decided that they would be best defined in the same way as for the current recommendations for vaccination. From the outset the Committee was of the view that vaccination has been established as the first-line intervention to prevent influenza and its complications, and was mindful that the use of antiviral treatments should not in any way detract from efforts to ensure that all eligible people are vaccinated at the beginning of each influenza season.\n\nThe Committee noted that the surveillance scheme used in the NHS to determine levels of influenza activity in the community was based on clinical consultations, but that influenza activity as defined by the threshold levels of these consultation rates did not always coincide with laboratory-based virological evidence. The Committee understood that the Health Protection Agency in England and similar organisations in Wales and Northern Ireland use information from a range of clinical, virological and epidemiological influenza surveillance schemes to identify when influenza is circulating in the community. The Committee heard from clinical specialists that the threshold levels are not suitable for defining when antiviral treatments would be most efficacious because they do not accurately identify periods when influenza, as opposed to influenza-like illness, is circulating.\n\nThe Committee considered the evidence for effectiveness of amantadine and noted that no new evidence on either the clinical or cost effectiveness of amantadine for the treatment of influenza had been published since the review of the evidence for TA\xa058. The Committee concluded that it had no basis on which to change the recommendations on the use of amantadine from the original appraisal (TA\xa058). Therefore amantadine is not recommended for the treatment of influenza.\n\nThe Committee then reviewed the evidence on the clinical effectiveness of oseltamivir and zanamivir for the treatment of influenza. The Committee noted that in all of the population subgroups, treatment with either antiviral drug was associated with reductions in the average duration of symptoms compared with placebo, although the difference was not statistically significant in all subgroups. The Committee acknowledged that the reduction in duration of symptoms was generally greater for the 'at-risk' population compared with healthy populations. The Committee heard from clinical experts that this increased reduction in duration of symptoms for the 'at-risk' group was plausible for a number of reasons. It is likely that people in 'at-risk' groups would have a longer duration of illness, and would therefore be more likely to benefit from antiviral treatment. There is also clinical rationale to suggest that people in 'at-risk' groups could also suffer from exacerbations of underlying conditions as a result of influenza. This could increase the duration and severity of influenza symptoms, which would mean an increased potential benefit from antiviral treatments. These exacerbations might also lead to a person not recovering completely, and future influenza infections and subsequent exacerbations being more frequent. The Committee concluded that there is evidence indicating clinical effectiveness of antiviral drugs in a wide range of clinical settings, but that their use is of greatest clinical importance for people in 'at-risk' groups.\n\nThe Committee noted that the probabilities for each antiviral drug being the 'best' treatment also differed according to population subgroup. The Committee discussed these results with clinical experts. The Committee was not persuaded that there was any plausible biological explanation for these observed differences. The Committee considered that the data were too sparse and uncertain to allow for any clear distinctions between the antiviral treatments to be made on the basis of clinical efficacy between different populations. The Committee concluded that oseltamivir and zanamivir are both clinically effective treatments for influenza, particularly for those people in 'at-risk' groups.\n\nThe Committee considered the evidence on adverse events associated with oseltamivir and zanamivir. The Committee was aware that very sparse adverse event data were reported in the included RCTs. However, it noted that no significant differences between the antiviral treatments compared with placebo were reported.\n\nThe Committee considered the structure of the economic models used to generate cost-effectiveness estimates for oseltamivir and zanamivir for the treatment of influenza. The Committee was aware that the models submitted by the manufacturer and the Assessment Group were not dynamic models. That is, the models did not account for effects of influenza treatment in reducing transmission of infection, the development of 'herd immunity', the potential for the development of drug resistance and the effect of treatment of influenza-like illness on attack rates. The Committee appreciated that some aspects of this approach to modelling additional benefits could improve the cost effectiveness of the antiviral agents but that there were potential disadvantages that would make treatment less cost effective. The Committee was also aware that dynamic models were technically complicated and that the current evidence would not have been sufficient to support this modelling approach. The Committee concluded that the evidence available from the submitted models was an appropriate basis on which to make a decision and that on balance an alternative dynamic modelling approach would not change its overall conclusions.\n\nThe Committee then reviewed the cost-effectiveness estimates of oseltamivir and zanamivir as submitted by the manufacturer of oseltamivir and the Assessment Group. In particular, the Committee considered the key inputs in the models were the probability that an influenza-like illness is true influenza and complication rates following influenza infection and subsequent related hospitalisation and mortality.\n\nThe Committee first considered the different estimates of the probability that an influenza-like illness is true influenza. The Committee noted that the probability used in the manufacturer's model was lower than that used in the Assessment Group model (for which different probabilities were used according to age group). The Committee was aware that the confidence intervals surrounding the probability estimates for different population subgroups used in the Assessment Group model were wide and overlapped with one another. The Committee heard from clinical experts that the probability of an influenza-like illness being true influenza in children was likely to be lower than that assumed in the Assessment Group model because of increased difficulties in diagnosis in children and the probability of other conditions such as respiratory syncytial virus, which can present as influenza-like illness. The Committee thought that this was particularly likely for otherwise healthy children and concluded that the estimate of 56% (influenza-like illness is true influenza) was too high and should be more closely aligned to that of adults (that is, 41%).\n\nThe Committee considered whether the vaccination status would affect the probability that a person presenting with an influenza-like illness would have true influenza. The Committee considered that this would depend on a number of factors, including whether the vaccine was appropriately matched to the currently circulating strain of influenza virus and whether sufficient time had elapsed since vaccination to ensure it was effective. The Committee noted that there were insufficient data on which to inform differential considerations on the basis of vaccination status. Therefore the Committee concluded that any recommendation on the use of antiviral drugs would not distinguish between vaccinated and non-vaccinated people.\n\nThe Committee then discussed whether increases in GP consultation rates (for example, as a result of a positive recommendation for the use of antiviral drugs) could result in more people presenting to a healthcare provider with an influenza-like illness that was not true influenza. The Committee heard from clinical experts that this was plausible. The Committee was also aware that current surveillance schemes are based in part on the number of GP consultations, and increases in consultation rates could lead to an apparent increase in influenza prevalence and thus reduction in the positive predictive value of influenza diagnoses. The Committee considered that such a scenario was more probable in healthy populations. The Committee concluded that for healthy populations increases in GP consultation rates would lead to decreases in the probabilities that an influenza-like illness was true influenza. The Committee was also aware that there would be extra costs associated with an increase in GP consultation rates. Therefore the Committee concluded that the base-case ICERs for these groups would be underestimates if a positive recommendation were given.\n\nThe Committee considered the effects of oseltamivir and zanamivir treatment on complication rates associated with influenza. The Committee noted that the economic model provided by the Assessment Group included complication rates based only on reductions in antibiotic use in the absence of more direct data. The Committee was aware that there may be additional, alternative, approaches to measuring complication rates and that there were wide confidence intervals and uncertainty in the relative reduction rates in antibiotic use, particularly for healthy adults and children. The Committee also considered that the lower severity and duration of influenza symptoms, as may occur in healthy populations compared with 'at-risk' populations as discussed in section 4.3.5, could lead to a lower incidence of complications and subsequent hospitalisations.\n\nThe Committee considered the effects of influenza on health-related quality of life. In the Assessment Group base case, an average quality of life decrement had been applied across the duration of an episode of influenza illness. The Committee noted that influenza is generally associated with worse disutility at the beginning rather than at the end of the illness. The Committee considered that it is more plausible that a reduction in symptoms arising from treatment would occur at the end of the illness. This would result in a lower impact on health-related quality of life, with an overall lower average quality of life decrement, compared with a reduction in symptoms at the beginning of the illness. The Committee noted that the Assessment Group estimated that in such a circumstance the average decrement in quality of life should be reduced to between 0.22 and 0.23 for healthy populations. The Committee considered that people in the 'at risk' population would be expected to have more severe symptoms for a longer period and that it is plausible that having to visit their GP to obtain treatment in the early phase of the illness might in itself cause additional impact on health-related quality of life. Therefore, taking all of these factors into account, the Committee accepted the average base-case decrement in quality of life for 'at risk' populations used in the Assessment Group base case (that is, between 0.5 and 0.6).\n\nThe Committee then considered the cost-effectiveness estimates for oseltamivir and zanamivir treatment in otherwise healthy populations. It considered that the most plausible presented ICERs in this group were from the scenarios exploring the combined effect of excluding hospitalisation and mortality benefits, increased GP consultation rates with a subsequent reduction in the probability that an influenza-like illness is true influenza and a reduced decrement in quality of life of 0.2. The point estimate ICERs resulting from these scenarios ranged from £21,000 to £31,500 per QALY gained in healthy children and from £39,900 to £65,600 per QALY gained for healthy adults. The Committee was also mindful of its conclusion that in children 56% is an overestimate of the probability that influenza-like illness is influenza, and that the estimate should be more closely aligned with that for adults (that is, 41%). Hence it considered that the ICERs of £21,000 to £31,500 per QALY gained in healthy children were underestimates of the true ICERs within the preferred set of assumptions accepted by the Committee. The Committee was also aware that the ICERs presented assumed treatment with oseltamivir in all cases, because oseltamivir dominated zanamivir in healthy populations. The Committee was mindful that if both oseltamivir and zanamivir were recommended, then the true ICERs for healthy populations would be higher. Therefore, the Committee concluded that oseltamivir and zanamivir for the treatment of influenza in otherwise healthy children and adults would not be a cost-effective use of NHS resources.\n\nThe Committee further considered the cost-effectiveness estimates of oseltamivir and zanamivir in 'at-risk' populations. Having reviewed a number of the key parameters from the economic models, the Committee concluded that for 'at-risk' populations the economic estimates submitted by the Assessment Group and the manufacturer of oseltamivir were plausible. The Committee concluded that because the base-case estimates were all less than £20,000 per QALY gained for these population subgroups, then oseltamivir and zanamivir, within their licensed indications, could be recommended as cost-effective uses of NHS resources.\n\nThe Committee then discussed whether both oseltamivir and zanamivir should be recommended for the treatment of influenza. The Committee was aware of the limitations in the evidence base for comparative efficacy of the two drugs and it was not persuaded that there was evidence of differential effectiveness. However, the Committee noted that the drugs were administered differently and that zanamivir was not licensed for children aged 5\xa0years or younger. The Committee concluded that it was therefore preferable not to give specific recommendations for oseltamivir or zanamivir, and that the decision as to which to prescribe should be made after consultation between the healthcare professional, the patient and carers on a case-by-case basis, taking into account the patient's preferences regarding drug delivery and potential adverse effects and contraindications. However, the Committee considered that if all other considerations are equal, the choice should be based on the less costly option within the marketing authorisations of the products.\n\nThe Committee considered the need for managing outbreaks that occur outside the influenza season as defined by the surveillance threshold. It noted that such outbreaks often occurred in residential care establishments and were frequently associated with poor outcomes and complications in vulnerable populations. The Committee noted that the population in residential care was most likely to be older people or people otherwise at risk of influenza complications. It was mindful that, because oseltamivir and zanamivir are effective only against true influenza, the cost effectiveness of treatment in such situations would depend on the probability that the influenza-like illness was influenza. The Committee noted that this probability was low in the absence of wider circulation of influenza. Therefore, the Committee considered it important that in such situations there should be firmer evidence that the influenza-like illness was influenza. Such evidence could be supplied by virological testing. The Committee considered other people who lived together in a residential setting, such as a prison or boarding school. It noted that such populations would comprise mostly healthy people for whom the consequences of influenza infection would be minor. The Committee agreed that such populations would not be exceptions and treatment during outbreaks outside the influenza season would not be cost effective unless people in those populations were in an 'at-risk' group. Therefore the Committee recommended that outside the periods when national surveillance indicates that influenza virus is circulating, oseltamivir and zanamivir could be recommended for treatment of influenza in 'at-risk' people living in long-term residential or nursing homes, but only if there is a high level of certainty that a localised outbreak is occurring, usually based on virological evidence of infection with influenza in the incident case or cases.", 'Recommendations for further research': 'The Committee recommended that a UK observational database is established to monitor the effectiveness of influenza treatment with the antiviral drugs oseltamivir and zanamivir. The Committee also recommended that cases of antiviral resistance to oseltamivir and zanamivir are monitored via the observational database.\n\nThe Committee recommended that further research is conducted into the probability that an influenza-like illness is true influenza.', 'Related NICE guidance': 'Respiratory tract infections – antibiotic prescribing. Prescribing of antibiotics for self-limiting respiratory tract infections in adults and children in primary care. NICE clinical guideline 69 (2008).\n\nOseltamivir, amantadine (review) and zanamivir for the prophylaxis of influenza. NICE technology appraisal guidance 158 (2008).', 'Review of guidance': 'The review date for a technology appraisal refers to the month and year in which the Guidance Executive will consider whether the technology should be reviewed. This decision will be taken in the light of information gathered by the Institute, and in consultation with consultees and commentators.\n\nThe guidance on this technology will be considered for review in November 2013.\n\nAndrew DillonChief ExecutiveFebruary 2009', 'Changes after publication': 'February 2014: minor maintenance\n\nMarch 2012: minor maintenance', 'About this guidance': "NICE technology appraisal guidance is about the use of new and existing medicines and treatments in the NHS in England and Wales.\n\nThis guidance was developed using the NICE multiple technology appraisal process.\n\nIt replaces 'Flu treatment – zanamivir (review), amantadine and oseltamivir' (NICE technology appraisal 58).\n\nThe review and re-appraisal of amantadine, oseltamivir and zanamivir for the treatment of influenza has resulted in a change in the guidance. Specifically:\n\npeople with chronic neurological conditions and people with chronic liver disease are now considered 'at risk'\n\nzanamivir is now recommended as a treatment option for children between the ages of 5 and 12 years in 'at-risk' groups if influenza is circulating and they can start treatment within 36 hours of first symptoms\n\noseltamivir and zanamivir are now recommended as treatment options for 'at-risk' people in long-term and residential nursing homes during localised outbreaks (when influenza is not circulating), if there is a high level of certainty that the causative agent is influenza.\n\nThis guidance has been prepared in the expectation that vaccination against influenza is undertaken in accordance with national guidelines. Vaccination has been established as the first-line intervention to prevent influenza and its complications, and the use of drugs described in this guidance should not in any way detract from efforts to ensure that all eligible people receive vaccination.\n\nWe have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available.\n\nYour responsibility\n\nThis guidance represents the views of NICE and was arrived at after careful consideration of the evidence available. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. However, the guidance does not override the individual responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.\n\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.\n\nCopyright\n\n© National Institute for Health and Clinical Excellence 2009. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE."}	https://www.nice.org.uk/guidance/ta168	Evidence-based recommendations on amantadine (Lysovir), oseltamivir (Tamiflu) and zanamivir (Relenza) for treating influenza in children and adults.
642ff4dd4cb1485d9b365a3b5650b592aa664073	nice	Laparoscopic cystectomy	Laparoscopic cystectomy # Guidance This document replaces previous guidance on laparoscopic cystectomy (Interventional Procedure Guidance 26). Current evidence on the safety and efficacy of laparoscopic cystectomy appears adequate to support the use of this procedure provided that normal arrangements are in place for clinical governance, consent and audit. Patient selection for laparoscopic cystectomy should involve a multidisciplinary team experienced in the management of bladder cancer. Clinicians undertaking laparoscopic cystectomy should have special training. The British Association of Urological Surgeons (BAUS) has produced training standards. Clinicians should submit data on all patients undergoing this procedure to the BAUS Cancer Registry & Sections Audit with a view to further publication on long-term survival outcomes.# The procedure # Indications and current treatments For most bladder cancer patients, the treatment will depend on whether or not the tumour has invaded the bladder's muscular layer. Tumours invading the muscular layer (as well as some 'high-risk', non-invading tumours) are usually treated by radical cystectomy or radiotherapy. When radical cystectomy is used reconstructive surgery is also required. Laparoscopic cystectomy is an alternative to radical cystectomy by open surgery. # Outline of the procedure Laparoscopic cystectomy is carried out with the patient under general anaesthesia. The abdomen is insufflated with carbon dioxide and small incisions are made to allow the introduction of a laparoscope and surgical instruments. The ureters are isolated, ligated and divided and the vascular pedicles to the bladder are ligated, transected and stapled. In men the prostate and seminal vesicles are dissected and removed with the bladder, and retrieved through an abdominal incision. In women, depending on the tumour burden and stage, the uterus and part of the vagina may need to be removed. Sometimes the ovaries are also removed. Urinary diversion or formation of a neo bladder can be done laparoscopically or, more commonly, by an open procedure. There are various ways of carrying out laparoscopic cystectomy and the procedure may be performed with computer (robotic) assistance. Sections 2.3 and 2.4 describe efficacy and safety outcomes which were available in the published literature and which the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview. # Efficacy A non-randomised comparative study of 65 patients reported a recurrence-free survival of 77% (23/30) for laparoscopic cystectomy compared with 80% (28/35) for open cystectomy at mean follow-up periods of 38 months and 46 months, respectively (p = 0.2). A non-randomised comparative study of 42 patients reported no disease-related deaths in the 20 patients treated by laparoscopic surgery compared with 5% (1/21) of patients in the open cystectomy group during a mean follow-up of 19.5 months and 19 months, respectively (p value not significant). A case series of 84 patients reported a disease-free survival of 83% (70/84) at a mean follow-up of 18 months. The study of 65 patients reported a lower mean requirement for analgesia in the laparoscopic group than in the open cystectomy group (32 mg and 65 mg % morphine equivalent, respectively; p = 0.001). The study of 42 patients reported a mean requirement for non-opioid analgesics of 2.2 vials/day in the laparoscopic group compared with 3.9 vials/day in the open cystectomy group (p < 0.05). The Specialist Advisers considered that key efficacy outcomes included need for blood transfusion, time to discharge, requirement for analgesia, time to return to full activity, histology clear margin rates, extent of lymph node dissection and cancer-specific 5-year survival. One stated that the procedure has not been performed for long enough or in sufficient numbers to be able to evaluate the incidence of local recurrence of cancer or subsequent metastases. # Safety Conversion to open surgery was reported in 5% (1/20) and 3% (1/33) of patients in two non-randomised controlled trials, and 0% (0/84) and 2% (2/83) in two case series. Fistulae (including vaginal, urinary and enterovesical) were reported in 1% (1/83), 2% (2/84), 3% (1/33) and 8% (1/13) of patients in the two case series of 83 and 84 patients, the non-randomised controlled trial of 54 patients comparing open cystectomy with robotically assisted cystectomies, and a further non-randomised controlled trial of 37 patients, respectively. Rectal injury was reported in 5% (1/20) and 3% (1/30) of patients in the non-randomised controlled trials of 44 and 65 patients, respectively. Other complications included abdominal abscess (8% ), percutaneous drainage of abscess (3% ), injury to artery (1% ), urinary leakage (1% ), urinary tract infection (10% ) and haematoma (4% ). There was a case report of port site metastasis in a patient 10 months after laparoscopic cystectomy; the patient was reported to have high-grade, high-stage transitional cell carcinoma. One Specialist Adviser considered that theoretical adverse events included difficulty controlling haemorrhage, bowel injury or obstruction, inadequate cancer clearance and port site metastasis. The Specialist Advisers stated that anecdotal adverse events include bowel fistula, peritonitis and prolonged operative time. One Adviser stated that the laparoscopic technique may not allow as radical an excision as open surgery, particularly for lymph nodes. # Other comments The Committee noted that the published evidence on laparoscopic cystectomy was in patients with bladder cancer. There may be other patients for whom the procedure might be beneficial: they should be referred by the specialist teams caring for them to units with experience in case selection and use of laparoscopic cystectomy (see 1.2 and 1.3). The Committee noted that most surgeons had stopped doing bladder reconstruction laparoscopically as part of this procedure.# Further information NICE has issued cancer service guidance on urological cancers. # Information for patients NICE has produced information on this procedure for patients and carers ('Understanding NICE guidance'). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.# About this guidance NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland. This guidance was developed using the NICE interventional procedure guidance process. It updates and replaces NICE interventional procedure guidance 26. We have produced a summary of this guidance for patients and carers. Information about the evidence it is based on is also available. Changes since publication January 2012: minor maintenance. Your responsibility This guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer. Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties. Copyright © National Institute for Health and Clinical Excellence 2009. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE. Contact NICE National Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT www.nice.org.uk nice@nice.org.uk	{'Guidance': 'This document replaces previous guidance on laparoscopic cystectomy (Interventional Procedure Guidance 26).\n\nCurrent evidence on the safety and efficacy of laparoscopic cystectomy appears adequate to support the use of this procedure provided that normal arrangements are in place for clinical governance, consent and audit.\n\nPatient selection for laparoscopic cystectomy should involve a multidisciplinary team experienced in the management of bladder cancer.\n\nClinicians undertaking laparoscopic cystectomy should have special training. The British Association of Urological Surgeons (BAUS) has produced training standards.\n\nClinicians should submit data on all patients undergoing this procedure to the BAUS Cancer Registry & Sections Audit with a view to further publication on long-term survival outcomes.', 'The procedure': "# Indications and current treatments\n\nFor most bladder cancer patients, the treatment will depend on whether or not the tumour has invaded the bladder's muscular layer. Tumours invading the muscular layer (as well as some 'high-risk', non-invading tumours) are usually treated by radical cystectomy or radiotherapy. When radical cystectomy is used reconstructive surgery is also required. Laparoscopic cystectomy is an alternative to radical cystectomy by open surgery.\n\n# Outline of the procedure\n\nLaparoscopic cystectomy is carried out with the patient under general anaesthesia. The abdomen is insufflated with carbon dioxide and small incisions are made to allow the introduction of a laparoscope and surgical instruments. The ureters are isolated, ligated and divided and the vascular pedicles to the bladder are ligated, transected and stapled.\n\nIn men the prostate and seminal vesicles are dissected and removed with the bladder, and retrieved through an abdominal incision. In women, depending on the tumour burden and stage, the uterus and part of the vagina may need to be removed. Sometimes the ovaries are also removed.\n\nUrinary diversion or formation of a neo bladder can be done laparoscopically or, more commonly, by an open procedure.\n\nThere are various ways of carrying out laparoscopic cystectomy and the procedure may be performed with computer (robotic) assistance.\n\nSections 2.3 and 2.4 describe efficacy and safety outcomes which were available in the published literature and which the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview.\n\n# Efficacy\n\nA non-randomised comparative study of 65 patients reported a recurrence-free survival of 77% (23/30) for laparoscopic cystectomy compared with 80% (28/35) for open cystectomy at mean follow-up periods of 38 months and 46 months, respectively (p = 0.2). A non-randomised comparative study of 42 patients reported no disease-related deaths in the 20 patients treated by laparoscopic surgery compared with 5% (1/21) of patients in the open cystectomy group during a mean follow-up of 19.5 months and 19 months, respectively (p value not significant). A case series of 84 patients reported a disease-free survival of 83% (70/84) at a mean follow-up of 18 months.\n\nThe study of 65 patients reported a lower mean requirement for analgesia in the laparoscopic group than in the open cystectomy group (32 mg and 65 mg % morphine equivalent, respectively; p = 0.001). The study of 42 patients reported a mean requirement for non-opioid analgesics of 2.2 vials/day in the laparoscopic group compared with 3.9 vials/day in the open cystectomy group (p < 0.05).\n\nThe Specialist Advisers considered that key efficacy outcomes included need for blood transfusion, time to discharge, requirement for analgesia, time to return to full activity, histology clear margin rates, extent of lymph node dissection and cancer-specific 5-year survival. One stated that the procedure has not been performed for long enough or in sufficient numbers to be able to evaluate the incidence of local recurrence of cancer or subsequent metastases.\n\n# Safety\n\nConversion to open surgery was reported in 5% (1/20) and 3% (1/33) of patients in two non-randomised controlled trials, and 0% (0/84) and 2% (2/83) in two case series.\n\nFistulae (including vaginal, urinary and enterovesical) were reported in 1% (1/83), 2% (2/84), 3% (1/33) and 8% (1/13) of patients in the two case series of 83 and 84 patients, the non-randomised controlled trial of 54 patients comparing open cystectomy with robotically assisted cystectomies, and a further non-randomised controlled trial of 37 patients, respectively. Rectal injury was reported in 5% (1/20) and 3% (1/30) of patients in the non-randomised controlled trials of 44 and 65 patients, respectively. Other complications included abdominal abscess (8% [1/13]), percutaneous drainage of abscess (3% [1/33]), injury to artery (1% [1/84]), urinary leakage (1% [1/83]), urinary tract infection (10% [8/84]) and haematoma (4% [3/84]).\n\nThere was a case report of port site metastasis in a patient 10 months after laparoscopic cystectomy; the patient was reported to have high-grade, high-stage transitional cell carcinoma.\n\nOne Specialist Adviser considered that theoretical adverse events included difficulty controlling haemorrhage, bowel injury or obstruction, inadequate cancer clearance and port site metastasis. The Specialist Advisers stated that anecdotal adverse events include bowel fistula, peritonitis and prolonged operative time. One Adviser stated that the laparoscopic technique may not allow as radical an excision as open surgery, particularly for lymph nodes.\n\n# Other comments\n\nThe Committee noted that the published evidence on laparoscopic cystectomy was in patients with bladder cancer. There may be other patients for whom the procedure might be beneficial: they should be referred by the specialist teams caring for them to units with experience in case selection and use of laparoscopic cystectomy (see 1.2 and 1.3).\n\nThe Committee noted that most surgeons had stopped doing bladder reconstruction laparoscopically as part of this procedure.", 'Further information': "NICE has issued cancer service guidance on urological cancers.\n\n# Information for patients\n\nNICE has produced information on this procedure for patients and carers ('Understanding NICE guidance'). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.", 'About this guidance': 'NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland.\n\nThis guidance was developed using the NICE interventional procedure guidance process.\n\nIt updates and replaces NICE interventional procedure guidance 26.\n\nWe have produced a summary of this guidance for patients and carers. Information about the evidence it is based on is also available.\n\nChanges since publication\n\nJanuary 2012: minor maintenance.\n\nYour responsibility\n\nThis guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.\n\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.\n\nCopyright\n\n© National Institute for Health and Clinical Excellence 2009. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.\n\nContact NICE\n\nNational Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT\n\nwww.nice.org.uk\n \n nice@nice.org.uk\n 0845 033 7780'}	https://www.nice.org.uk/guidance/ipg287
e63d8ac986f11fdaf328df9875982cfd8fb54691	nice	Extracorporeal photopheresis for Crohn's disease	Extracorporeal photopheresis for Crohn's disease Evidence-based recommendations on extracorporeal photopheresis for Crohn's disease. This involves collecting blood from the person, separating the white blood cells from the whole blood, treating with ultraviolet light and re-infusing into the person. The aim is to produce a generalised immune response against the cells that cause the inflammation. # Guidance Current evidence on extracorporeal photopheresis (ECP) for Crohn's disease is based on reports that include a very small number of patients. These reports describe no major safety issues but they provide little evidence of efficacy. Therefore, this procedure should not be used outside the context of research.# The procedure # Indications and current treatments Crohn's disease is a chronic inflammatory disorder that can affect any part of the gastrointestinal tract from the mouth to the anus, but most commonly causes inflammation and ulceration of the ileum and the colon. It may cause the intestine to develop fistulae to the bowel or skin, or strictures causing narrowing of the bowel. Symptoms of Crohn's disease include diarrhoea, weight loss, rectal bleeding and fever. Complications may include rectal abscesses and joint disease. Some people with Crohn's disease have long periods of symptom-free remission. Disease severity is assessed using the Crohn's Disease Activity Index (CDAI), which ranges from 0 to 600 (a score lower than 150 indicates inactive disease; above 450 represents severe, active disease). Conservative treatment includes dietary measures and drug therapy. Corticosteroids and immunosuppressive agents are used with the aim of controlling inflammation and other symptoms, and reducing relapse. Surgical removal of the affected bowel is sometimes necessary but this is not curative as the disease can recur in other sites. # Outline of the procedure Extracorporeal photopheresis involves drawing blood from the patient via a peripheral line. The leukocyte-containing buffy coat cells, which include mononuclear cells (one subgroup of which is the T-cells that are thought to be involved in Crohn's disease) and platelets are separated from the red blood cells. The red blood cells and the remaining plasma are then returned to the patient via the same indwelling catheter. A photosensitive drug (8-methoxypsoralen) and an anticoagulant are added to the buffy coat cells, which are then passed through a sterile chamber and irradiated with ultraviolet light to activate the drug. The activated drug binds to the DNA in the buffy coat cells, arresting cell proliferation and initiating changes that lead to cell death. The buffy coat cells are then returned to the patient. These re-infused dying cells produce a generalised immune response against the pathogenic T-cell clones that are involved in the pathogenesis of inflammation in Crohn's disease. Extracorporeal photopheresis is usually carried out over 2 consecutive days at intervals of 2–4 weeks for about 20 treatment sessions. One ECP session takes about 3–4 hours. Sections 2.3 and 2.4 describe efficacy and safety outcomes which were available in the published literature and which the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview. # Efficacy In a case series of 28 patients (some refractory or intolerant to immunosuppressants or anti-tumour necrosis factor alfa agents) treated by ECP, 50% (14/28) of patients reported a clinical response and 25% (7/28) were in remission at 12-week follow-up. In a case series of 10 patients, a response (defined as a 50% reduction in steroid use) was seen in 8 patients (median follow-up of 10 weeks), with remission in 4 patients (defined by a CDAI score lower than 150 at median follow-up of 20 weeks). Three of the 4 patients remained in remission at the end of the follow-up period (mean 16.5 weeks, range 4–20 weeks). In the case series of 28 patients the mean Inflammatory Bowel Disease Questionnaire score improved from 122 points at baseline to 154 points at 12-week follow-up (scoring system not defined) (p < 0.001). The Specialist Advisers stated that key efficacy outcomes for this procedure included improved quality of life, reduction of bowel motion frequency and abdominal cramps, reduced steroid use and reduction in inflammatory markers such as faecal calprotectin. # Safety In the case series of 28 patients, 7% (2/28) of patients discontinued treatment because of adverse events. One patient had nausea and malaise, and one patient had increased C-reactive protein concentration and fever. Headaches and nasopharyngitis occurred in 29% (8/28) of patients, and nausea occurred in 18% (5/28) of patients. Adverse events that followed the procedure in the case series of 10 patients and two case series each of 2 patients included two instances of asymptomatic hypotension, one of mild headache and one of a small haematoma at the infusion site. One patient developed monoclonal gammopathy. Worsening of anaemia following the procedure was reported in 3 patients. The Specialist Advisers stated that published and anecdotal adverse events following this procedure include vasovagal episodes such as hypotension and fits, light sensitivity or allergy to the photoactivating agent, anaemia and central venous line infection. They added that theoretical adverse events include haemorrhage caused by heparin use and malignancy from light exposure.# Further information NICE has produced interventional procedures guidance on leukapheresis for inflammatory bowel disease and technology appraisals guidance on infliximab for Crohn's disease. # Information for patients NICE has produced information on this procedure for patients and carers ('Understanding NICE guidance'). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.# About this guidance NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland. This guidance was developed using the NICE interventional procedure guidance process. We have produced a summary of this guidance for patients and carers. Information about the evidence it is based on is also available. Changes since publication January 2012: minor maintenance. Your responsibility This guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer. Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties. Copyright © National Institute for Health and Clinical Excellence 2009. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE. Contact NICE National Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT www.nice.org.uk nice@nice.org.uk	{'Guidance ': "Current evidence on extracorporeal photopheresis (ECP) for Crohn's disease is based on reports that include a very small number of patients. These reports describe no major safety issues but they provide little evidence of efficacy. Therefore, this procedure should not be used outside the context of research.", 'The procedure': "# Indications and current treatments\n\nCrohn's disease is a chronic inflammatory disorder that can affect any part of the gastrointestinal tract from the mouth to the anus, but most commonly causes inflammation and ulceration of the ileum and the colon. It may cause the intestine to develop fistulae to the bowel or skin, or strictures causing narrowing of the bowel. Symptoms of Crohn's disease include diarrhoea, weight loss, rectal bleeding and fever. Complications may include rectal abscesses and joint disease. Some people with Crohn's disease have long periods of symptom-free remission.\n\nDisease severity is assessed using the Crohn's Disease Activity Index (CDAI), which ranges from 0 to 600 (a score lower than 150 indicates inactive disease; above 450 represents severe, active disease).\n\nConservative treatment includes dietary measures and drug therapy. Corticosteroids and immunosuppressive agents are used with the aim of controlling inflammation and other symptoms, and reducing relapse. Surgical removal of the affected bowel is sometimes necessary but this is not curative as the disease can recur in other sites.\n\n# Outline of the procedure\n\nExtracorporeal photopheresis involves drawing blood from the patient via a peripheral line. The leukocyte-containing buffy coat cells, which include mononuclear cells (one subgroup of which is the T-cells that are thought to be involved in Crohn's disease) and platelets are separated from the red blood cells. The red blood cells and the remaining plasma are then returned to the patient via the same indwelling catheter.\n\nA photosensitive drug (8-methoxypsoralen) and an anticoagulant are added to the buffy coat cells, which are then passed through a sterile chamber and irradiated with ultraviolet light to activate the drug. The activated drug binds to the DNA in the buffy coat cells, arresting cell proliferation and initiating changes that lead to cell death.\n\nThe buffy coat cells are then returned to the patient. These re-infused dying cells produce a generalised immune response against the pathogenic T-cell clones that are involved in the pathogenesis of inflammation in Crohn's disease.\n\nExtracorporeal photopheresis is usually carried out over 2 consecutive days at intervals of 2–4 weeks for about 20 treatment sessions. One ECP session takes about 3–4 hours.\n\nSections 2.3 and 2.4 describe efficacy and safety outcomes which were available in the published literature and which the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview.\n\n# Efficacy\n\nIn a case series of 28 patients (some refractory or intolerant to immunosuppressants or anti-tumour necrosis factor alfa agents) treated by ECP, 50% (14/28) of patients reported a clinical response and 25% (7/28) were in remission at 12-week follow-up. In a case series of 10 patients, a response (defined as a 50% reduction in steroid use) was seen in 8 patients (median follow-up of 10 weeks), with remission in 4 patients (defined by a CDAI score lower than 150 at median follow-up of 20 weeks). Three of the 4 patients remained in remission at the end of the follow-up period (mean 16.5 weeks, range 4–20 weeks).\n\nIn the case series of 28 patients the mean Inflammatory Bowel Disease Questionnaire score improved from 122 points at baseline to 154 points at 12-week follow-up (scoring system not defined) (p < 0.001).\n\nThe Specialist Advisers stated that key efficacy outcomes for this procedure included improved quality of life, reduction of bowel motion frequency and abdominal cramps, reduced steroid use and reduction in inflammatory markers such as faecal calprotectin.\n\n# Safety\n\nIn the case series of 28 patients, 7% (2/28) of patients discontinued treatment because of adverse events. One patient had nausea and malaise, and one patient had increased C-reactive protein concentration and fever. Headaches and nasopharyngitis occurred in 29% (8/28) of patients, and nausea occurred in 18% (5/28) of patients.\n\nAdverse events that followed the procedure in the case series of 10 patients and two case series each of 2 patients included two instances of asymptomatic hypotension, one of mild headache and one of a small haematoma at the infusion site. One patient developed monoclonal gammopathy. Worsening of anaemia following the procedure was reported in 3 patients.\n\nThe Specialist Advisers stated that published and anecdotal adverse events following this procedure include vasovagal episodes such as hypotension and fits, light sensitivity or allergy to the photoactivating agent, anaemia and central venous line infection. They added that theoretical adverse events include haemorrhage caused by heparin use and malignancy from light exposure.", 'Further information': "NICE has produced interventional procedures guidance on leukapheresis for inflammatory bowel disease and technology appraisals guidance on infliximab for Crohn's disease.\n\n# Information for patients\n\nNICE has produced information on this procedure for patients and carers ('Understanding NICE guidance'). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.", 'About this guidance': 'NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland.\n\nThis guidance was developed using the NICE interventional procedure guidance process.\n\nWe have produced a summary of this guidance for patients and carers. Information about the evidence it is based on is also available.\n\nChanges since publication\n\nJanuary 2012: minor maintenance.\n\nYour responsibility\n\nThis guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.\n\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.\n\nCopyright\n\n© National Institute for Health and Clinical Excellence 2009. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.\n\nContact NICE\n\nNational Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT\n\nwww.nice.org.uk\n \n nice@nice.org.uk\n 0845 033 7780'}	https://www.nice.org.uk/guidance/ipg288	Evidence-based recommendations on extracorporeal photopheresis for Crohn's disease. This involves collecting blood from the person, separating the white blood cells from the whole blood, treating with ultraviolet light and re-infusing into the person. The aim is to produce a generalised immune response against the cells that cause the inflammation.
92ca1fe40e182a39bd27394db06e1a6f47a3c26a	nice	Intraocular lens insertion for correction of refractive error, with preservation of the natural lens	Intraocular lens insertion for correction of refractive error, with preservation of the natural lens # Guidance Current evidence on intraocular lens (IOL) insertion for correction of refractive error, with preservation of the natural lens is available for large numbers of patients. There is good evidence of short-term safety and efficacy. However, there is an increased risk of cataract, corneal damage or retinal detachment and there are no long-term data about this. Therefore, the procedure may be used with normal arrangements for clinical governance and audit, but with special arrangements for consent. Clinicians wishing to undertake IOL insertion for correction of refractive error, with preservation of the natural lens should ensure that patients understand the risks of having an artificial lens implanted for visual impairment that might otherwise be corrected using spectacles or contact lenses. They should understand the possibility of cataract, corneal damage or retinal detachment, and the lack of evidence relating to long-term outcomes. Patients should be provided with clear information. In addition, the use of NICE's information for patients ('Understanding NICE guidance') is recommended. Both clinicians and manufacturers are encouraged to collect long-term data on people who undergo IOL insertion, and to publish their findings. NICE may review the procedure on publication of further evidence.# The procedure # Indications and current treatments There are several types of refractive error including myopia, hypermetropia and presbyopia. Refractive errors can usually be corrected by wearing spectacles or contact lenses. Surgical treatments include photorefractive keratectomy (PRK), laser in situ keratomileusis (LASIK) and insertion of corneal implants. The procedure may be indicated for people with a high degree of myopia, or those for whom wearing spectacles is difficult, for example because of a disability or professional requirements. # Outline of the procedure The procedure is carried out with the patient under local anaesthesia. The pupil is dilated using topical medication, and a phakic IOL is inserted into the anterior or the posterior eye chamber via a small corneal incision. Depending on its design, the phakic IOL is anchored to the iris, placed in the angle between the cornea and the iris, or positioned to float over the surface of the natural lens. A nylon suture is sometimes used to close the incision. Several different devices can be used for this procedure. Sections 2.3 and 2.4 describe efficacy and safety outcomes which were available in the published literature and which the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview. # Efficacy In a randomised controlled trial (RCT) of 50 eyes (with the fellow eye as control), mean Manifest Refraction Spherical Equivalent (MRSE) was –0.95 ± 0.45 D in phakic IOL-treated eyes and –0.74 ± 0.67 D in LASIK-treated eyes at 1-year follow-up (p not significant). A non-RCT of 9239 eyes reported that mean post-procedural MRSE was –1.78 ± 2.03 D in phakic IOL-treated eyes, 0.36 ± 1.30 D in LASIK-treated eyes and –0.18 ± 0.5 D in PRK-treated eyes (level of significance not stated). In a non-RCT of 769 eyes, correction to within 0.5 D of that intended was achieved in 69% (127/184) of phakic IOL-treated eyes and 57% (57/100) of LASIK-treated eyes at 1-year follow-up (p = 0.05). A case series of 1140 phakic IOL-treated eyes reported that the proportion of eyes with uncorrected visual acuity (UCVA) of 20/20 or better increased from 0% (0/622) at baseline to 27% (62/231) at 3-year follow-up (significance not stated). The Specialist Advisers stated that the key efficacy outcomes for this procedure include improvements in UCVA and best spectacle-corrected visual acuity (BSCVA), independence from optical aids and maintenance of quality of vision. # Safety In a non-RCT of 9239 eyes, retinal detachment was reported in 4% (12/294) of phakic IOL-treated eyes, less than 1% (11/3009) of LASIK-treated eyes and less than 1% (9/5936) of PRK-treated eyes (retinal detachments occurred after a mean of 20.5, 24.6 and 53.6 months, respectively). A meta-analysis of 6338 eyes reported new-onset cataract development in 1% (15/1161) of eyes treated with angle-fixed anterior chamber IOL, less than 1% (20/2781) of eyes treated with iris-fixed anterior chamber IOL, and 9% (223/2396) of eyes treated with posterior chamber IOL (median follow-up 1 year). Anterior subcapsular cataract was reported in 2% (1/43) of toric phakic IOL-treated eyes in an RCT of 88 eyes at 2-year follow-up. A case series of 399 eyes reported that explantation because of endothelial cell loss was necessary in 1% (3/399) of eyes (mean follow-up 4 years). In the same study, mean endothelial cell density decreased significantly from 2836 ± 398 cells/mm2 at baseline to 2791 ± 246 cells/mm2 4 years after insertion of a phakic IOL (p = 0.004), and from 2755 ± 362 cells/mm2 to 2698 ± 576 cells/mm2 after insertion of a second type of phakic IOL at the same timepoint (p = 0.002). A case series of 263 eyes implanted with a phakic IOL reported halo and glare symptoms in 60% (157/263) of treated eyes at 1-year follow-up (reported as 'significant' in 21% ). The Specialist Advisers stated that key safety outcomes include glaucoma, loss of lines of BSCVA, reduced contrast sensitivity, night vision disturbances and the need for additional refractive surgery.# Further information Clinicians must report any instances of intraocular lens removal because of adverse events to the Medicines and Healthcare products Regulatory Agency (MHRA). NICE has published interventional procedures guidance on several procedures relating to refractive error and IOL insertion. For more information see our website. # Information for patients NICE has produced information on this procedure for patients and carers ('Understanding NICE guidance'). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.# About this guidance NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland. This guidance was developed using the NICE interventional procedure guidance process. We have produced a summary of this guidance for patients and carers. Information about the evidence it is based on is also available. Changes since publication January 2012: minor maintenance. Your responsibility This guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer. Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties. Copyright © National Institute for Health and Clinical Excellence 2009. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE. Contact NICE National Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT www.nice.org.uk nice@nice.org.uk	{'Guidance ': "Current evidence on intraocular lens (IOL) insertion for correction of refractive error, with preservation of the natural lens is available for large numbers of patients. There is good evidence of short-term safety and efficacy. However, there is an increased risk of cataract, corneal damage or retinal detachment and there are no long-term data about this. Therefore, the procedure may be used with normal arrangements for clinical governance and audit, but with special arrangements for consent.\n\nClinicians wishing to undertake IOL insertion for correction of refractive error, with preservation of the natural lens should ensure that patients understand the risks of having an artificial lens implanted for visual impairment that might otherwise be corrected using spectacles or contact lenses. They should understand the possibility of cataract, corneal damage or retinal detachment, and the lack of evidence relating to long-term outcomes. Patients should be provided with clear information. In addition, the use of NICE's information for patients ('Understanding NICE guidance') is recommended.\n\nBoth clinicians and manufacturers are encouraged to collect long-term data on people who undergo IOL insertion, and to publish their findings. NICE may review the procedure on publication of further evidence.", 'The procedure': "# Indications and current treatments\n\nThere are several types of refractive error including myopia, hypermetropia and presbyopia.\n\nRefractive errors can usually be corrected by wearing spectacles or contact lenses. Surgical treatments include photorefractive keratectomy (PRK), laser in situ keratomileusis (LASIK) and insertion of corneal implants.\n\nThe procedure may be indicated for people with a high degree of myopia, or those for whom wearing spectacles is difficult, for example because of a disability or professional requirements.\n\n# Outline of the procedure\n\nThe procedure is carried out with the patient under local anaesthesia. The pupil is dilated using topical medication, and a phakic IOL is inserted into the anterior or the posterior eye chamber via a small corneal incision. Depending on its design, the phakic IOL is anchored to the iris, placed in the angle between the cornea and the iris, or positioned to float over the surface of the natural lens. A nylon suture is sometimes used to close the incision.\n\nSeveral different devices can be used for this procedure.\n\nSections 2.3 and 2.4 describe efficacy and safety outcomes which were available in the published literature and which the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview.\n\n# Efficacy\n\nIn a randomised controlled trial (RCT) of 50 eyes (with the fellow eye as control), mean Manifest Refraction Spherical Equivalent (MRSE) was –0.95 ± 0.45 D in phakic IOL-treated eyes and –0.74 ± 0.67 D in LASIK-treated eyes at 1-year follow-up (p not significant). A non-RCT of 9239 eyes reported that mean post-procedural MRSE was –1.78 ± 2.03 D in phakic IOL-treated eyes, 0.36 ± 1.30 D in LASIK-treated eyes and –0.18 ± 0.5 D in PRK-treated eyes (level of significance not stated).\n\nIn a non-RCT of 769 eyes, correction to within 0.5 D of that intended was achieved in 69% (127/184) of phakic IOL-treated eyes and 57% (57/100) of LASIK-treated eyes at 1-year follow-up (p = 0.05).\n\nA case series of 1140 phakic IOL-treated eyes reported that the proportion of eyes with uncorrected visual acuity (UCVA) of 20/20 or better increased from 0% (0/622) at baseline to 27% (62/231) at 3-year follow-up (significance not stated).\n\nThe Specialist Advisers stated that the key efficacy outcomes for this procedure include improvements in UCVA and best spectacle-corrected visual acuity (BSCVA), independence from optical aids and maintenance of quality of vision.\n\n# Safety\n\nIn a non-RCT of 9239 eyes, retinal detachment was reported in 4% (12/294) of phakic IOL-treated eyes, less than 1% (11/3009) of LASIK-treated eyes and less than 1% (9/5936) of PRK-treated eyes (retinal detachments occurred after a mean of 20.5, 24.6 and 53.6 months, respectively).\n\nA meta-analysis of 6338 eyes reported new-onset cataract development in 1% (15/1161) of eyes treated with angle-fixed anterior chamber IOL, less than 1% (20/2781) of eyes treated with iris-fixed anterior chamber IOL, and 9% (223/2396) of eyes treated with posterior chamber IOL (median follow-up 1 year). Anterior subcapsular cataract was reported in 2% (1/43) of toric phakic IOL-treated eyes in an RCT of 88 eyes at 2-year follow-up.\n\nA case series of 399 eyes reported that explantation because of endothelial cell loss was necessary in 1% (3/399) of eyes (mean follow-up 4 years). In the same study, mean endothelial cell density decreased significantly from 2836 ± 398 cells/mm2 at baseline to 2791 ± 246 cells/mm2 4 years after insertion of a phakic IOL (p = 0.004), and from 2755 ± 362 cells/mm2 to 2698 ± 576 cells/mm2 after insertion of a second type of phakic IOL at the same timepoint (p = 0.002).\n\nA case series of 263 eyes implanted with a phakic IOL reported halo and glare symptoms in 60% (157/263) of treated eyes at 1-year follow-up (reported as 'significant' in 21% [54/263]).\n\nThe Specialist Advisers stated that key safety outcomes include glaucoma, loss of lines of BSCVA, reduced contrast sensitivity, night vision disturbances and the need for additional refractive surgery.", 'Further information': "Clinicians must report any instances of intraocular lens removal because of adverse events to the Medicines and Healthcare products Regulatory Agency (MHRA).\n\nNICE has published interventional procedures guidance on several procedures relating to refractive error and IOL insertion. For more information see our website.\n\n# Information for patients\n\nNICE has produced information on this procedure for patients and carers ('Understanding NICE guidance'). It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.", 'About this guidance': 'NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland.\n\nThis guidance was developed using the NICE interventional procedure guidance process.\n\nWe have produced a summary of this guidance for patients and carers. Information about the evidence it is based on is also available.\n\nChanges since publication\n\nJanuary 2012: minor maintenance.\n\nYour responsibility\n\nThis guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.\n\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.\n\nCopyright\n\n© National Institute for Health and Clinical Excellence 2009. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.\n\nContact NICE\n\nNational Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT\n\nwww.nice.org.uk\n \n nice@nice.org.uk\n 0845 033 7780'}	https://www.nice.org.uk/guidance/ipg289
d372949f826e98519b74067f8dbb26e669117390	nice	Physical activity for children and young people	Physical activity for children and young people This guideline covers promoting physical activity for children and young people aged under 18 at home, preschool, school and in the community. It includes raising awareness of the benefits of physical activity, listening to what children and young people want, planning and providing spaces and facilities, and helping families build physical activity into their daily lives. # Introduction The Department of Health (DH) asked NICE to produce public health guidance on physical activity, play and sport for pre-school and school-age children in family, pre-school, school and community settings. The guidance is for all those who have a direct or indirect role in – and responsibility for – promoting physical activity for children and young people. This includes those working in the NHS, education, local authorities and the wider public, private, voluntary and community sectors. It will also be of interest to parents, grandparents and other carers (including professional carers), children and young people and other members of the public. It includes recommendations for schools, but does not make recommendations for the national curriculum. The recommendations relate to all children and young people up to the age of 18, including those with a medical condition or disability (except where clinical assessment or monitoring is required prior to and/or during physical activity). The guidance does not cover specialised services for children and young people with a disability. There is a specific focus on children aged 11 and under and girls aged 11 to 18. The guidance complements and supports, but does not replace, NICE guidance on obesity, physical activity, physical activity and the environment, depression among children and young people and social and emotional wellbeing in schools. The Programme Development Group (PDG) developed these recommendations on the basis of reviews of the evidence, an economic analysis, expert advice, stakeholder comments and fieldwork. Members of the PDG are listed in appendix A. The methods used to develop the guidance are summarised in appendix B. Supporting documents used to prepare this document are listed in appendix E. Full details of the evidence collated, including fieldwork data and activities and stakeholder comments, along with a list of the stakeholders involved and NICE's supporting process and methods manuals are also available.# Recommendations People have the right to be involved in discussions and make informed decisions about their care, as described in making decisions about your care. Making decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding. # Definitions Physical activity is 'any force exerted by skeletal muscle that results in energy expenditure above resting level' (Caspersen et al. 1985). The recommendations refer to opportunities for moderate to vigorous-intensity physical activity in children and young people. The UK recommendations on the type, intensity and duration of activity should be accessed (see the UK Chief Medical Officers' physical activity guidelines for more information). Moderate-intensity activity increases breathing and heart rates to a level where the pulse can be felt and the person feels warmer. It might make someone sweat on a hot or humid day (or when indoors). Vigorous activity results in being out of breath or sweating. Opportunities for moderate to vigorous physical activity include everything from competitive sport and formal exercise to active play and other physically demanding activities (such as dancing, swimming or skateboarding). They also include some of the actions that can be involved in daily life (such as walking, cycling or using other modes of travel involving physical activity). # Groupings, themes and links The recommendations are grouped as follows: national policy high level policy and strategy local strategic planning local organisations: planning, delivery and training local practitioners: delivery. There are a number of key themes: Promoting the benefits of physical activity and encouraging participation (recommendations 1 and 15) Ensuring high-level strategic policy planning for children and young people supports the physical activity agenda (recommendation 2) Consultation with, and the active involvement of, children and young people (recommendations 3, 6,11 and 14) The planning and provision of spaces, facilities and opportunities (recommendations 2, 4, 9, 10 and 13) The need for a skilled workforce (recommendations 7 and 8) Promoting physically active and sustainable travel (recommendations 5 and 12) The diagram below shows the structure of, and the links between, the 15 recommendations. # Who should take action? The recommendations are aimed at the following organisations and groups although each organisation and group should be aware of all the recommendations and the links between them: Children's trusts and services: 2, 4, 6, 7, 10, 13 Community and voluntary groups (such as those running sports and other organised activities): 3, 6 to 11, 13 to 15 Early years providers: 4, 10, 12, 13, 15 Government departments: 1 Local authorities (leisure and related services): 2 to 4, 6 to 15 Local authorities (transport and planning, regeneration): 2 to 5, 12 Local strategic partnerships: 2, 3 Organisations offering practitioners education and training: 7, 8 Parents, families and carers: 13, 15 Police: 4, 5 Primary care trusts: 2 to 4, 6, 9, 15 Private sector providers: 4, 6 to 11, 13 to 15 Schools and colleges: 4 to 7, 9 to 15. All the organisations, groups and people listed under 'Who should take action?' in each recommendation are equally responsible for ensuring the recommendation is put into practice. # The recommendations ## National policy Who is the target population? Children and young people aged 18 and under, their families and carers. Planners and providers of services and facilities. Who should take action? Department of Health, Department for Children, Schools and Families and Department for Culture, Media and Sport working with: Department for Business, Enterprise and Regulatory Reform Department for Communities and Local Government Department for Energy and Climate Change Department for Environment, Food and Rural Affairs Department for Innovation, Universities & Skills Department for Transport Cabinet Office Home Office Ministry of Justice. What action should they take? Deliver a long-term (minimum 5 years) national campaign to promote physical activity among children and young people. The campaign should be integrated with and support other national health campaigns and strategies to increase participation in play and sport and reduce obesity (such as 'Change4Life'). Use research, consult and actively involve children and young people and their parents to determine the best media to use, the most effective messages and the most appropriate language for different groups. (Examples of different groups that could be covered include families, parents and carers, and children of different ages, ethnicity and who have different levels of physical ability.) Ensure the campaign is consistent and sustained. It should convey that physical activity: is healthy, fun and enjoyable, makes you feel good and can be sociable (that is, it can be undertaken with existing friends or can help develop new ones) promotes children and young people's independence helps develop children's movement skills can involve a wide variety of formal and informal activities such as play, dance, swimming, the gym, sport (including street sport and games) and physically active travel (such as walking, cycling and wheelchair travel) can (and should) become a regular part of daily life and that small lifestyle changes can be worthwhile (for example, active travel to school, the shops or the park, using the stairs and ramps instead of lifts and helping with housework) can be maintained by trying new and challenging activities to keep children and young people interested and motivated is something that adults, especially parents and carers, should incorporate into their lives to set an example. Ensure the campaign addresses any concerns that parents and carers may have about their children's safety. Encourage regional and local campaigns to use the same messages, as well as promoting examples of local opportunities to be physically active. Develop resources for regional and local dissemination of the campaign (for example, promotional materials and support for those delivering it). (For more on training see recommendation 8.) Use process, impact and outcome measures to ensure national, regional and local campaigns are delivered effectively. For recommendations on the principles of evaluation, see NICE's guideline on behaviour change: general approaches. ## High level policy and strategy Who is the target population? Children and young people aged 18 and under, their families and carers. Who should take action? Chairs of local strategic partnerships. Directors of children's services. Directors of public health. What action should they take? Ensure the following explicitly address the need for children and young people to be physically active: children and young people's plans joint strategic needs assessments local development and planning frameworks sustainable community plans and strategies. Ensure there is a coordinated local strategy to increase physical activity among children and young people, their families and carers. The strategy should ensure: there are local indoor and outdoor opportunities for physical activity where children and young people feel safe individuals responsible for increasing physical activity are aware of national and local government strategies as well as local plans for increasing physical activity partnership working is developed and supported within local physical activity networks physical activity partnerships establish and deliver multi-component interventions involving schools, families and communities. (Partners may include: schools, colleges, out-of-school services, children's centres and play services, youth services, further education institutions, community clubs and groups and private sector providers. Out-of-school services are defined as those providing activities that take place outside the formal school day, possibly as part of extended school services. They could involve using school facilities during the evening, weekends and school holidays) local factors that help children and young people to be (or which prevent them from being) physically active are identified and acted upon local transport and school travel plans are coordinated so that all local journeys can be carried out using a physically active mode of travel. Ensure physical activity initiatives aimed at children and young people are regularly evaluated. Evaluations should measure uptake among different groups (for example, among those with disabilities or from different ethnic backgrounds). Any changes in physical activity, physical skills and health outcomes should be recorded. In addition, progress towards local area agreement targets should be monitored. Identify a senior council member to be a champion for children and young people's physical activity. They should: promote the importance of encouraging physical activity as part of all council portfolios ensure physical activity is a key priority when developing local authority programmes and targets promote partnership working with council member leads of relevant departments (for example, transport, leisure and health) explain to the public the local authority's role in promoting physical activity. ## Local strategic planning Who is the target population? Children and young people aged 18 and under, their families and carers. Who should take action? All local authority departments and other local strategic partnership agencies responsible for physical activity facilities and services for children and young people. Policy makers and planners working in the public, voluntary, community and private sectors. What action should they take? Identify groups of local children and young people who are unlikely to participate in at least 1 hour of moderate to vigorous physical activity a day. Work with Public Health England Centres, schools and established community partnerships and voluntary organisations to achieve this. Involve these children and young people in the design, planning and delivery of physical activity opportunities, using the information gathered. Consult with different groups of children and young people and their families on a regular basis to understand the factors that help or prevent them from being physically active. Pay particular attention to those who are likely to be less physically active. Ensure children and young people from different socioeconomic and minority ethnic groups are actively involved in the provision of activities. Also ensure those with a disability (or who are living with a family member who has a disability) are actively involved. Use the information gathered to increase opportunities for children and young people to be physically active and to plan dedicated programmes that tackle any inequalities in provision. For further recommendations on community engagement, see NICE's guideline on community engagement. Who is the target population? Children and young people aged 18 and under, their families and carers. Who should take action? The following should take action in partnership with, or as part of, the local strategic partnership: Directors of children's services. Directors of leisure and cultural services. Directors of planning and regeneration. Governors and heads of schools and colleges, office managers and other decision-makers involved with buildings and outdoor spaces within the public, voluntary, community and private sectors. Planning and regeneration service managers and project managers and those involved in developing the 'Unitary development plan' (UDP) or other strategic planning documents. Representatives from crime and disorder reduction partnerships. What action should they take? Ensure physical activity facilities are suitable for children and young people with different needs and their families, particularly those from lower socioeconomic groups, those from minority ethnic groups with specific cultural requirements and those who have a disability. Provide children and young people with places and facilities (both indoors and outdoors) where they feel safe taking part in physical activities. These could be provided by the public, voluntary, community and private sectors (for example, in schools, youth clubs, local business premises and private leisure facilities). Local authorities should coordinate the availability of facilities, where appropriate. They should also ensure all groups have access to these facilities, including those with disabilities. Make school facilities available to children and young people before, during and after the school day, at weekends and during school holidays. These facilities should also be available to public, voluntary, community and private sector groups and organisations offering physical activity programmes and opportunities for physically active play. Actively promote public parks and facilities as well as more non-traditional spaces (for example, car parks outside working hours) as places where children and young people can be physically active. Town planners should make provision for children, young people and their families to be physically active in an urban setting. They should ensure open spaces and outdoor facilities encourage physical activity (including activities which are appealing to children and young people, for example, in-line skating). They should also ensure physical activity facilities are located close to walking and cycling routes. Ensure the spaces and facilities used for physical activity meet recommended safety standards for design, installation and maintenance. For example, outdoor play areas should have areas of shade from the sun and sheltered areas where children can play to reduce the impact of adverse weather. Assess all proposals for signs restricting physical activity in public spaces and facilities (such as those banning ball games) to judge the effect on physical activity levels. For further recommendations on the environment, see NICE's guideline on physical activity and the environment. Who is the target population? Children and young people aged 18 and under, their families and carers. Who should take action? Governors and heads of schools and colleges. Local transport authorities and executives. Police casualty reduction officers. Road safety officers. School travel advisers. Transport planners. What action should they take? Ensure local transport and school travel plans continue to be fully aligned with other local authority plans which may impact on children and young people's physical activity. This includes local area agreements, local area play strategies and healthy school plans. Liaise with the local strategic partnership to achieve this. Ensure local transport plans continue to be developed in conjunction with local authority departments and other agencies that provide spaces and facilities for children and young people to be physically active. Ensure local transport plans acknowledge any potential impact on opportunities for children and young people to be physically active. Transport plans should aim to increase the number of children and young people who regularly walk, cycle and use other modes of physically active travel. They should make provision for the additional needs of, or support required by, children, young people and their parents or carers with a disability or impaired mobility. For recommendations on local transport plans, see NICE's guideline on physical activity and the environment. Continue working with schools to develop, implement and promote school travel plans (see recommendation 12). This may, for example, include: mapping safe routes to school; organising walk and bike to school days and walking buses; organising cycle and road safety training; and helping children to be 'streetwise'. Organise training courses for school travel plan advisers. Identify any aspect of transport policies which discourages children and young people from using modes of travel involving physical activity (such as walking or cycling). For example, policies that aim to keep traffic moving may make it difficult to cross the road. Consider how these policies can be improved to encourage physically active travel. ## Local organisations: planning, delivery and training Who is the target population? Children and young people aged 18 and under, their families and carers. Who should take action? Public, voluntary, community and private sector managers and decision-makers responsible for – or able to influence – opportunities for children and young people to be physically active. Governors and heads of schools and colleges. What action should they take? Identify local factors that may affect whether or not children and young people are physically active by regularly consulting with them, their parents and carers. Find out what type of physical activities children and young people enjoy, based on existing research or local consultation (for example, some might prefer non-competitive or single-gender activities). Actively involve them in planning the resulting physical activities. Remove locally identified barriers to participation, such as lack of privacy in changing facilities, inadequate lighting, poorly maintained facilities and lack of access for children and young people with a disability. Any dress policy should be practical, affordable and acceptable to participants without compromising their safety or restricting participation. Provide regular local programmes and other opportunities for children and young people to be physically active in a challenging environment where they feel safe (both indoors and outdoors). Ensure these programmes and opportunities are well-publicised. Ensure physical activity programmes are run by people with the relevant training or experience. Who is the target population? People who provide programmes or opportunities for children and young people aged 18 and under to be physically active. Who should take action? Employers or supervisors of the above. What action should they take? Ensure informal and formal physical activity sessions for children and young people (including play) are led by staff or volunteers who have achieved the relevant sector standards or qualifications for working with children. This includes the requirements for child protection, health and safety, equality and diversity. Ensure staff and volunteers have the skills (including interpersonal skills) to design, plan and deliver physical activity sessions (including active play sessions) that meet children and young people's different needs and abilities. Those leading activities should make them enjoyable. The leaders should also be inspiring. They should raise children and young people's aspirations about what they can participate in – and the level of ability they can achieve. In addition, leaders should help foster children and young people's personal development. Use community networks and partnerships to encourage, develop and support local communities and volunteers involved in providing physical activities for children and young people. For recommendations on the principles of networking and partnership working, see NICE's guideline on community engagement. Employers should provide regular and relevant development opportunities for employees and volunteers. The impact on practitioner performance and on children and young people's experiences should be monitored. Who is the target population? People who provide and deliver physical activity programmes (formal and informal) and other opportunities for children and young people aged 18 and under to be physically active. Who should take action? Education and training organisations. What action should they take? Establish continuing professional development (CPD) programmes for people involved in organising and running formal and informal physical activities. The education and training should enable them to: give children and young people information and advice on physical activity, taking into account their needs (for example, their developmental age, physical ability and any medical conditions they may have) give children and young people confidence in their own abilities and motivate them to be physically active (this includes encouraging them to set goals, where appropriate) understand the practical issues and problems that may discourage families or groups of children and young people from getting involved. (This may include, for example, time constraints, access issues – including accessibility for those with a disability – and the cultural appropriateness of activities) develop and foster partnership working and get the local community involved. Monitor and evaluate the impact of training on practitioner performance. Train people to deliver physical activity CPD programmes. Who is the target population? Children and young people aged 4 to 18 who attend school or other education institutions. Who should take action? Public, voluntary, community and private sector organisations involved in designing physical activity projects and programmes. Governors and heads of schools and colleges. What action should they take? Identify education institutions willing to deliver multi-component physical activity programmes involving school, family and community-based activities. Identify families, community members, groups and organisations and private sector organisations willing to contribute. Develop multi-component physical activity programmes. These should include: education and advice to increase awareness of the benefits of physical activity and to give children and young people the confidence and motivation to get involved policy and environmental changes, such as creating a more supportive school environment and new opportunities for physical activity during breaks and after school the family: by providing homework activities which children and their parents or carers can do together, or advice on how to create a supportive home environment. (For example, advice on how they might help their child become involved in an activity.) It could also include school-based family activity days the community: for example, by setting up family fun days and schemes such as 'Play in the park'. Who is the target population? Children aged up to 11. Who should take action? Public, voluntary, community and private sector managers and decision-makers responsible for – or able to influence – opportunities for children to be physically active including: early years providers and carers of young children, including those involved with nurseries, playgroups and creches school governors, head teachers and teachers those working in children's centres. What action should they take? Ensure opportunities, facilities and equipment are available to encourage children to develop movement skills, regardless of their ability or disability (for a definition of movement skills see glossary). Provide children with access to environments that stimulate their need to explore and which safely challenge them. (Examples include adventure playgrounds, parks, woodland, common land or fun trails.) Also provide them with the necessary equipment. The aim is to develop their risk awareness and an understanding of their own abilities as necessary life skills. Ensure children have the opportunity to explore a range of physical activities to help them identify those they can enjoy by themselves and those they can do with friends and family. Provide daily opportunities for participation in physically active play by providing guidance and support, equipment and facilities. Keep children motivated to be physically active by updating and varying the way physical activities are delivered (including the resources and environments used). Ensure opportunities are available after school, at weekends, during half-term breaks and during the longer school holidays. Activities should be led by appropriately trained and qualified staff (paid or voluntary) and take place in schools and other community settings. Who is the target population? Girls and young women aged 11 to 18. Who should take action? Public, voluntary, community and private sector managers and decision-makers able to influence physical activity facilities, opportunities and programmes for girls and young women. What action should they take? Consult with girls and young women to find out what type of physical activities they prefer. Actively involve them in the provision of a range of options in response. This may include formal and informal, competitive and non-competitive activities such as football, wheelchair basketball, dance, aerobics and the gym. Activities may be delivered in single and mixed- gender groups. Offer school-based physical activities, including extra-curricular ones. Provide advice on self-monitoring and individually tailored feedback and advice. Address any psychological, social and environmental barriers to physical activity. For example, provide opportunities in easily accessible community settings with appropriate changing facilities offering privacy. Any dress policy should be practical, affordable and acceptable to participants without compromising their safety or restricting participation. For further recommendations on community engagement, see NICE's guideline on community engagement. This recommendation has been replaced by newer guidance. See recommendation 8 in NICE's guideline on physical activity: walking and cycling. Who is the target population? Children aged up to 11. Who should take action? Children's centre staff. Early years providers such as playgroup (creche) leaders and child minders. Parents and carers. Teachers and school support staff. Those providing local opportunities for physical activity in the voluntary, community and private sectors. What action should they take? Provide a range of indoor and outdoor physical activities for children on a daily basis, including opportunities for unstructured, spontaneous play. Tailor activities according to the child's developmental age and physical ability. Ensure they are inclusive, progressive and enjoyable. The activities should develop the child's movement skills (such as crawling, running, hopping, skipping, climbing, throwing, catching and kicking a ball). Children should also experience more advanced activities such as swimming, cycling, playing football and dancing. Provide opportunities at intervals throughout the day in pre-school establishments; during playtimes and lunch breaks at school; as part of extra-curricular and extended school provision; and during leisure time (including weekends and holidays) in wider community settings and the private sector. Help children identify activities they can enjoy by themselves and those they can enjoy with their friends and families. Who is the target population? Girls and young women aged 11 to 18. Who should take action? Practitioners who lead physical activities including youth leaders, teachers, coaches and volunteers. What action should they take? Support participants of all abilities in a non-judgemental and inclusive way. Emphasise the opportunities for participation, enjoyment and personal development, rather than focusing on the evaluation of performance. Encourage those who initially choose not to participate to be involved with physical activities in other ways. Help them move gradually towards full participation. Encourage a dress code that minimises their concerns about body image. It should be practical, affordable and acceptable to them, without compromising their safety or restricting participation. Provide appropriate role models. Who is the target population? Children and young people aged 18 and under, their families and carers. Who should take action? Groups and individuals who have regular contact with children, young people, their parents and carers including: health practitioners local authority personnel physical activity professionals in the public and private sector teachers and early years providers volunteers and staff from community organisations. What action should they take? Ensure parents and carers are aware of government advice on how much physical activity children and young people should be doing (see the UK Chief Medical Officers' physical activity guidelines). Provide information and advice on the benefits of physical activity, emphasising how enjoyable it is. Provide examples of local opportunities. Encourage parents and carers to get involved in physical activities with their children. Encourage parents and carers to complete at least some local journeys (or some part of a local journey) with young children using a physically active mode of travel. This should take place on most days of the week. The aim is to establish physically active travel (such as walking or cycling) as a life-long habit from an early age. Parents and carers should also be encouraged to allow their children to become more independent, by gradually allowing them to walk, cycle or use another physically active mode of travel for short distances. Act as a role model by incorporating physical activity into daily life. For example, opt for travel involving physical activity (such as walking or cycling), use the stairs and regularly participate in recreational activities or sport. Promote physically active travel as an option for all the family. Raise awareness of how it can help children and young people achieve the recommended daily amount of physical activity.# Public health need and practice Children and young people's participation in physical activity is important for their healthy growth and development. It can reduce the risk of chronic conditions (for example, obesity) and improve their general health and wellbeing. Current guidelines recommend that children and young people should do a minimum of 60 minutes of at least moderate-intensity physical activity each day. At least twice a week, this should include activities to improve bone health (weight-bearing activities that produce high physical stresses on the bones, such as running and jumping), muscle strength and flexibility (DH 2004). The best way to encourage children and young people to be physically active may differ according to their age, developmental stage, culture and gender. For example, improving their physical skills and general ability to participate may make physical activity more enjoyable. It may also help increase their activity levels throughout childhood and into adulthood. Physical inactivity in England is estimated to cost £8.2 billion a year. This includes both the direct costs of treating major, lifestyle-related diseases and the indirect costs of sickness absence (DH 2004). A sedentary lifestyle is also estimated to cause 54,000 premature deaths a year (Department for Culture, Media and Sport 2002). These costs are predicted to rise. # Children and young people's activity Objectively measured physical activity data collected in a regional study between 2003 and 2005 suggests that a large majority of children aged 11 are not active enough. Only 2.5% (boys 5.1%, girls 0.4%) did more than 60 minutes of moderate to vigorous physical activity daily (the internationally recognised minimum recommendation for children). They were most active in summer and least active in winter (Riddoch et al. 2007). In the 'Health survey for England 2007' (The Information Centre 2008a), 63% of girls (compared with 72% of boys) reported being physically active for 60 minutes or more on 7 days a week. Once they reached 10, girls' activity declined with age. At 15, 47% of them achieved the recommended amount – compared with 66% of boys of the same age (The Information Centre 2008a). The 2006 survey found a link between parents' and their children's activity levels, particularly among girls (The Information Centre 2008b). Physical activity among those aged 2 to 15 varies according to a range of factors including gender, ethnicity and socioeconomic status (DH 2003; The Information Centre 2008a; 2008b). There was little difference between boys and girls from the main minority ethnic groups in England (Black Caribbean, Indian, Pakistani, Bangladeshi, Chinese and Irish) when it came to participation in sports and exercise, active play and walking. The largest ethnic differences were for sports and exercise, where Indian, Pakistani, Bangladeshi and Chinese children participated less in sports and exercise than children from the general population (DH 2003). Overall, physical activity did not differ significantly according to household income (The Information Centre 2008a; 2008b). However, the number of those participating in sports and exercise on at least one day increased according to income level, especially among girls. The number who regularly undertook continuous walks of at least 5 minutes on five or more days a week, and the mean number of days spent walking in the preceding week, decreased as income levels increased (The Information Centre 2008b). It is important to note that the health survey provided self-reported data (or parent-reported data for under 13s) as opposed to objectively measured activity (as in the regional study by Riddoch et al.). However, although the reported activity data in the survey are likely to be less accurate, its larger sample size and greater geographical range does give an idea of general trends. The number of children walking to school has fallen significantly during the last decade. In 2006, 52% of children aged 5 to 10 and 41% of those aged 11 to 16 walked to school. Only 3% of children aged 5 to 16 cycled to school (Department for Transport 2008). The 2007/08 'School sport survey' (Department for Children, Schools and Families 2008a) found that 90% of pupils surveyed participated in at least 2 hours of 'high quality' physical education (PE) and out-of-hours school sport in a typical week, compared with 62% in 2003/04. (Seventy eight percent of them participated in at least 120 minutes of curriculum PE – compared with just 34% in the first survey.) # National policy Many national policies are relevant to children and young people's physical activity. Important initiatives and policies include the following. 'The children's plan' (Department for Children, Schools and Families 2007b) aims to secure the health and wellbeing of children and young people, safeguard the young and vulnerable, increase educational attainment, increase participation and achievement and keep them on the path to success. It recognises that children and young people need to enjoy childhood as well as grow up prepared for adult life. It puts play at the heart of this ambition. 'The children's plan one year on: a progress report' (Department for Children, Schools and Families 2008a) sets out the progress made and the next steps required to achieve these goals. 'Change4Life' aims to improve both children and young people's diets and physical activity and 'so reduce the threat to their future health and happiness' (DH 2008a). One of its objectives is to increase the time they participate in regular physical activities. There is a particular emphasis on parent/child activities and the need to avoid prolonged periods of inactivity or sedentary behaviour. It encompasses current health campaigns and healthy living initiatives. Initially its focus is families with children aged 0 to 11. 'Healthy weight. Healthy lives. A cross-government strategy for England' (DH 2008b) supports the obesity public service agreement (PSA) target. It aims to bring together all sectors to promote healthy eating and to help children build physical activity into their daily lives. 'Choosing activity: a physical activity action plan' (DH 2005). This cross-government plan aims to promote physical activity for all, in accordance with the Chief Medical Officer's report (DH 2004). It encourages physical activity in early years establishments, schools and further and higher education, and aims to extend the use of education facilities as a community resource for sport and physical activity (including out-of-hours), building community capacity for clubs, coaches and volunteers in community sport, and outdoor play. It is linked to a number of PSA targets, two of which are relevant: PSA 12: Reducing the rate of increase in obesity among children under 11 as a first step towards a long-term national ambition, by 2020, to reduce the proportion of overweight and obese children to 2000 levels in the context of tackling obesity across the population (HM Treasury 2008a). PSA 22: In addition to at least 2 hours per week of high quality PE and sport in school for all aged 5 to 16, all children and young people aged 5–19 will be offered opportunities to participate in a further 3 hours per week of sporting activities provided through schools, further education (FE) colleges, clubs and community providers (HM Treasury 2008b). The government's updated plan for physical activity ('The physical activity plan', DH 2009) includes a number of cross-government initiatives. It sets out the cost of physical inactivity in terms of health and the wider impact on the economy. It also sets out how individuals, employers, local authorities, primary care trusts and the voluntary sector can work in partnership to improve physical activity among the population as a whole. The 'Child health promotion programme' (DH 2008c) highlights the importance of improving the health and wellbeing of children, as part of an integrated approach to supporting children and families. 'Every child's future matters' (Sustainable Development Commission 2007) and 'Every child matters: change for children' (Department for Education and Skills 2004) focus on wellbeing from birth to 19. They aim to ensure children and young people are 'healthy, stay safe, enjoy and achieve, make a positive contribution and achieve economic wellbeing'. A number of initiatives aim to ensure the health and wellbeing of children at school. These include: The National Healthy Schools Programme (DH 2007) 'Extended schools: building on experience' (Department for Children, Schools and Families 2007a) 'PE and sport strategy for young people (PESSYP)' (Department for Children, Schools and Families 2008c) 'Health challenge England' (DH 2006). There is an increasing emphasis on the importance of play, with the introduction of a cross-government programme to promote play and work to develop a regional infrastructure and local services. 'The play strategy' aims to create safe, welcoming, interesting, accessible and free places to play in every residential community. Children and young people will have a role in planning. It is backed by £235 million of dedicated investment (Department for Children, Schools and Families 2008d) 'Time for play' (Department for Culture, Media and Sport 2006) 'Getting serious about play' (Department for Culture, Media and Sport 2004). A number of initiatives focus on increasing participation in sport and sporting success. These include: 'Playing to win: a new era for sport' (Department for Culture Media and Sport 2008a) 'Before, during and after: making the most of the London 2012 games' (Department for Culture Media and Sport 2008b) 'Sport England strategy 2008–2011' (Sport England 2008). 'Free swimming for the under 16s', a cross government initiative announced in July 2008. The government is making available £25 million per annum in 2009/10 and 2010/11 and £10 million in capital funding in 2008/09 to modernise pool provision (Burnham 2008). National policies on active travel and children focus predominantly on school journeys. They aim to reduce car use and promote sustainable modes of travel. Each local education authority should have a sustainable modes of travel strategy to meet the school travel needs of their area (HM Government 2006). A joint Department for Children, Schools and Families and Department for Transport target is for all schools to have an approved school travel plan that addresses sustainability and pupil health and fitness by March 2010 (Department for Education and Skills 2006a). 'Travelling to school initiative' (Department for Transport 2005a) 'Sustainable schools for pupils, communities and the environment' (Department for Education and Skills 2006b). The Department for Transport's home zone initiative aims to make streets more attractive to pedestrians and cyclists by introducing ways to reduce traffic speed (traffic calming measures), parking areas, benches and play areas (Department for Transport 2005b). 'Building brighter futures: next steps for the children's workforce' (Department for Children, Schools and Families 2008e) sets out how the government is further improving the skills and capacity of people who work with children. The aim is to deliver the high-quality, personalised and integrated services detailed in the 'Children's plan' (Department for Children, Schools and Families 2007b). # Non-government initiatives Non-government initiatives to encourage children and young people to be physically active are also common in England. Some of the organisations working in this area are listed below. Play England, part of the National Children's Bureau, provides advice and support to promote good practice. It also works to ensure that policy makers, planners and the public recognise the importance of play. Resources include briefing papers, research reports and a 'Neighbourhood play toolkit CD ROM'. Play England has a contract with the Department for Children Schools and Families and Department for Culture Media and Sport to support the government's 'Play pathfinder' and 'Playbuilder' programmes. Youth Sport Trust supports the nationwide network of school sports partnerships. It also works with under-represented groups through programmes such as Girls in Sport, Living for Sport, YoUR Activity, TOP Activity and the Playground to Podium framework for young disabled people. The British Heart Foundation runs initiatives and provides physical activity resources. These include: the 'Healthy schools physical activity toolkit' which supports the National Healthy Schools Programme; 'Get moving, get active participation award', a foundation key stage 1 participation award, developed with the Youth Sport Trust; and 'Active club resource pack' for out of school clubs developed with 4children. The Fitness Industry Association runs 'go' (an outreach programme) and the 'Adopt a School' programme. Both were developed to help build stronger links between the fitness industry and schools. 'go' aims to help teenage girls (aged 15 and 16) to understand the benefits of being active and show that it can be fun. 'Adopt a school' targets children aged 10 and 11 in the final year of primary school. While the examples above are by no means exhaustive they demonstrate the current plethora of policies, initiatives and resources. However, many of them focus on sport and sporting opportunities; only a minority appear to promote lifetime physical activity or focus on lifestyle and unstructured activities (Cale and Harris 2006).# Considerations The PDG took account of a number of factors and issues in making the recommendations. # Value of physical activity Physical activity is important for children and young people's health and wellbeing and contributes to their physical, social, emotional and psychological development. Physical activity can help prevent long-term medical conditions and help manage existing conditions. The Chief Medical Officer's recommendation is for children and young people to do a minimum of 60 minutes moderate to vigorous physical activity daily. This should include weight-bearing activities to improve bone health, muscle strength and flexibility at least twice a week. The PDG notes that there is likely to be a link between the amount and intensity of physical activity and its effect on health. Recent evidence suggests that children aged 9 may need 120 minutes per day and young people aged 15 may need 90 minutes per day, to reduce their risk of cardiovascular disease (Andersen et al. 2006). All children and young people should have the opportunity to be involved in physical activity and should be encouraged and supported to participate. Provision and support should be available irrespective of disability, health status, religion, ethnicity, social, economic and other circumstances. The PDG believes that only by fostering enjoyment and competence will children and young people be intrinsically motivated to increase and sustain their physical activity levels. When encouraging younger children to be physically active the focus should be on fun, enjoyment and active participation, rather than on the need to understand and conform to rules or master complex skills. The PDG recognised that the recommendations are more likely to be implemented if they complement current policies that advocate physical activity. # Children and young people's needs Children and young people need to participate in a wide range of different physical activities. Children and young people need opportunities, time, space, facilities and equipment, permission and encouragement to be sufficiently physically active. They can be physically active through play and other spontaneous activities, as well as by taking part in structured or organised programmes. Children and young people need to take risks and challenge themselves when involved in physically active play, sports and other activities, so they can learn their own boundaries. It was not within the PDG's remit to consider what might constitute an acceptable level of risk for children and young people when undertaking physical activity in different settings. The PDG recognises that activities need to be tailored to the individual's developmental stage and physical ability. Activities also need to be sensitive to culture and gender issues. While it is important to take individual needs and preferences into account, the PDG believes it is also important to raise aspirations and encourage children and young people to explore a variety of options. # Factors that encourage or hinder physical activity Parents, carers and other family members have a crucial role in encouraging young children to be physically active and in developing their movement skills. They can do this by providing a range of opportunities for physically active play and by playing active games with them. They can also encourage them to walk or cycle (or use other modes of travel involving physical activity) to get to and from different destinations. In addition, they can offer positive feedback, generally show an interest and act as positive role models. The influence of peers is important and can serve to encourage or discourage physical activity. Helping children and young people to be involved in the design of activities or play spaces is an important way of encouraging them to be more physically active. Children and young people's opportunities to be physically active can be affected by environmental, economic and social factors and perceptions about safety and accessibility. Weather conditions – and their perception of what type of conditions make it suitable to be outside – can also affect the opportunities they take. The interests of the community as a whole need to be balanced with the interests of children and young people when promoting unsupervised activity in local neighbourhoods. Contemporary society is generally perceived as risky. Media reporting and a private and public culture which emphasises health and safety, blame and rights have made risk aversion a dominant social value. Children and young people benefit from exposure to risks and challenges to help them develop skills and confidence. Many forms of physical activity and play (and the environments where they take place) have inherent risks. Unnecessary risk can be minimised through the use of risk-benefit assessment, safety precautions and safety equipment. Parents' and service providers' fears of injury and litigation can prevent children and young people from being physically active, even though the fear of risk may not necessarily correspond to reality. Paradoxically, in the long run, this can put children and young people at greater risk from the conditions associated with lack of activity – such as obesity, heart disease and cancer. The PDG recognises the need for service providers to comply with health and safety legislation but cautions against an overly protective and risk-averse approach which may limit children and young people's physical activity. The physical and psychological benefits associated with physical activity and the health risks associated with a sedentary lifestyle should be considered when appraising risk. Some children and young people need special consideration. They include: Those who are 'not in education, employment or training' (NEET). PDG experience shows that physical activity has been used to get some of these young people back into education, training or employment. Physical activity programmes may also provide a positive diversion for children and young people who are at risk of offending. Looked after children and young people, many of whom move between residential care, foster carers or their own family home. This lack of continuity in their home life reduces their opportunities to access leisure facilities or participate in organised activities on a regular basis. In addition, as social groups are hard to maintain this may limit peer interaction and play. Children of asylum seekers, refugees and travellers, many of whom have limited access to regular leisure, sport and play activities due to their transient lifestyle. Young carers – children and young people who are providing care for a family member. The 2001 census identified 175,000 – and many more go unreported. Their responsibilities in the home limit the time they have for socialising with peers and getting involved in play or other types of physical activity. Those who are disabled or from a family where someone else is disabled. Those who are being educated at home. Children who do not attend early years services. Young people in the criminal justice system. Children with physical disabilities, even those with severe impairments, can take part in physical activities to benefit their physical and social development. Children with the same impairment may display a wide range of abilities and therefore should not be treated as a single group. Many children who are disabled highlight social issues, rather than their impairment, as a barrier to participation. If they are encouraged to communicate their preferences, changes can be made to the physical environment, activities and the attitudes of others to help them to participate. Practitioners can encourage and nurture positive peer interaction through play and other physical activity opportunities. The transitions between education institutions – and from education to employment – are times when young people may have less opportunity for physical activities. # Other issues Despite extensive searches, it was difficult to find many high quality controlled studies demonstrating the effectiveness of interventions. Where there was little evidence from controlled studies, the PDG considered observational data and evidence from practice. It also drew on the expertise and experience of its members to supplement the evidence There was a lack of consistency in the way children and young people's physical activity was measured, making it difficult to assess the effectiveness of comparative studies. In addition, some studies focussed on increases in particular types of physical activity rather than overall levels of activity. As interventions may result in children and young people getting involved in one type of physical activity at the expense of another, overall, it might not lead to them being more physically active. In other words, the cumulative impact of implementing the recommendations may not be as great as indicated for particular interventions. There is little published evidence on the costs or cost-effectiveness of interventions. The economic review team, working with members of the PDG, undertook some exploratory economic analysis to estimate potential costs and benefits. Many physical activities involve volunteers (either parents, young people or members of the local community). Those who undertake this kind of work (young people in particular), can act as inspirational role models to others. It is important to ensure this base of volunteers is sustained by providing them with training and support. National volunteering schemes such as 'Vinvolved' and many traditional volunteering and interest groups offer this kind of support to young people and, increasingly, their parents and carers. Practitioners' opinions about what children and young people would like to do may differ from the reality; it may be difficult for them to keep up to date with the activities that children and young people are interested in. The PDG also acknowledges that some children and young people may not be aware of the range of physical activities they could get involved in. It was not possible to address all aspects of the original DH referral. The guidance focuses on children aged 11 and under and adolescent girls. However, many of the recommendations relate to all children and young people under 18, as it also focuses on physically active travel and physical activity for all children and young people aged under 18 in community and family settings. Physical activity as part of the national curriculum was not part of the scope of this guidance, however it does cover physical activity in extra-curricular and extended school settings.# Recommendations for research The PDG recommends that the following research questions should be addressed. It notes that 'effectiveness' in this context relates not only to the size of the effect, but also to cost effectiveness and duration of effect. It also takes into account any harmful/negative side effects. The PDG considered that research funding agencies should establish a nationally coordinated programme to evaluate the most effective and cost effective ways of increasing children and young people's physical activity levels. # Recommendation 1 Develop valid, sensitive, and reliable tools to measure physical activity in children and young people. The tools should measure the amount and pattern of activity (including sedentary behaviour). # Recommendation 2 Future research should be conducted with greater rigour, improved study design, appropriate sample sizes, and valid and reliable measures of physical activity. It should include long-term follow-up of participants and monitoring of implementation fidelity. Studies should seek to identify causal pathways leading to a change in physical activity and health outcomes (such as a decrease in body fat and an increase in self-esteem). They should identify any potential mediating variables. They should also investigate the relationship between the length and intensity of the intervention and changes in physical activity (including sedentary behaviour). # Recommendation 3 Determine the most effective and cost-effective methods of increasing (and sustaining) the number and length of journeys children and young people take using a physically active mode of travel. The focus should be on journeys in the wider community (that is, not just on those to and from school). # Recommendation 4 Determine the most effective and cost-effective methods of increasing and sustaining different types of physical activity among specific groups of children and young people. Groupings could be by: age, culture, ethnicity, disability (including families where someone else is disabled), gender, geographic area (for example, inner-city, urban, rural), religion or socioeconomic status. Particular attention should be given to disadvantaged groups. The interventions examined may target specific behaviours (for example, active play). # Recommendation 5 Determine to what extent different types of physical activity displace others and the factors leading to sedentary behaviour over time. More detail on the evidence gaps identified during the development of this guidance is in appendix D.# Glossary Access/accessibility The ability to use a facility because, for instance, it is free or affordable, it does not require people to travel a long distance to use it and the environment and activities are suitable for those with disabilities. Examples of facilities include playgrounds, parks or open spaces and leisure, youth or community centres. Active play The Children's Play Council (now Play England) defines play as: ' …freely chosen, personally directed, intrinsically motivated behaviour that actively engages the child...' (National Playing Fields Association 2000). Active play involves physical activity. Displacement Displacement occurs when children and young people get involved in one type of physical activity at the expense of another, resulting in their overall physical activity levels remaining the same. Intrinsic motivation Intrinsic motivation is an internal factor, such as an interest in learning a skill or the desire for further personal development. It compares with extrinsic motivation, which is inspired by external factors such as being given a monetary incentive. Movement skills Movement skills use skeletal muscles to achieve a physical goal. They are learnt and refined throughout life. Gross movement skills include: rolling over, sitting up, crawling, walking, running, jumping, hopping and skipping. Fine movement skills include the ability to manipulate small objects and transfer them from hand to hand, and tasks that involve hand-eye coordination. School travel plan A written document detailing a package of measures to improve safety and reduce car use, backed by a partnership involving the school, education and local authority transport officers, the police and the health authority. It is based on consultation with teachers, parents, pupils and governors and other local people. It must include: information about the school, a description and analysis of journeys made and the associated problems, a survey of pupils' current and preferred mode of travel, consultation findings, clearly defined targets and objectives, details of proposed measures and a timetable for implementation, clearly defined responsibilities and proposals for monitoring and review. Sedentary lifestyle The Health Survey for England (2005) defines children as sedentary if they either do no physical activity at all or less than 30 minutes a day of moderate intensity activity. Sport Sport means all forms of physical activity which, through casual or organised participation, aim at expressing or improving physical fitness and mental well-being, forming social relationships or obtaining results in competition at all levels.# References Andersen LB, Harro M, Sardinha LB Et al. (2006) Physical activity and clustered risk in children: across sectional study. The European Youth Heart Study. The Lancet 368: 299–304. Burnham A (2008) Written ministerial statement on free swimming. Cale L, Harris J (2006) Interventions to promote young people's physical activity: Issues, implications and recommendations for practice. Health Education Journal 65: 320–337. Caspersen CJ, Powell KE, Christensen G (1985) Physical activity, exercise and physical fitness: definitions and distinctions of health-related research. Public Health Reports 100: 126–131. Department for Children, Schools and Families (2007a) Extended schools: building on experience. London: Department for Children, Schools and Families. Department for Children, Schools and Families (2007b) The children's plan. Building brighter futures. Norwich: The Stationery Office. Department for Children, Schools and Families (2008a) 2007/08 school sport survey. Department for Children, Schools and Families (2008b) The children's plan one year on: a progress report. Nottingham: Department for Children, Schools and Families. Department for Children, Schools and Families (2008c) PE & sport strategy for young people. Department for Children, Schools and Families (2008d) The play strategy. Nottingham: Department for Children, Schools and Families. Department for Children, Schools and Families (2008e) Building brighter futures: next steps for the children's workforce. Nottingham: Department for Children, Schools and Families. Department for Culture, Media and Sport (2002) Game plan: a strategy for delivering government's sport and physical activity objectives. London: Cabinet Office. Department for Culture, Media and Sport (2004) Getting serious about play. London: Department for Culture, Media and Sport. Department for Culture, Media and Sport (2006) Time for play. London: Department for Culture, Media and Sport. Department for Culture, Media and Sport (2008a) Playing to win: a new era for sport. London: Department for Culture, Media and Sport. Department for Culture, Media and Sport (2008b) Before, during and after: making the most of the London 2012 games. London: Department for Culture, Media and Sport. Department for Education and Skills (2004) Every child matters: change for children. London: The Stationery Office. Department for Education and Skills (2006a) Sustainable schools for pupils, communities and the environment. An action plan for the DfES. Nottingham: Department for Education and Skills. Department for Education and Skills (2006b) Sustainable schools for pupils, communities and the environment. Nottingham: Department for Education and Skills. Department for Transport (2005a) Travelling to school initiative: report on the findings of the initial evaluation. Department for Transport (2005b) Home zones. Challenging the future of our streets. London: Department for Transport. Department for Transport (2008) Travel to school personal travel factsheet. Department of Health (2003) Health survey for England 2002. London: Department of Health. Department of Health (2004) At least five a week: evidence on the impact of physical activity and its relationship to health. London: Department of Health. Department of Health (2005) Choosing activity: a physical activity action plan. London: Department of Health. Department of Health (2006) Health challenge England. London: Department of Health. Department of Health and Department for Children, Schools and Families (2007) Introduction to the national healthy schools programme. London: Department of Health. Department of Health (2008a) Department of Health (2008a) Change4Life. Department of Health (2008b) Healthy weight. Healthy lives. A cross-government strategy for England. London: Department of Health. Department of Health (2008c) Child health promotion programme. London: Department of Health. Department of Health (2009) The physical activity plan. London: Department of Health. HM Government (2006) Education and Inspections Act 2006. London: The Stationery Office. HM Treasury (2008a) Public service agreement 12 2005–2008. HM Treasury (2008b) Public service agreement 22 2008–2011. National Playing Fields Association, Children's Play Council and PLAY LINK (2000) Best play. London: National Playing Fields Association. Riddoch CJ, Mattocks C, Deere K et al. (2007) Objective measurement of levels and patterns of physical activity. Archives of Disease in Childhood 92: 963–969. Sport England (2008) Sport England strategy 2008–2011. London: Sport England. Sustainable Development Commission (2007) Every child's future matters. London: Sustainable Development Commission. The Information Centre (2008a) Health survey for England 2007. Leeds: The Information Centre. The Information Centre (2008b) Health survey for England 2006. Leeds: The Information Centre.# Appendix B: Summary of the methods used to develop this guidance # Introduction The reports of the reviews and economic appraisal include full details of the methods used to select the evidence (including search strategies), assess its quality and summarise it. The minutes of the PDG meetings provide further detail about the Group's interpretation of the evidence and development of the recommendations. All supporting documents are listed in appendix E. # Key questions The key questions were established as part of the scope. They formed the starting point for the reviews of evidence and facilitated the development of recommendations by the PDG. The overarching questions were: . Which strategies, policies, campaigns, interventions and approaches are effective and cost effective in helping children of different ages (with low levels of physical activity) to become more physically active? . What are the barriers and facilitators to children's participation in physical activity? . Which physical activity strategies, policies, campaigns, interventions and approaches are effective and cost effective in reducing health inequalities among pre-school and school-age children? These questions were refined further in relation to the topic of each review (see reviews for further details). # Reviewing the evidence A total of eight reviews were conducted. ## Identifying the evidence Searches were conducted for studies published from January 1990 to April 2007 (except where stated). The following databases were searched for reviews 2, 4, 5, 6, and 7. Additional searches for these reviews and details for the other reviews are listed separately. Applied Social Sciences Index and Abstracts ArticleFirst Cambridge Scientific Abstract CINAHL Cochrane Library CSA Environmental Sciences EMBASE ERIC Geobase Global Health ISI Social Science Citation Index MEDLINE PubMed PsycINFO Science Citation Index SIGLE Sociological Abstracts SPORTDiscus TRIS online Web of Science. The following databases were searched from 2001 for longitudinal or cohort studies: MEDLINE Metalib (including ArticleFirst, Physical Education Index, PSYCinfo, SPORTDiscus, Web of Science, Zetoc) PubMed. Web searches were also conducted: a key source was a briefing paper on obesity produced by the NHS. In addition to searching the main databases from 2000 to April 2007, manual searches were conducted of the following key peer-reviewed journals: 'International journal of behavioural nutrition and physical activity' 'Journal of physical activity & health' 'Obesity reviews' 'Pediatric exercise science' 'Preventive medicine' 'Sports medicine'. Primary research articles, reviews and book chapters, as well as research team members' files were also searched. In addition, the websites of four UK and US organisations involved in commissioning, undertaking or cataloguing research on physical activity and young people were searched for 'grey' literature. These were: Play England Sustrans Active Living Research (US) Institute of Education, University of London The following databases were searched to identify non-intervention qualitative studies published since 1990: CINAHL CSA Environmental Sciences EMBASE Environmental Sciences and Pollution Management ERIC Index to Thesis PsycINFO Science Citation Index and SSCI SIGLE (ends 2005) SPORTDiscus TRIS online. In addition, the websites of four UK and US organisations involved in commissioning, undertaking or cataloguing research on physical activity and young people were searched for 'grey' literature. These were: Play England Sustrans Active Living Research (US) Institute of Education, University of London In addition to the main database search, the following were also searched: Environline EPPI Centre Databases HMIC NRR TRANSPORT The 'Journal of physical activity and health'. Two PDG members helped to identify a list of relevant references, based on an iterative search of material in the Children's Play Information Service at the National Children's Bureau. This was supplemented by web searches and re-interrogation of the search results from the other reviews. References were screened for relevance by two reviewers. # Selection criteria Inclusion and exclusion criteria for each review varied. However, in general studies were included as follows. Review 1: Studies conducted in England or the UK (as long as they included England) that questioned children and young people on physical activity in childhood and adulthood. Review 2: Studies classified as review papers and using systematic methodologies, if they looked at the association between quantitatively measured variables and children or adolescents' (<19 years old) physical activity. Review 3: Studies which explored children's, adolescents' (<19 years old) or carers' experiences of sport, play and active travel. Methods and results had to be clearly reported and the study had to be relevant to the UK. Reviews 4, 5, 6 and 7: Intervention studies on children under eight, active travel, adolescent girls, and family and communities, if they reported on physical activity or physical skills. See the reviews for further details. Review 8: Material directly applicable to the UK. It was not limited by quality or study design, but needed to illustrate or describe the opinions and experiences of children, parents and practitioners about how to stimulate – or help stimulate – active play. Studies were excluded if: they focused on treating obesity they were from less economically developed countries they were studies about ethnic groups that do not have large populations in England the intervention involved the school curriculum/physical education the study involved a change to the built or natural environment. ## Quality appraisal For reviews 3–7, included papers were assessed for methodological rigour and quality using the NICE methodology checklist, as set out in the NICE technical manual 'Methods for development of NICE public health guidance' (see appendix E). Each study was described by study type and graded (++, +, -) to reflect the risk of potential bias arising from its design and execution. Meta-analyses, systematic reviews of randomised controlled trials (RCTs) or RCTs (including cluster RCTs). Systematic reviews of, or individual, non-randomised controlled trials, case-control studies, cohort studies, controlled before-and-after (CBA) studies, interrupted time series (ITS) studies, correlation studies. Non-analytical studies (for example, case reports, case series). Expert opinion, formal consensus. ++ All or most of the criteria have been fulfilled. Where they have not been fulfilled the conclusions are thought very unlikely to alter. - Some criteria have been fulfilled. Those criteria that have not been fulfilled or not adequately described are thought unlikely to alter the conclusions. - Few or no criteria fulfilled. The conclusions of the study are thought likely or very likely to alter. The studies were also assessed for their applicability to the UK. ## Summarising the evidence and making evidence statements The review data was summarised in evidence tables (see full reviews). The findings from the included papers in each review were synthesised and used as the basis for a number of evidence statements relating to each review question. The evidence statements reflect the strength (quantity, type and quality) of evidence and its applicability to the populations and settings in the scope. # Economic analysis The economic appraisal consisted of a review of economic evaluations and a cost-effectiveness analysis. ## Review of economic evaluations: 'A rapid review of economic literature related to the promotion of physical activity, play and sport for pre-school and school age children in family, pre-school, school and community settings' The following databases were searched for economic literature that had not been identified through the search of the effectiveness reviews: EconLIT Health Economic Evaluation Database (HEED) NHS Economic Evaluation Database (NHS EED). Relevant websites were searched (for example, Sport England and Department for Transport). Other sources included papers identified from the personal libraries or collections of members of the health economics team. Studies were included if they were: based in economically developed countries and considered the promotion of physical activity, play and sport for children economic evaluations or contained cost, resource use or outcomes data which could be used to inform the economic modelling. ## Cost-effectiveness analysis: 'A cost-effectiveness scenario analysis of four interventions to increase child and adolescent physical activity: the case of walking buses, free swimming, dance classes and community sports' An economic model was constructed to incorporate data from the reviews of effectiveness (reviews 4,5,6,7) and cost effectiveness. # Fieldwork Fieldwork was carried out to evaluate how relevant and useful NICE's recommendations are for practitioners and how feasible it would be to put them into practice. It was conducted with practitioners and commissioners who are involved in providing physical activity services for children and young people. They included those working in the NHS, education, local authorities and the voluntary and community sector. The fieldwork comprised three studies conducted by Greenstreet Berman: Ten workshops carried out in Birmingham, Liverpool, London, Newcastle with representatives from a variety of professional groups. These included: local authority sports, health and play promotion/development services and children's services; primary care trusts (health improvement representatives), county sports partnerships, Play England, Youth Sport Trust and Sport England. Thirty-two telephone interviews with representatives from education, parent/carer associations, pre-school organisations and local clubs and associations. Each interview covered five of the draft recommendations. Local clubs: draft recommendations 4, 6, 7, 8, 9,10, 12, 13, 14 Parents and carers: draft recommendations 6, 9, 10, 11, 12, 13, 14, 15 Education: draft recommendations 4, 6, 7, 8, 9, 10, 11, 12. An online survey of schools, covering the eight draft recommendations that were directly relevant to them (4, 6, 7, 8, 9, 10, 11, 12). The three studies were commissioned to ensure there was ample geographical and sector coverage. The main issues arising are set out in appendix C fieldwork findings. The full fieldwork report is 'Fieldwork on the promotion of physical activity, active play and sport for pre-school and school age children in family, pre-school, school and community setting'. # How the PDG formulated the recommendations At its meetings in 2007/2008, the PDG considered the evidence to determine: whether there was sufficient evidence (in terms of quantity, quality and applicability) to form a judgement whether, on balance, the evidence demonstrates that the intervention is effective or ineffective, or whether it is equivocal where there is an effect, the typical size of effect. The PDG developed draft recommendations through informal consensus, based on the following criteria: Strength (quality and quantity) of evidence of effectiveness and its applicability to the populations/settings referred to in the scope. Effect size and potential impact on population health and/or reducing inequalities in health. Cost effectiveness (for the NHS and other public sector organisations). Balance of risks and benefits. Ease of implementation and the anticipated extent of change in practice that would be required. The PDG also considered whether a recommendation should only be implemented as part of a research programme where evidence was lacking. Where possible, recommendations were linked to evidence statements (see appendix C for details of evidence statements). Where a recommendation was inferred from the evidence, this was indicated by the reference 'IDE' (inference derived from the evidence). The draft guidance, including the recommendations, was released for consultation in August 2008. At its meeting in October 2008, the PDG amended the guidance in light of comments from stakeholders and experts and the fieldwork. The guidance was signed off by the NICE Guidance Executive in December 2008.# Appendix C: The evidence This appendix sets out the evidence statements taken from eight reviews provided by external contractors/public health collaborating centres (see appendix A for details of the external contractors and collaborating centres ) and links them to the relevant recommendations (see appendix B for the key to study types and quality assessments). The evidence statements are presented here without references – these can be found in the full review (see appendix E for details of the full review). It also sets out a brief summary of findings from the economic appraisal and the fieldwork. The eight reviews are: Review 1: 'Descriptive epidemiology' Review 2: 'Correlates of physical activity in children: a review of quantitative systematic reviews' Review 3: 'The views of children on the barriers and facilitators to participation in physical activity: a review of qualitative studies' Review 4: 'Intervention review: under eights' Review 5: 'Intervention review: children and active travel' Review 6: 'Intervention review: adolescent girls' Review 7: 'Intervention review: family and community' Review 8: 'Review of learning from practice: children and active play'. Evidence statement number 2.4 indicates that the linked statement is numbered 4 in review 2 'Correlates of physical activity in children: a review of quantitative systematic reviews'. Evidence statement 4.1 indicates that the linked statement is numbered 1 in review 4 'Intervention review: under eights'. See the reviews and the economic appraisal. Where a recommendation is not directly taken from the evidence statements, but is inferred from the evidence, this is indicated by IDE (inference derived from the evidence). Recommendation 1: evidence statements 2.4, 3.1, 3.2, 3.3, 3.4, 7.1b, 7.6, 8.4 Recommendation 2: evidence statements 3.1, 3.2, 7.5 Recommendation 3: evidence statements 3.1, 3.2, 3.3, 3.4 Recommendation 4: evidence statements 2.5, 8.1 Recommendation 5: evidence statements 5.1, 5.2, 5.3, 5.4 Recommendation 6: evidence statements 3.1, 3.2, 3.4 Recommendation 7: evidence statement 3.2 Recommendation 8: evidence statements 3.1, 8.1 Recommendation 9: evidence statement 7.5 Recommendation 10: evidence statements 3.2, 4.3, 8.4 Recommendation 11: evidence statement 3.1, 6.1 Recommendation 12: evidence statements 2.4, 3.3, 5.1, 5.2, 5.3, 5.4 Recommendation 13: evidence statements 3.2, 4.3 Recommendation 14: evidence statements 3.1 Recommendation 15: evidence statements 2.4, 3.2, 7.1a, 7.5, 8.5 # Evidence statements ## Evidence statement 2.4 There is evidence from four systematic reviews of observational studies that: there is a large positive association between parental and social support and physical activity in young people. ## Evidence statement 2.5 There is evidence from four systematic reviews of observational studies that there is a: small-to-moderate positive association between access to facilities and participation in physical activity in young people moderate negative association between distance from home to school and physical activity in young people moderate-to-strong positive association between time spent outside and physical activity in young people small negative association between local crime and physical activity in young people. ## Evidence statement 3.1 There is evidence from 15 UK qualitative studies of adolescent girls (reported in 16 papers) (two ; six and eight ) that the main barriers to being physically active were: social pressure to conform, (for example, wanting to fit in) negative experience of the school environment (for example, inappropriate school PE kit and discomfort about sharing showers, changing rooms) negative experiences of sports facilities (for example, public spaces such as gyms or exercise classes were intimidating to teenage girls) having to perform in public (for example, being forced to perform a skill in front of peers) fear of forced competition (one study reported that creating a supportive environment for the delivery of a curricula focused on participation rather than competition and empowering students led to non-active student becoming more active) fear of sexual or racial harassment (for example, Asian girls described needing escorting by family member to places to participate in sports). The main facilitators to being physically active were: social and family influences (for example, social sanctioning of activities by peers provided opportunities to gain social standing and was likely to encourage continued or increased participation; having active siblings and supportive parents) enjoyment (for example, enjoyment and fun during sport and physical activity; enjoyment might outweigh the impact of negative peer pressure not to participate) socialisation (for example, sport provides the opportunity to socialise with friends and extend friendship networks beyond school) intrinsic and extrinsic rewards (for example, wanting to participate in sport as a means to achieve a socially desirable body type; receiving praise and encouragement from PE teachers helped with self confidence and a positive self identity). ## Evidence statement 3.2 There is evidence from five UK qualitative studies of children aged 8 and under (three and two ) that: there were far fewer barriers to physical activity and sport compared with other age groups. Barriers were: dislike of a focus on team sports (for example, team sport focus in primary schools) gender and cultural stereotyping about appropriateness of some sports for particular genders by parents and peers for example, parent viewing boys more active than girls; some sports were more 'appropriate' for boys to play than girls; boys not allowing girls to play 'boys games') costs of participation in organised sports (for example, cost in terms of time and money in participating) dislike of physical activities becoming less fun and more technical and performance-orientated (for example, girls stopped participating in ballet as it became more technical and less fun-orientated). The main facilitators for children aged 8 and under were: enjoyment (for example, creative and fun activities; participating in their favourite sports or activities; older children involving younger children) parental and peer support (for example, physical activity was healthy; girls and boys enjoyed playing sports more if they had started at a younger age) participation in age appropriate activities (for example, fun-based dance activities at younger ages; parent seeing a progression from fun to more structured activity as children became older). ## Evidence statement 3.3 There is evidence from three UK qualitative studies of children and active travel that the main barriers to active travel were: children and parents' fear of traffic (for example, children feeling unsafe when playing and walking outside, particularly after school) parental restrictions on independent movement (for example, parental restrictions on a child's range , plus place and destinations) school influence over cycling policy and storage facilities (for example, absence of any school provision of facilities reflecting a lack of support for cycling) limited play destinations locally (for example, too far to travel to independently; access dangers due to traffic; play equipment unsuitable) adult disapproval of children playing outside (for example, children told off for cycling or playing in streets by adults). Only one study reported any facilitators for walking and cycling. These included: providing personal freedom (for example, reported that walking and cycling increased their personal freedom and independence) enjoyment and fun with friends (for example, older children enjoyed walking to school because they could mix with their friends) the opportunity to explore local surroundings (for example, gave them the chance to explore local neighbourhoods with their friends and/or alone). ## Evidence statement 3.4 There is evidence from two UK studies and two international qualitative studies (both Australian), of families and community that barriers to physical activity and sport were related to personal safety of children while playing outside unsupervised. Common issues were: perceived stranger danger (for example, both parents and children independently reported fear of strangers) risk of personal accidents (for example, both parents and children independently reported risk of accidents or getting hurt) intimidation from older children (for example, both parents and children independently reported the risk of intimidation or bullying by older children; fear of rival gangs for different areas) poor quality of places to play (for example, presence of drug taking equipment (like syringes) in play areas; poorly maintained toilets, shaded areas and lighting). Facilitators were that children: valued opportunities for independent outdoor play (for example, the chance to play away from adult supervision with friends; parents preferring these places for independent play to be courtyards or cul-de-sacs rather than through roads) preferred activities that emphasised fun, play and enjoyment rather than skills practice (for example, older children attending athletics club liked playing with friends). ## Evidence statement 4.3 There is evidence from one cluster randomised controlled trial in the UK (+), one controlled non-randomised trial in Greece (+) and one controlled before-and-after trial in the USA (-) that supervised physical activity interventions conducted in the pre-school setting can be effective in improving core physical skills such as: running, galloping, hopping, sliding, leaping, skipping and general motor agility. ## Evidence statement 5.1 There is evidence from five UK studies (all uncontrolled before-and-after studies ) that cycling promotion projects, targeting primary and secondary school children can lead to large self-reported increases in cycling both at 9 to 11 months and over 20 to 23 months. Characteristics of successful interventions included the involvement of external agencies to facilitate schools to promote and maintain cycling, with the support of parents and the local community. There is evidence from two studies (uncontrolled before-and-after studies ), where cycling infrastructure was commonly part of the local transport infrastructure or children were encouraged to cycle to curriculum-related events or sports fixtures, that self-reported levels of walking declined over 20 and 23 months, implying that some of the increase in cycling may have been offset by a decrease in walking. The evidence is applicable to the UK. ## Evidence statement 5.2 There is evidence from one UK study (randomised controlled trial ) to suggest that the introduction of school travel plans and direct support from a school travel plan adviser at primary schools did not lead to increases in self-reported levels of walking and cycling at 12 months. There is evidence from one US and one UK study (uncontrolled before-and after-study ) to suggest that a mix of promotional measures including curriculum, parental and community promotions (for example, mapping safe routes to school, walk and bike to school days) can increase self-reported walking and cycling at 24 months. In the UK study, this activity was in support of a travel plan. The evidence is applicable to the UK. ## Evidence statement 5.3 There is evidence from three UK studies (uncontrolled before-and-after studies ) to suggest that walking buses (volunteer-led walking groups supported by parents and teachers plus the involvement of the local highways or transport authority) led to increases in self-reported walking among 5 to 11 year olds, and reduced car use for children's' journeys to and from school at 10 weeks and 14 to 30 months. There is evidence from one study (uncontrolled before-and-after study ) to suggest that the provision of a walking bus may in itself not be sufficient to stem a more general decline in walking to and from school. Retaining volunteers to act as coordinators for these schemes appears to be a key factor in the sustainability of walking buses. Currently walking buses are found to be commonly delivered in the UK, however evidence for their applicability remains uncertain (as they may be applicable only to the specific populations or settings included in the studies). ## Evidence statement 5.4 There is evidence from one UK study (controlled before-and-after study ), and two UK (uncontrolled before-and-after studies ) and one Australian studies (uncontrolled before-and-after study )to suggest that walking promotion schemes, involving promotional materials, incentives and rewards (such as travel diaries for children and parents and provision of 'park and walk' parking areas close to school and restriction of parking outside of schools), can lead to increases in self-reported walking to school among 4 to 11 year olds, and reduced car use for children's' journeys to and from school at 4 to 10 weeks and 41 to 48 months. There is evidence from one UK study (controlled before-and-after study ) to suggest that walking campaign packs alone, including promotion materials for children and parents, did not lead to increases in walking among 4 to 11 year olds at 4 weeks. There is evidence from two UK and one Australia study (uncontrolled before-and-after study ) to suggest that targeting children and parents who live a short distance to school (1 mile or less) may support interventions to encourage increase walking levels for the school journey. The evidence mainly comes from UK studies and so is directly applicable only to populations or settings included in the studies (primary school settings). The success of broader application is uncertain. ## Evidence statement 6.1 There is evidence from three cluster randomised controlled trials (one each in Australia , France , and Ireland ), and one controlled non-randomised trial in the USA (-), that school-based interventions outside of physical education lessons, targeting the single behaviour of physical activity, can lead to moderate-to-large increases in physical activity in adolescent girls for up to 6 months. One randomised controlled trial (++) and one cluster randomised controlled trial (+) (both from the USA), failed to show an effect. Characteristics of successful interventions were not consistent across studies, although three of the four successful trials targeted girls only. Successful interventions included self-monitoring techniques, stage-matched counselling, teacher-led extra-curricula physical activity, and multi-level programming targeting psychological, social and environmental correlates. The evidence is drawn from non-UK studies and therefore the applicability to the UK is limited. ## Evidence statement 7.1a There is evidence from two randomised controlled trials in the USA (one and one ) that family-based physical activity interventions targeting overweight/obese children and/or those at risk for overweight/obesity, can lead to increases in physical activity in young people. However, two randomised controlled trials in the USA (both ) failed to show an effect in the same target group. Characteristics of successful interventions included being located in the home and therefore not involving attendance at external sites and focused on small, specific lifestyle changes (2000 more steps per day and a single dietary target). In contrast, unsuccessful interventions required regular attendance at sites external to the home for education and/or physical activity sessions, broader physical activity and dietary behaviour change, and were with 8 to 9 year old African-American girls. ## Evidence statement 7.1b There is evidence from one randomised controlled trial in the USA (+), one randomised non-controlled trial in the USA (+), one controlled non-randomised trial (+) and one uncontrolled before-and-after study (-) that family-based interventions, targeting physical activity, can lead to increases in physical activity in young people. One randomised controlled trial in the USA (++) and one uncontrolled before-and-after study in the USA (-) failed to show an effect. One randomised controlled trial in the USA (-) showed a negative effect. Successful interventions were located mostly in the home and predominantly involved information packs. Two of the successful interventions involved either mothers and daughters or grandmothers, mothers, and daughters exercising together. Unsuccessful interventions all involved regular attendance at physical activity and education sessions outside of the home. Other differences between successful and unsuccessful interventions were not consistent. ## Evidence statement 7.5 There is evidence from two cluster randomised controlled trials in Belgium and France (both ) and three controlled non-randomised trials in the Netherlands, Greece and the USA (one and two ) that interventions involving both the school and family and/or community agencies lead to positive changes in physical activity in boys and girls aged 13 or under. These positive outcomes may include an actual increase in physical activity or less of a decline in physical activity relative to controls. Successful interventions had multiple components. At the school level this included computer-tailored advice, changes to the school environment, classroom sessions, physical activity sessions, and physical education. Family components included facilitating social support for physical activity, education on creating a supportive home environment, homework activities involving parents, and community sport information. One cluster randomised controlled trial in the USA (+) and one uncontrolled before-and-after study in the USA (-) failed to show an effect. The characteristics of these unsuccessful interventions were not consistently different from those of successful interventions. ## Evidence statement 7.6 There is evidence from one controlled non-randomised trial in the USA (+) that social marketing interventions can increase levels of free-time physical activity in children and adolescents (9 to 15 year olds). The social marketing campaign employed engaging messages (primarily via TV advertisements) and promoted opportunities to incorporate physical activity into daily lives. The sustained nature of the campaign (2 years) was considered important to its success. Behavioural changes were seen in the activities targeted by the campaign (for example, free-time activities) and there were no effects on participation in organised sport. ## Evidence statement 8.1 There is strong support for the principle of ensuring that children in the foundation stage are given the opportunity for regular outdoor play as part of the school day. Outdoor play should provide opportunities for movement and challenge, and opportunities to play safely with natural elements. Children's play in outdoor space can be optimised through a number of practical measures such as: seeing the indoor and outdoor spaces as one environment; providing materials specifically for physically active play; making links to the curriculum; provide for diverse active activities; planning to take account of issues such as weather, light, wind direction. The indoor environment can also be optimised for active play, through providing sufficient space; allowing freedom to move from one area to another; providing good opportunities for energetic physical movement; dividing space into active and quiet zones. Adults can help to facilitate active play through: creating the right context for play in which children feel secure and still have the necessary freedom and autonomy to explore through free play; observing play and understanding children's interests, in order to guide the provision of resources and environments for play; interacting appropriately and intervening only when necessary; creating the right environment for play including materials and resources for play, as well as the actual place to play. Practitioners may limit the amount of outdoor play offered to children due to a number of assumptions: that the outside is dangerous; that higher adult/child ratios are needed outside; that educators are merely supervisors outdoors, and that no learning happens outside; that the weather is a barrier; and that being outside is somehow less healthy. All of these assumptions can be tackled to increase active play outdoors. There appears to be a strong consensus among practitioners that there should be much more out of hours use of school grounds. For older children, play facilities are most valued when they are close at hand. If a facility is more than a few hundred metres away, regular use declines dramatically. ## Evidence statement 8.4 It is well acknowledged that physical education contributes to the development of core skills. However, there appears to be much less consensus on the role of play in developing core skills. Core skills can be developed through natural active play, especially when the play is determined by the children themselves. The role of the play practitioner may be less about planning complex programmes to focus on core skill development, but instead facilitating active play. ## Evidence statement 8.5 There is often reluctance by parents and professional carers to also go outside and supervise children playing outdoors in poor weather. It appears that practitioners are put off by the weather more than children. There are many examples of ways that this has been tackled, through encouraging children to spend time outside independently or under supervision in all weathers; encouraging parents and carers to allow their children to be outside; and encouraging nursery and teaching staff to spend time outside with children as part of their formal and informal activities. There is a great deal of experience of a positive approach to bad weather, much of which has been incorporated into the UK Forest Schools movement, building on its origins in Sweden. # Cost-effectiveness evidence For this guidance the economic appraisal consisted of a review of economic evaluations and a cost-effectiveness analysis. 'A rapid review of economic literature related to the promotion of physical activity, play and sport for pre-school and school age children in family, pre-school, school and community settings'. 'A cost-effectiveness scenario analysis of four interventions to increase child and adolescent physical activity: the case of walking buses, free swimming, dance classes and community sports'. ## Review of economic evaluations Overall, the rapid review found that there was very limited economic evidence with respect to the promotion of physical activity, play and sport in the four core areas identified. Only two economic evaluations were appraised on the strength of their evidence, both were from the USA and considered interventions to modify the behaviour of obese children, while one study also considered the behaviour of their obese parents. However, these studies were considered not to be relevant to the development of the guidance due their targeting of only obese children. ## Cost-effectiveness analysis A case study or scenario analysis approach was taken to model four different physical activity programmes and consider the cost effectiveness of each as far as was practical with the available data. The programmes considered were: walking buses free swimming dance classes community sports. The analysis sought to estimate the additional minutes of physical exercise derived from the interventions, and these minutes of exercise per year were used to derive the short-term quality of life improvements for children. However, there was uncertainty associated with the cost-effectiveness results as, due to the limitations of the evidence, it was necessary to make a number of unverified assumptions within the analyses. The results were also shown to be sensitive to changes in these assumptions. Only walking buses were estimated to be cost effective. This was assuming a cost-effectiveness threshold of £20,000 per QALY and because of their relatively low cost and that children benefited by being engaged in the activity on a regular basis over time. However, due to the number of assumptions made producing the cost-effectiveness estimates, the PDG was cautious in drawing conclusions. # Fieldwork findings Fieldwork aimed to test the relevance, usefulness and feasibility of putting the recommendations into practice. The PDG considered the findings when developing the final recommendations. For details, see the fieldwork section in appendix B and the final fieldwork report. Participants with a direct or indirect role in promoting physical activity, play and sport with children were very positive about the recommendations and their potential to help promote physical activity. Many participants stated that the recommendations would be both useful and relevant and that, if successfully implemented, would have a significant impact on policy and service provision. Potentially, they could address inconsistencies in the provision and quality of physical activity initiatives. For service providers and practitioners who are not doing much work in this area, the recommendations were seen to provide useful guidance to help develop new policies. For those already heavily involved in physical activity work, they served to provide reassurance and weight to that work. They were also seen to reinforce aspects of the 'Early years' foundation stage framework, particularly in relation to the provision of safe, secure and challenging environments for physical activity. Practitioners said the recommendations did not offer a new approach but agreed that the measures had not been implemented universally. Feedback suggests that many of the stakeholders who should be involved in implementing the recommendations may not be aware that guidance published by NICE would directly impact on their work. They believed wider and more systematic implementation would be achieved if there was an awareness-raising campaign.# Appendix D: Gaps in the evidence The PDG identified a number of gaps in the evidence related to the programmes under examination, based on an assessment of the evidence in the various reviews. These gaps are set out below. The qualitative literature mainly focuses on school and sport. There is little evidence on formal or informal activities outside school such as yoga, dance, aerobics and play, or activities in social settings. Provision of non-competitive recreational physical activities has rarely been compared with more traditional school sporting activities (in or outside normal school hours). Comparisons between recreational physical activities organised with groups of friends – or with groups of a similar ability – are also lacking. There is limited evidence about what prevents children and young people from being physically active – or what encourages them. Lack of detail in the intervention descriptions means it is unclear whether the barriers or facilitators identified in the qualitative literature were addressed. Few studies report on all physical activities that the participant is involved in. Most only report changes in the activity targeted by the intervention. Whether or not one type of physical activity will displace another – and the factors affecting any such displacement – are not identified. Few studies have investigated the relationship between children's and parents' physical activity over time. There is little evidence about what encourages families to be physically active (either together or split into adult–child groups). There is also little evidence about how families manage competing priorities when planning such activities. Little is known about how children and young people view travel involving physical activity (such as walking and cycling) and how to promote it to them. The exception relates to journeys to and from school. There is little evidence on how to sustain 'active' travel initiatives. For example, little is known about how best to recruit and retain walking bus leaders and local champions, or how effective it is to use pedometers to promote walking among children and young people. In addition, the effect of the environment on uptake (that is, urban versus rural settings and flat versus hilly terrain) has not been properly considered. The intervention literature has methodological limitations. Descriptions of the interventions and evaluation methods used are limited (which may, to some extent, reflect publishing restrictions). In addition, implementation fidelity is rarely assessed and few studies have long-term follow-up. Often studies do not take potential mediator variables into account and do not use objective measures of overall physical activity when measuring effectiveness. Much of the evidence comes from urban settings and its relevance to children from rural areas needs to be considered. No studies were identified that measured the use of rewards to increase participation in – and enjoyment of – organised physical activity. No studies were found which evaluated UK-based, multi-component interventions. Evidence is scarce on how to encourage groups of children and young people who are least likely to be physically active. They include: those with disabilities (or from families where someone else is disabled), those with special educational needs and those from certain minority ethnic groups or traveller and refugee communities. There is a lack of evidence on the effectiveness of private or community-based physical activity provision. There is little evidence of what works to encourage young children to be physically active. For example, the mediating role of parents and practitioners has not been explored. In addition, the evidence about whether or not play initiatives encourage pre-school children to be active is contradictory. There is virtually no evidence on the cost-effectiveness of interventions to increase children and young people's physical activity levels. Many studies use weak measurements of effectiveness (as noted above). As a result, the opportunities to use modelling methods to estimate cost-effectiveness were limited. Few longitudinal studies track the relationship between physical activity and health outcomes. Likewise, few interventions have been well-evaluated over the longer term. The Group made 5 recommendations for research.# Appendix E: Supporting documents Supporting documents include: Reviews: Review 1: 'Descriptive epidemiology' Review 2: 'Correlates of physical activity in children: a review of quantitative systematic reviews' Review 3: 'The views of children on the barriers and facilitators to participation in physical activity: a review of qualitative studies' Review 4: 'Intervention review: under eights' Review 5: 'Intervention review: children and active travel' Review 6: 'Intervention review: adolescent girls' Review 7: 'Intervention review: family and community' Review 8: 'Review of learning from practice: children and active play'. Economic analysis: Review of economic evaluations: 'A rapid review of economic literature related to the promotion of physical activity, play and sport for pre-school and school age children in family, pre-school, school and community settings' Cost-effectiveness analysis: 'A cost effectiveness scenario analysis of four interventions to increase child and adolescent physical activity: the case of walking buses, free swimming, dance classes and community sports'. Fieldwork report: 'Fieldwork on the promotion of physical activity, active play and sport for pre-school and school age children in family, pre-school, school and community setting'.# Finding more information You can see everything NICE says on this topic in the NICE Pathway on physical activity. To find NICE guidance on related topics, including guidance in development, see our topic page for physical activity. For full details of the evidence and the guideline committee's discussions, see the evidence reviews. You can also find information about how the guideline was developed. NICE has produced tools and resources to help you put this guideline into practice. For general help and advice on putting NICE guidelines into practice, see resources to help you put guidance into practice.	{'Introduction': "The Department of Health (DH) asked NICE to produce public health guidance on physical activity, play and sport for pre-school and school-age children in family, pre-school, school and community settings.\n\nThe guidance is for all those who have a direct or indirect role in – and responsibility for – promoting physical activity for children and young people. This includes those working in the NHS, education, local authorities and the wider public, private, voluntary and community sectors. It will also be of interest to parents, grandparents and other carers (including professional carers), children and young people and other members of the public. It includes recommendations for schools, but does not make recommendations for the national curriculum.\n\nThe recommendations relate to all children and young people up to the age of 18, including those with a medical condition or disability (except where clinical assessment or monitoring is required prior to and/or during physical activity). The guidance does not cover specialised services for children and young people with a disability. There is a specific focus on children aged\xa011 and under and girls aged\xa011 to 18.\n\nThe guidance complements and supports, but does not replace, NICE guidance on obesity, physical activity, physical activity and the environment, depression among children and young people and social and emotional wellbeing in schools.\n\nThe Programme Development Group (PDG) developed these recommendations on the basis of reviews of the evidence, an economic analysis, expert advice, stakeholder comments and fieldwork.\n\nMembers of the PDG are listed in appendix A. The methods used to develop the guidance are summarised in appendix B. Supporting documents used to prepare this document are listed in appendix E. Full details of the evidence collated, including fieldwork data and activities and stakeholder comments, along with a list of the stakeholders involved and NICE's supporting process and methods manuals are also available.", 'Recommendations ': "People have the right to be involved in discussions and make informed decisions about their care, as described in making decisions about your care.\n\nMaking decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.\n\n# Definitions\n\nPhysical activity is 'any force exerted by skeletal muscle that results in energy expenditure above resting level' (Caspersen et al. 1985).\n\nThe recommendations refer to opportunities for moderate to vigorous-intensity physical activity in children and young people. The UK recommendations on the type, intensity and duration of activity should be accessed (see the UK Chief Medical Officers' physical activity guidelines for more information).\n\nModerate-intensity activity increases breathing and heart rates to a level where the pulse can be felt and the person feels warmer. It might make someone sweat on a hot or humid day (or when indoors). Vigorous activity results in being out of breath or sweating.\n\nOpportunities for moderate to vigorous physical activity include everything from competitive sport and formal exercise to active play and other physically demanding activities (such as dancing, swimming or skateboarding). They also include some of the actions that can be involved in daily life (such as walking, cycling or using other modes of travel involving physical activity).\n\n# Groupings, themes and links\n\nThe recommendations are grouped as follows:\n\nnational policy\n\nhigh level policy and strategy\n\nlocal strategic planning\n\nlocal organisations: planning, delivery and training\n\nlocal practitioners: delivery.\n\nThere are a number of key themes:\n\nPromoting the benefits of physical activity and encouraging participation (recommendations 1 and 15)\n\nEnsuring high-level strategic policy planning for children and young people supports the physical activity agenda (recommendation 2)\n\nConsultation with, and the active involvement of, children and young people (recommendations 3, 6,11 and 14)\n\nThe planning and provision of spaces, facilities and opportunities (recommendations 2, 4, 9, 10 and 13)\n\nThe need for a skilled workforce (recommendations 7 and 8)\n\nPromoting physically active and sustainable travel (recommendations 5 and 12)\n\nThe diagram below shows the structure of, and the links between, the 15 recommendations.\n\n# Who should take action?\n\nThe recommendations are aimed at the following organisations and groups although each organisation and group should be aware of all the recommendations and the links between them:\n\nChildren's trusts and services: 2, 4, 6, 7, 10, 13\n\nCommunity and voluntary groups (such as those running sports and other organised activities): 3, 6 to 11, 13 to 15\n\nEarly years providers: 4, 10, 12, 13, 15\n\nGovernment departments: 1\n\nLocal authorities (leisure and related services): 2 to 4, 6 to 15\n\nLocal authorities (transport and planning, regeneration): 2 to 5, 12\n\nLocal strategic partnerships: 2, 3\n\nOrganisations offering practitioners education and training: 7, 8\n\nParents, families and carers: 13, 15\n\nPolice: 4, 5\n\nPrimary care trusts: 2 to 4, 6, 9, 15\n\nPrivate sector providers: 4, 6 to 11, 13 to 15\n\nSchools and colleges: 4 to 7, 9 to 15.\n\nAll the organisations, groups and people listed under 'Who should take action?' in each recommendation are equally responsible for ensuring the recommendation is put into practice.\n\n# The recommendations\n\n## National policy\n\nWho is the target population?\n\nChildren and young people aged 18 and under, their families and carers.\n\nPlanners and providers of services and facilities.\n\nWho should take action?\n\nDepartment of Health, Department for Children, Schools and Families and Department for Culture, Media and Sport working with:\n\n\n\nDepartment for Business, Enterprise and Regulatory Reform\n\nDepartment for Communities and Local Government\n\nDepartment for Energy and Climate Change\n\nDepartment for Environment, Food and Rural Affairs\n\nDepartment for Innovation, Universities & Skills\n\nDepartment for Transport\n\nCabinet Office\n\nHome Office\n\nMinistry of Justice.\n\n\n\nWhat action should they take?\n\nDeliver a long-term (minimum 5\xa0years) national campaign to promote physical activity among children and young people. The campaign should be integrated with and support other national health campaigns and strategies to increase participation in play and sport and reduce obesity (such as 'Change4Life').\n\nUse research, consult and actively involve children and young people and their parents to determine the best media to use, the most effective messages and the most appropriate language for different groups. (Examples of different groups that could be covered include families, parents and carers, and children of different ages, ethnicity and who have different levels of physical ability.)\n\nEnsure the campaign is consistent and sustained. It should convey that physical activity:\n\n\n\nis healthy, fun and enjoyable, makes you feel good and can be sociable (that is, it can be undertaken with existing friends or can help develop new ones)\n\npromotes children and young people's independence\n\nhelps develop children's movement skills\n\ncan involve a wide variety of formal and informal activities such as play, dance, swimming, the gym, sport (including street sport and games) and physically active travel (such as walking, cycling and wheelchair travel)\n\ncan (and should) become a regular part of daily life and that small lifestyle changes can be worthwhile (for example, active travel to school, the shops or the park, using the stairs and ramps instead of lifts and helping with housework)\n\ncan be maintained by trying new and challenging activities to keep children and young people interested and motivated\n\nis something that adults, especially parents and carers, should incorporate into their lives to set an example.\n\n\n\nEnsure the campaign addresses any concerns that parents and carers may have about their children's safety.\n\nEncourage regional and local campaigns to use the same messages, as well as promoting examples of local opportunities to be physically active.\n\nDevelop resources for regional and local dissemination of the campaign (for example, promotional materials and support for those delivering it). (For more on training see recommendation 8.)\n\nUse process, impact and outcome measures to ensure national, regional and local campaigns are delivered effectively. For recommendations on the principles of evaluation, see NICE's guideline on behaviour change: general approaches.\n\n## High level policy and strategy\n\nWho is the target population?\n\nChildren and young people aged 18 and under, their families and carers.\n\nWho should take action?\n\nChairs of local strategic partnerships.\n\nDirectors of children's services.\n\nDirectors of public health.\n\nWhat action should they take?\n\nEnsure the following explicitly address the need for children and young people to be physically active:\n\n\n\nchildren and young people's plans\n\njoint strategic needs assessments\n\nlocal development and planning frameworks\n\nsustainable community plans and strategies.\n\n\n\nEnsure there is a coordinated local strategy to increase physical activity among children and young people, their families and carers.\n\nThe strategy should ensure:\n\n\n\nthere are local indoor and outdoor opportunities for physical activity where children and young people feel safe\n\nindividuals responsible for increasing physical activity are aware of national and local government strategies as well as local plans for increasing physical activity\n\npartnership working is developed and supported within local physical activity networks\n\nphysical activity partnerships establish and deliver multi-component interventions involving schools, families and communities. (Partners may include: schools, colleges, out-of-school services, children's centres and play services, youth services, further education institutions, community clubs and groups and private sector providers. Out-of-school services are defined as those providing activities that take place outside the formal school day, possibly as part of extended school services. They could involve using school facilities during the evening, weekends and school holidays)\n\nlocal factors that help children and young people to be (or which prevent them from being) physically active are identified and acted upon\n\nlocal transport and school travel plans are coordinated so that all local journeys can be carried out using a physically active mode of travel.\n\n\n\nEnsure physical activity initiatives aimed at children and young people are regularly evaluated. Evaluations should measure uptake among different groups (for example, among those with disabilities or from different ethnic backgrounds). Any changes in physical activity, physical skills and health outcomes should be recorded. In addition, progress towards local area agreement targets should be monitored.\n\nIdentify a senior council member to be a champion for children and young people's physical activity. They should:\n\n\n\npromote the importance of encouraging physical activity as part of all council portfolios\n\nensure physical activity is a key priority when developing local authority programmes and targets\n\npromote partnership working with council member leads of relevant departments (for example, transport, leisure and health)\n\nexplain to the public the local authority's role in promoting physical activity.\n\n\n\n## Local strategic planning\n\nWho is the target population?\n\nChildren and young people aged\xa018 and under, their families and carers.\n\nWho should take action?\n\nAll local authority departments and other local strategic partnership agencies responsible for physical activity facilities and services for children and young people.\n\nPolicy makers and planners working in the public, voluntary, community and private sectors.\n\nWhat action should they take?\n\nIdentify groups of local children and young people who are unlikely to participate in at least 1\xa0hour of moderate to vigorous physical activity a day. Work with Public Health England Centres, schools and established community partnerships and voluntary organisations to achieve this.\n\nInvolve these children and young people in the design, planning and delivery of physical activity opportunities, using the information gathered.\n\nConsult with different groups of children and young people and their families on a regular basis to understand the factors that help or prevent them from being physically active. Pay particular attention to those who are likely to be less physically active. Ensure children and young people from different socioeconomic and minority ethnic groups are actively involved in the provision of activities. Also ensure those with a disability (or who are living with a family member who has a disability) are actively involved.\n\nUse the information gathered to increase opportunities for children and young people to be physically active and to plan dedicated programmes that tackle any inequalities in provision.\n\nFor further recommendations on community engagement, see NICE's guideline on community engagement.\n\nWho is the target population?\n\nChildren and young people aged 18 and under, their families and carers.\n\nWho should take action?\n\nThe following should take action in partnership with, or as part of, the local strategic partnership:\n\nDirectors of children's services.\n\nDirectors of leisure and cultural services.\n\nDirectors of planning and regeneration.\n\nGovernors and heads of schools and colleges, office managers and other decision-makers involved with buildings and outdoor spaces within the public, voluntary, community and private sectors.\n\nPlanning and regeneration service managers and project managers and those involved in developing the 'Unitary development plan' (UDP) or other strategic planning documents.\n\nRepresentatives from crime and disorder reduction partnerships.\n\nWhat action should they take?\n\nEnsure physical activity facilities are suitable for children and young people with different needs and their families, particularly those from lower socioeconomic groups, those from minority ethnic groups with specific cultural requirements and those who have a disability.\n\nProvide children and young people with places and facilities (both indoors and outdoors) where they feel safe taking part in physical activities. These could be provided by the public, voluntary, community and private sectors (for example, in schools, youth clubs, local business premises and private leisure facilities). Local authorities should coordinate the availability of facilities, where appropriate. They should also ensure all groups have access to these facilities, including those with disabilities.\n\nMake school facilities available to children and young people before, during and after the school day, at weekends and during school holidays. These facilities should also be available to public, voluntary, community and private sector groups and organisations offering physical activity programmes and opportunities for physically active play.\n\nActively promote public parks and facilities as well as more non-traditional spaces (for example, car parks outside working hours) as places where children and young people can be physically active.\n\nTown planners should make provision for children, young people and their families to be physically active in an urban setting. They should ensure open spaces and outdoor facilities encourage physical activity (including activities which are appealing to children and young people, for example, in-line skating). They should also ensure physical activity facilities are located close to walking and cycling routes.\n\nEnsure the spaces and facilities used for physical activity meet recommended safety standards for design, installation and maintenance. For example, outdoor play areas should have areas of shade from the sun and sheltered areas where children can play to reduce the impact of adverse weather.\n\nAssess all proposals for signs restricting physical activity in public spaces and facilities (such as those banning ball games) to judge the effect on physical activity levels.\n\nFor further recommendations on the environment, see NICE's guideline on physical activity and the environment.\n\nWho is the target population?\n\nChildren and young people aged 18 and under, their families and carers.\n\nWho should take action?\n\nGovernors and heads of schools and colleges.\n\nLocal transport authorities and executives.\n\nPolice casualty reduction officers.\n\nRoad safety officers.\n\nSchool travel advisers.\n\nTransport planners.\n\nWhat action should they take?\n\nEnsure local transport and school travel plans continue to be fully aligned with other local authority plans which may impact on children and young people's physical activity. This includes local area agreements, local area play strategies and healthy school plans. Liaise with the local strategic partnership to achieve this.\n\nEnsure local transport plans continue to be developed in conjunction with local authority departments and other agencies that provide spaces and facilities for children and young people to be physically active.\n\nEnsure local transport plans acknowledge any potential impact on opportunities for children and young people to be physically active. Transport plans should aim to increase the number of children and young people who regularly walk, cycle and use other modes of physically active travel. They should make provision for the additional needs of, or support required by, children, young people and their parents or carers with a disability or impaired mobility. For recommendations on local transport plans, see NICE's guideline on physical activity and the environment.\n\nContinue working with schools to develop, implement and promote school travel plans (see recommendation 12). This may, for example, include: mapping safe routes to school; organising walk and bike to school days and walking buses; organising cycle and road safety training; and helping children to be 'streetwise'.\n\nOrganise training courses for school travel plan advisers.\n\nIdentify any aspect of transport policies which discourages children and young people from using modes of travel involving physical activity (such as walking or cycling). For example, policies that aim to keep traffic moving may make it difficult to cross the road. Consider how these policies can be improved to encourage physically active travel.\n\n## Local organisations: planning, delivery and training\n\nWho is the target population?\n\nChildren and young people aged 18 and under, their families and carers.\n\nWho should take action?\n\nPublic, voluntary, community and private sector managers and decision-makers responsible for – or able to influence – opportunities for children and young people to be physically active.\n\nGovernors and heads of schools and colleges.\n\nWhat action should they take?\n\nIdentify local factors that may affect whether or not children and young people are physically active by regularly consulting with them, their parents and carers.\n\nFind out what type of physical activities children and young people enjoy, based on existing research or local consultation (for example, some might prefer non-competitive or single-gender activities). Actively involve them in planning the resulting physical activities.\n\nRemove locally identified barriers to participation, such as lack of privacy in changing facilities, inadequate lighting, poorly maintained facilities and lack of access for children and young people with a disability. Any dress policy should be practical, affordable and acceptable to participants without compromising their safety or restricting participation.\n\nProvide regular local programmes and other opportunities for children and young people to be physically active in a challenging environment where they feel safe (both indoors and outdoors). Ensure these programmes and opportunities are well-publicised.\n\nEnsure physical activity programmes are run by people with the relevant training or experience.\n\nWho is the target population?\n\nPeople who provide programmes or opportunities for children and young people aged 18 and under to be physically active.\n\nWho should take action?\n\nEmployers or supervisors of the above.\n\nWhat action should they take?\n\nEnsure informal and formal physical activity sessions for children and young people (including play) are led by staff or volunteers who have achieved the relevant sector standards or qualifications for working with children. This includes the requirements for child protection, health and safety, equality and diversity.\n\nEnsure staff and volunteers have the skills (including interpersonal skills) to design, plan and deliver physical activity sessions (including active play sessions) that meet children and young people's different needs and abilities. Those leading activities should make them enjoyable. The leaders should also be inspiring. They should raise children and young people's aspirations about what they can participate in – and the level of ability they can achieve. In addition, leaders should help foster children and young people's personal development.\n\nUse community networks and partnerships to encourage, develop and support local communities and volunteers involved in providing physical activities for children and young people. For recommendations on the principles of networking and partnership working, see NICE's guideline on community engagement.\n\nEmployers should provide regular and relevant development opportunities for employees and volunteers. The impact on practitioner performance and on children and young people's experiences should be monitored.\n\nWho is the target population?\n\nPeople who provide and deliver physical activity programmes (formal and informal) and other opportunities for children and young people aged 18 and under to be physically active.\n\nWho should take action?\n\nEducation and training organisations.\n\nWhat action should they take?\n\nEstablish continuing professional development (CPD) programmes for people involved in organising and running formal and informal physical activities. The education and training should enable them to:\n\n\n\ngive children and young people information and advice on physical activity, taking into account their needs (for example, their developmental age, physical ability and any medical conditions they may have)\n\ngive children and young people confidence in their own abilities and motivate them to be physically active (this includes encouraging them to set goals, where appropriate)\n\nunderstand the practical issues and problems that may discourage families or groups of children and young people from getting involved. (This may include, for example, time constraints, access issues – including accessibility for those with a disability – and the cultural appropriateness of activities)\n\ndevelop and foster partnership working and get the local community involved.\n\n\n\nMonitor and evaluate the impact of training on practitioner performance.\n\nTrain people to deliver physical activity CPD programmes.\n\nWho is the target population?\n\nChildren and young people aged 4 to 18 who attend school or other education institutions.\n\nWho should take action?\n\nPublic, voluntary, community and private sector organisations involved in designing physical activity projects and programmes.\n\nGovernors and heads of schools and colleges.\n\nWhat action should they take?\n\nIdentify education institutions willing to deliver multi-component physical activity programmes involving school, family and community-based activities. Identify families, community members, groups and organisations and private sector organisations willing to contribute.\n\nDevelop multi-component physical activity programmes. These should include:\n\n\n\neducation and advice to increase awareness of the benefits of physical activity and to give children and young people the confidence and motivation to get involved\n\npolicy and environmental changes, such as creating a more supportive school environment and new opportunities for physical activity during breaks and after school\n\nthe family: by providing homework activities which children and their parents or carers can do together, or advice on how to create a supportive home environment. (For example, advice on how they might help their child become involved in an activity.) It could also include school-based family activity days\n\nthe community: for example, by setting up family fun days and schemes such as 'Play in the park'.\n\n\n\nWho is the target population?\n\nChildren aged up to 11.\n\nWho should take action?\n\nPublic, voluntary, community and private sector managers and decision-makers responsible for – or able to influence – opportunities for children to be physically active including:\n\nearly years providers and carers of young children, including those involved with nurseries, playgroups and creches\n\nschool governors, head teachers and teachers\n\nthose working in children's centres.\n\nWhat action should they take?\n\nEnsure opportunities, facilities and equipment are available to encourage children to develop movement skills, regardless of their ability or disability (for a definition of movement skills see glossary).\n\nProvide children with access to environments that stimulate their need to explore and which safely challenge them. (Examples include adventure playgrounds, parks, woodland, common land or fun trails.) Also provide them with the necessary equipment. The aim is to develop their risk awareness and an understanding of their own abilities as necessary life skills.\n\nEnsure children have the opportunity to explore a range of physical activities to help them identify those they can enjoy by themselves and those they can do with friends and family.\n\nProvide daily opportunities for participation in physically active play by providing guidance and support, equipment and facilities. Keep children motivated to be physically active by updating and varying the way physical activities are delivered (including the resources and environments used).\n\nEnsure opportunities are available after school, at weekends, during half-term breaks and during the longer school holidays. Activities should be led by appropriately trained and qualified staff (paid or voluntary) and take place in schools and other community settings.\n\nWho is the target population?\n\nGirls and young women aged 11 to 18.\n\nWho should take action?\n\nPublic, voluntary, community and private sector managers and decision-makers able to influence physical activity facilities, opportunities and programmes for girls and young women.\n\nWhat action should they take?\n\nConsult with girls and young women to find out what type of physical activities they prefer. Actively involve them in the provision of a range of options in response. This may include formal and informal, competitive and non-competitive activities such as football, wheelchair basketball, dance, aerobics and the gym. Activities may be delivered in single and mixed- gender groups.\n\nOffer school-based physical activities, including extra-curricular ones. Provide advice on self-monitoring and individually tailored feedback and advice.\n\nAddress any psychological, social and environmental barriers to physical activity. For example, provide opportunities in easily accessible community settings with appropriate changing facilities offering privacy. Any dress policy should be practical, affordable and acceptable to participants without compromising their safety or restricting participation.\n\nFor further recommendations on community engagement, see NICE's guideline on community engagement.\n\nThis recommendation has been replaced by newer guidance. See recommendation\xa08 in NICE's guideline on physical activity: walking and cycling.\n\nWho is the target population?\n\nChildren aged up to 11.\n\nWho should take action?\n\nChildren's centre staff.\n\nEarly years providers such as playgroup (creche) leaders and child minders.\n\nParents and carers.\n\nTeachers and school support staff.\n\nThose providing local opportunities for physical activity in the voluntary, community and private sectors.\n\nWhat action should they take?\n\nProvide a range of indoor and outdoor physical activities for children on a daily basis, including opportunities for unstructured, spontaneous play.\n\nTailor activities according to the child's developmental age and physical ability. Ensure they are inclusive, progressive and enjoyable. The activities should develop the child's movement skills (such as crawling, running, hopping, skipping, climbing, throwing, catching and kicking a ball). Children should also experience more advanced activities such as swimming, cycling, playing football and dancing.\n\nProvide opportunities at intervals throughout the day in pre-school establishments; during playtimes and lunch breaks at school; as part of extra-curricular and extended school provision; and during leisure time (including weekends and holidays) in wider community settings and the private sector.\n\nHelp children identify activities they can enjoy by themselves and those they can enjoy with their friends and families.\n\nWho is the target population?\n\nGirls and young women aged 11 to 18.\n\nWho should take action?\n\nPractitioners who lead physical activities including youth leaders, teachers, coaches and volunteers.\n\nWhat action should they take?\n\nSupport participants of all abilities in a non-judgemental and inclusive way. Emphasise the opportunities for participation, enjoyment and personal development, rather than focusing on the evaluation of performance.\n\nEncourage those who initially choose not to participate to be involved with physical activities in other ways. Help them move gradually towards full participation.\n\nEncourage a dress code that minimises their concerns about body image. It should be practical, affordable and acceptable to them, without compromising their safety or restricting participation.\n\nProvide appropriate role models.\n\nWho is the target population?\n\nChildren and young people aged 18 and under, their families and carers.\n\nWho should take action?\n\nGroups and individuals who have regular contact with children, young people, their parents and carers including:\n\nhealth practitioners\n\nlocal authority personnel\n\nphysical activity professionals in the public and private sector\n\nteachers and early years providers\n\nvolunteers and staff from community organisations.\n\nWhat action should they take?\n\nEnsure parents and carers are aware of government advice on how much physical activity children and young people should be doing (see the UK Chief Medical Officers' physical activity guidelines).\n\nProvide information and advice on the benefits of physical activity, emphasising how enjoyable it is. Provide examples of local opportunities.\n\nEncourage parents and carers to get involved in physical activities with their children.\n\nEncourage parents and carers to complete at least some local journeys (or some part of a local journey) with young children using a physically active mode of travel. This should take place on most days of the week. The aim is to establish physically active travel (such as walking or cycling) as a life-long habit from an early age. Parents and carers should also be encouraged to allow their children to become more independent, by gradually allowing them to walk, cycle or use another physically active mode of travel for short distances.\n\nAct as a role model by incorporating physical activity into daily life. For example, opt for travel involving physical activity (such as walking or cycling), use the stairs and regularly participate in recreational activities or sport.\n\nPromote physically active travel as an option for all the family. Raise awareness of how it can help children and young people achieve the recommended daily amount of physical activity.", 'Public health need and practice': "Children and young people's participation in physical activity is important for their healthy growth and development. It can reduce the risk of chronic conditions (for example, obesity) and improve their general health and wellbeing. Current guidelines recommend that children and young people should do a minimum of 60 minutes of at least moderate-intensity physical activity each day. At least twice a week, this should include activities to improve bone health (weight-bearing activities that produce high physical stresses on the bones, such as running and jumping), muscle strength and flexibility (DH 2004).\n\nThe best way to encourage children and young people to be physically active may differ according to their age, developmental stage, culture and gender. For example, improving their physical skills and general ability to participate may make physical activity more enjoyable. It may also help increase their activity levels throughout childhood and into adulthood.\n\nPhysical inactivity in England is estimated to cost £8.2 billion a year. This includes both the direct costs of treating major, lifestyle-related diseases and the indirect costs of sickness absence (DH 2004). A sedentary lifestyle is also estimated to cause 54,000 premature deaths a year (Department for Culture, Media and Sport 2002). These costs are predicted to rise.\n\n# Children and young people's activity\n\nObjectively measured physical activity data collected in a regional study between 2003 and 2005 suggests that a large majority of children aged 11 are not active enough. Only 2.5% (boys 5.1%, girls 0.4%) did more than 60 minutes of moderate to vigorous physical activity daily (the internationally recognised minimum recommendation for children). They were most active in summer and least active in winter (Riddoch et al. 2007).\n\nIn the 'Health survey for England 2007' (The Information Centre 2008a), 63% of girls (compared with 72% of boys) reported being physically active for 60 minutes or more on 7 days a week. Once they reached 10, girls' activity declined with age. At 15, 47% of them achieved the recommended amount – compared with 66% of boys of the same age (The Information Centre 2008a).\n\nThe 2006 survey found a link between parents' and their children's activity levels, particularly among girls (The Information Centre 2008b).\n\nPhysical activity among those aged 2 to 15 varies according to a range of factors including gender, ethnicity and socioeconomic status (DH 2003; The Information Centre 2008a; 2008b). There was little difference between boys and girls from the main minority ethnic groups in England (Black Caribbean, Indian, Pakistani, Bangladeshi, Chinese and Irish) when it came to participation in sports and exercise, active play and walking. The largest ethnic differences were for sports and exercise, where Indian, Pakistani, Bangladeshi and Chinese children participated less in sports and exercise than children from the general population (DH 2003).\n\nOverall, physical activity did not differ significantly according to household income (The Information Centre 2008a; 2008b). However, the number of those participating in sports and exercise on at least one day increased according to income level, especially among girls. The number who regularly undertook continuous walks of at least 5\xa0minutes on five or more days a week, and the mean number of days spent walking in the preceding week, decreased as income levels increased (The Information Centre 2008b).\n\nIt is important to note that the health survey provided self-reported data (or parent-reported data for under 13s) as opposed to objectively measured activity (as in the regional study by Riddoch et al.). However, although the reported activity data in the survey are likely to be less accurate, its larger sample size and greater geographical range does give an idea of general trends.\n\nThe number of children walking to school has fallen significantly during the last decade. In 2006, 52% of children aged 5 to 10 and 41% of those aged 11 to 16 walked to school. Only 3% of children aged 5 to 16 cycled to school (Department for Transport 2008).\n\nThe 2007/08 'School sport survey' (Department for Children, Schools and Families 2008a) found that 90% of pupils surveyed participated in at least 2\xa0hours of 'high quality' physical education (PE) and out-of-hours school sport in a typical week, compared with 62% in 2003/04. (Seventy eight percent of them participated in at least 120\xa0minutes of curriculum PE – compared with just 34% in the first [2003/04] survey.)\n\n# National policy\n\nMany national policies are relevant to children and young people's physical activity. Important initiatives and policies include the following.\n\n'The children's plan' (Department for Children, Schools and Families 2007b) aims to secure the health and wellbeing of children and young people, safeguard the young and vulnerable, increase educational attainment, increase participation and achievement and keep them on the path to success. It recognises that children and young people need to enjoy childhood as well as grow up prepared for adult life. It puts play at the heart of this ambition. 'The children's plan one year on: a progress report' (Department for Children, Schools and Families 2008a) sets out the progress made and the next steps required to achieve these goals.\n\n'Change4Life' aims to improve both children and young people's diets and physical activity and 'so reduce the threat to their future health and happiness' (DH 2008a). One of its objectives is to increase the time they participate in regular physical activities. There is a particular emphasis on parent/child activities and the need to avoid prolonged periods of inactivity or sedentary behaviour. It encompasses current health campaigns and healthy living initiatives. Initially its focus is families with children aged 0 to 11.\n\n'Healthy weight. Healthy lives. A cross-government strategy for England' (DH 2008b) supports the obesity public service agreement (PSA) target. It aims to bring together all sectors to promote healthy eating and to help children build physical activity into their daily lives.\n\n'Choosing activity: a physical activity action plan' (DH 2005). This cross-government plan aims to promote physical activity for all, in accordance with the Chief Medical Officer's report (DH 2004). It encourages physical activity in early years establishments, schools and further and higher education, and aims to extend the use of education facilities as a community resource for sport and physical activity (including out-of-hours), building community capacity for clubs, coaches and volunteers in community sport, and outdoor play. It is linked to a number of PSA targets, two of which are relevant:\n\n\n\nPSA 12: Reducing the rate of increase in obesity among children under 11 as a first step towards a long-term national ambition, by 2020, to reduce the proportion of overweight and obese children to 2000 levels in the context of tackling obesity across the population (HM Treasury 2008a).\n\nPSA 22: In addition to at least 2 hours per week of high quality PE and sport in school for all aged 5 to 16, all children and young people aged 5–19 will be offered opportunities to participate in a further 3 hours per week of sporting activities provided through schools, further education (FE) colleges, clubs and community providers (HM Treasury 2008b).\n\n\n\nThe government's updated plan for physical activity ('The physical activity plan', DH 2009) includes a number of cross-government initiatives. It sets out the cost of physical inactivity in terms of health and the wider impact on the economy. It also sets out how individuals, employers, local authorities, primary care trusts and the voluntary sector can work in partnership to improve physical activity among the population as a whole.\n\nThe 'Child health promotion programme' (DH 2008c) highlights the importance of improving the health and wellbeing of children, as part of an integrated approach to supporting children and families. 'Every child's future matters' (Sustainable Development Commission 2007) and 'Every child matters: change for children' (Department for Education and Skills 2004) focus on wellbeing from birth to 19. They aim to ensure children and young people are 'healthy, stay safe, enjoy and achieve, make a positive contribution and achieve economic wellbeing'.\n\nA number of initiatives aim to ensure the health and wellbeing of children at school. These include:\n\n\n\nThe National Healthy Schools Programme (DH 2007)\n\n'Extended schools: building on experience' (Department for Children, Schools and Families 2007a)\n\n'PE and sport strategy for young people (PESSYP)' (Department for Children, Schools and Families 2008c)\n\n'Health challenge England' (DH 2006).\n\n\n\nThere is an increasing emphasis on the importance of play, with the introduction of a cross-government programme to promote play and work to develop a regional infrastructure and local services.\n\n\n\n'The play strategy' aims to create safe, welcoming, interesting, accessible and free places to play in every residential community. Children and young people will have a role in planning. It is backed by £235 million of dedicated investment (Department for Children, Schools and Families 2008d)\n\n'Time for play' (Department for Culture, Media and Sport 2006)\n\n'Getting serious about play' (Department for Culture, Media and Sport 2004).\n\nA number of initiatives focus on increasing participation in sport and sporting success. These include:\n\n'Playing to win: a new era for sport' (Department for Culture Media and Sport 2008a)\n\n'Before, during and after: making the most of the London 2012 games' (Department for Culture Media and Sport 2008b)\n\n'Sport England strategy 2008–2011' (Sport England 2008).\n\n\n\n'Free swimming for the under 16s', a cross government initiative announced in July 2008. The government is making available £25 million per annum in 2009/10 and 2010/11 and £10 million in capital funding in 2008/09 to modernise pool provision (Burnham 2008).\n\nNational policies on active travel and children focus predominantly on school journeys. They aim to reduce car use and promote sustainable modes of travel. Each local education authority should have a sustainable modes of travel strategy to meet the school travel needs of their area (HM Government 2006). A joint Department for Children, Schools and Families and Department for Transport target is for all schools to have an approved school travel plan that addresses sustainability and pupil health and fitness by March 2010 (Department for Education and Skills 2006a).\n\n\n\n'Travelling to school initiative' (Department for Transport 2005a)\n\n'Sustainable schools for pupils, communities and the environment' (Department for Education and Skills 2006b).\n\n\n\nThe Department for Transport's home zone initiative aims to make streets more attractive to pedestrians and cyclists by introducing ways to reduce traffic speed (traffic calming measures), parking areas, benches and play areas (Department for Transport 2005b).\n\n'Building brighter futures: next steps for the children's workforce' (Department for Children, Schools and Families 2008e) sets out how the government is further improving the skills and capacity of people who work with children. The aim is to deliver the high-quality, personalised and integrated services detailed in the 'Children's plan' (Department for Children, Schools and Families 2007b).\n\n# Non-government initiatives\n\nNon-government initiatives to encourage children and young people to be physically active are also common in England. Some of the organisations working in this area are listed below.\n\nPlay England, part of the National Children's Bureau, provides advice and support to promote good practice. It also works to ensure that policy makers, planners and the public recognise the importance of play. Resources include briefing papers, research reports and a 'Neighbourhood play toolkit CD ROM'. Play England has a contract with the Department for Children Schools and Families and Department for Culture Media and Sport to support the government's 'Play pathfinder' and 'Playbuilder' programmes.\n\nYouth Sport Trust supports the nationwide network of school sports partnerships. It also works with under-represented groups through programmes such as Girls in Sport, Living for Sport, YoUR Activity, TOP Activity and the Playground to Podium framework for young disabled people.\n\nThe British Heart Foundation runs initiatives and provides physical activity resources. These include: the 'Healthy schools physical activity toolkit' which supports the National Healthy Schools Programme; 'Get moving, get active participation award', a foundation key stage 1 participation award, developed with the Youth Sport Trust; and 'Active club resource pack' for out of school clubs developed with 4children.\n\nThe Fitness Industry Association runs 'go' (an outreach programme) and the 'Adopt a School' programme. Both were developed to help build stronger links between the fitness industry and schools. 'go' aims to help teenage girls (aged 15 and 16) to understand the benefits of being active and show that it can be fun. 'Adopt a school' targets children aged 10 and 11 in the final year of primary school.\n\nWhile the examples above are by no means exhaustive they demonstrate the current plethora of policies, initiatives and resources. However, many of them focus on sport and sporting opportunities; only a minority appear to promote lifetime physical activity or focus on lifestyle and unstructured activities (Cale and Harris 2006).", 'Considerations': "The PDG took account of a number of factors and issues in making the recommendations.\n\n# Value of physical activity\n\nPhysical activity is important for children and young people's health and wellbeing and contributes to their physical, social, emotional and psychological development.\n\nPhysical activity can help prevent long-term medical conditions and help manage existing conditions.\n\nThe Chief Medical Officer's recommendation is for children and young people to do a minimum of 60 minutes moderate to vigorous physical activity daily. This should include weight-bearing activities to improve bone health, muscle strength and flexibility at least twice a week. The PDG notes that there is likely to be a link between the amount and intensity of physical activity and its effect on health. Recent evidence suggests that children aged 9 may need 120 minutes per day and young people aged 15 may need 90 minutes per day, to reduce their risk of cardiovascular disease (Andersen et al. 2006).\n\nAll children and young people should have the opportunity to be involved in physical activity and should be encouraged and supported to participate. Provision and support should be available irrespective of disability, health status, religion, ethnicity, social, economic and other circumstances.\n\nThe PDG believes that only by fostering enjoyment and competence will children and young people be intrinsically motivated to increase and sustain their physical activity levels.\n\nWhen encouraging younger children to be physically active the focus should be on fun, enjoyment and active participation, rather than on the need to understand and conform to rules or master complex skills.\n\nThe PDG recognised that the recommendations are more likely to be implemented if they complement current policies that advocate physical activity.\n\n# Children and young people's needs\n\nChildren and young people need to participate in a wide range of different physical activities.\n\nChildren and young people need opportunities, time, space, facilities and equipment, permission and encouragement to be sufficiently physically active. They can be physically active through play and other spontaneous activities, as well as by taking part in structured or organised programmes.\n\nChildren and young people need to take risks and challenge themselves when involved in physically active play, sports and other activities, so they can learn their own boundaries. It was not within the PDG's remit to consider what might constitute an acceptable level of risk for children and young people when undertaking physical activity in different settings.\n\nThe PDG recognises that activities need to be tailored to the individual's developmental stage and physical ability. Activities also need to be sensitive to culture and gender issues. While it is important to take individual needs and preferences into account, the PDG believes it is also important to raise aspirations and encourage children and young people to explore a variety of options.\n\n# Factors that encourage or hinder physical activity\n\nParents, carers and other family members have a crucial role in encouraging young children to be physically active and in developing their movement skills. They can do this by providing a range of opportunities for physically active play and by playing active games with them. They can also encourage them to walk or cycle (or use other modes of travel involving physical activity) to get to and from different destinations. In addition, they can offer positive feedback, generally show an interest and act as positive role models.\n\nThe influence of peers is important and can serve to encourage or discourage physical activity.\n\nHelping children and young people to be involved in the design of activities or play spaces is an important way of encouraging them to be more physically active.\n\nChildren and young people's opportunities to be physically active can be affected by environmental, economic and social factors and perceptions about safety and accessibility. Weather conditions – and their perception of what type of conditions make it suitable to be outside – can also affect the opportunities they take.\n\nThe interests of the community as a whole need to be balanced with the interests of children and young people when promoting unsupervised activity in local neighbourhoods.\n\nContemporary society is generally perceived as risky. Media reporting and a private and public culture which emphasises health and safety, blame and rights have made risk aversion a dominant social value. Children and young people benefit from exposure to risks and challenges to help them develop skills and confidence. Many forms of physical activity and play (and the environments where they take place) have inherent risks. Unnecessary risk can be minimised through the use of risk-benefit assessment, safety precautions and safety equipment. Parents' and service providers' fears of injury and litigation can prevent children and young people from being physically active, even though the fear of risk may not necessarily correspond to reality. Paradoxically, in the long run, this can put children and young people at greater risk from the conditions associated with lack of activity – such as obesity, heart disease and cancer.\n\nThe PDG recognises the need for service providers to comply with health and safety legislation but cautions against an overly protective and risk-averse approach which may limit children and young people's physical activity. The physical and psychological benefits associated with physical activity and the health risks associated with a sedentary lifestyle should be considered when appraising risk.\n\nSome children and young people need special consideration. They include:\n\nThose who are 'not in education, employment or training' (NEET). PDG experience shows that physical activity has been used to get some of these young people back into education, training or employment. Physical activity programmes may also provide a positive diversion for children and young people who are at risk of offending.\n\nLooked after children and young people, many of whom move between residential care, foster carers or their own family home. This lack of continuity in their home life reduces their opportunities to access leisure facilities or participate in organised activities on a regular basis. In addition, as social groups are hard to maintain this may limit peer interaction and play.\n\nChildren of asylum seekers, refugees and travellers, many of whom have limited access to regular leisure, sport and play activities due to their transient lifestyle.\n\nYoung carers – children and young people who are providing care for a family member. The 2001 census identified 175,000 – and many more go unreported. Their responsibilities in the home limit the time they have for socialising with peers and getting involved in play or other types of physical activity.\n\nThose who are disabled or from a family where someone else is disabled.\n\nThose who are being educated at home.\n\nChildren who do not attend early years services.\n\nYoung people in the criminal justice system.\n\nChildren with physical disabilities, even those with severe impairments, can take part in physical activities to benefit their physical and social development. Children with the same impairment may display a wide range of abilities and therefore should not be treated as a single group. Many children who are disabled highlight social issues, rather than their impairment, as a barrier to participation. If they are encouraged to communicate their preferences, changes can be made to the physical environment, activities and the attitudes of others to help them to participate. Practitioners can encourage and nurture positive peer interaction through play and other physical activity opportunities.\n\nThe transitions between education institutions – and from education to employment – are times when young people may have less opportunity for physical activities.\n\n# Other issues\n\nDespite extensive searches, it was difficult to find many high quality controlled studies demonstrating the effectiveness of interventions. Where there was little evidence from controlled studies, the PDG considered observational data and evidence from practice. It also drew on the expertise and experience of its members to supplement the evidence\n\nThere was a lack of consistency in the way children and young people's physical activity was measured, making it difficult to assess the effectiveness of comparative studies. In addition, some studies focussed on increases in particular types of physical activity rather than overall levels of activity. As interventions may result in children and young people getting involved in one type of physical activity at the expense of another, overall, it might not lead to them being more physically active. In other words, the cumulative impact of implementing the recommendations may not be as great as indicated for particular interventions.\n\nThere is little published evidence on the costs or cost-effectiveness of interventions. The economic review team, working with members of the PDG, undertook some exploratory economic analysis to estimate potential costs and benefits.\n\nMany physical activities involve volunteers (either parents, young people or members of the local community). Those who undertake this kind of work (young people in particular), can act as inspirational role models to others. It is important to ensure this base of volunteers is sustained by providing them with training and support. National volunteering schemes such as 'Vinvolved' and many traditional volunteering and interest groups offer this kind of support to young people and, increasingly, their parents and carers.\n\nPractitioners' opinions about what children and young people would like to do may differ from the reality; it may be difficult for them to keep up to date with the activities that children and young people are interested in. The PDG also acknowledges that some children and young people may not be aware of the range of physical activities they could get involved in.\n\nIt was not possible to address all aspects of the original DH referral. The guidance focuses on children aged 11 and under and adolescent girls. However, many of the recommendations relate to all children and young people under 18, as it also focuses on physically active travel and physical activity for all children and young people aged under 18 in community and family settings. Physical activity as part of the national curriculum was not part of the scope of this guidance, however it does cover physical activity in extra-curricular and extended school settings.", 'Recommendations for research': "The PDG recommends that the following research questions should be addressed. It notes that 'effectiveness' in this context relates not only to the size of the effect, but also to cost effectiveness and duration of effect. It also takes into account any harmful/negative side effects.\n\nThe PDG considered that research funding agencies should establish a nationally coordinated programme to evaluate the most effective and cost effective ways of increasing children and young people's physical activity levels.\n\n# Recommendation 1\n\nDevelop valid, sensitive, and reliable tools to measure physical activity in children and young people. The tools should measure the amount and pattern of activity (including sedentary behaviour).\n\n# Recommendation 2\n\nFuture research should be conducted with greater rigour, improved study design, appropriate sample sizes, and valid and reliable measures of physical activity. It should include long-term follow-up of participants and monitoring of implementation fidelity. Studies should seek to identify causal pathways leading to a change in physical activity and health outcomes (such as a decrease in body fat and an increase in self-esteem). They should identify any potential mediating variables. They should also investigate the relationship between the length and intensity of the intervention and changes in physical activity (including sedentary behaviour).\n\n# Recommendation 3\n\nDetermine the most effective and cost-effective methods of increasing (and sustaining) the number and length of journeys children and young people take using a physically active mode of travel. The focus should be on journeys in the wider community (that is, not just on those to and from school).\n\n# Recommendation 4\n\nDetermine the most effective and cost-effective methods of increasing and sustaining different types of physical activity among specific groups of children and young people. Groupings could be by: age, culture, ethnicity, disability (including families where someone else is disabled), gender, geographic area (for example, inner-city, urban, rural), religion or socioeconomic status. Particular attention should be given to disadvantaged groups. The interventions examined may target specific behaviours (for example, active play).\n\n# Recommendation 5\n\nDetermine to what extent different types of physical activity displace others and the factors leading to sedentary behaviour over time.\n\nMore detail on the evidence gaps identified during the development of this guidance is in appendix D.", 'Glossary ': "Access/accessibility\n\nThe ability to use a facility because, for instance, it is free or affordable, it does not require people to travel a long distance to use it and the environment and activities are suitable for those with disabilities. Examples of facilities include playgrounds, parks or open spaces and leisure, youth or community centres.\n\nActive play\n\nThe Children's Play Council (now Play England) defines play as: ' …freely chosen, personally directed, intrinsically motivated behaviour that actively engages the child...' (National Playing Fields Association 2000). Active play involves physical activity.\n\nDisplacement\n\nDisplacement occurs when children and young people get involved in one type of physical activity at the expense of another, resulting in their overall physical activity levels remaining the same.\n\nIntrinsic motivation\n\nIntrinsic motivation is an internal factor, such as an interest in learning a skill or the desire for further personal development. It compares with extrinsic motivation, which is inspired by external factors such as being given a monetary incentive.\n\nMovement skills\n\nMovement skills use skeletal muscles to achieve a physical goal. They are learnt and refined throughout life. Gross movement skills include: rolling over, sitting up, crawling, walking, running, jumping, hopping and skipping. Fine movement skills include the ability to manipulate small objects and transfer them from hand to hand, and tasks that involve hand-eye coordination.\n\nSchool travel plan\n\nA written document detailing a package of measures to improve safety and reduce car use, backed by a partnership involving the school, education and local authority transport officers, the police and the health authority. It is based on consultation with teachers, parents, pupils and governors and other local people. It must include: information about the school, a description and analysis of journeys made and the associated problems, a survey of pupils' current and preferred mode of travel, consultation findings, clearly defined targets and objectives, details of proposed measures and a timetable for implementation, clearly defined responsibilities and proposals for monitoring and review.\n\nSedentary lifestyle\n\nThe Health Survey for England (2005) defines children as sedentary if they either do no physical activity at all or less than 30 minutes a day of moderate intensity activity.\n\nSport\n\nSport means all forms of physical activity which, through casual or organised participation, aim at expressing or improving physical fitness and mental well-being, forming social relationships or obtaining results in competition at all levels.", 'References': "Andersen LB, Harro M, Sardinha LB Et al. (2006) Physical activity and clustered risk in children: across sectional study. The European Youth Heart Study. The Lancet 368: 299–304.\n\nBurnham A (2008) Written ministerial statement on free swimming.\n\nCale L, Harris J (2006) Interventions to promote young people's physical activity: Issues, implications and recommendations for practice. Health Education Journal 65: 320–337.\n\nCaspersen CJ, Powell KE, Christensen G (1985) Physical activity, exercise and physical fitness: definitions and distinctions of health-related research. Public Health Reports 100: 126–131.\n\nDepartment for Children, Schools and Families (2007a) Extended schools: building on experience. London: Department for Children, Schools and Families.\n\nDepartment for Children, Schools and Families (2007b) The children's plan. Building brighter futures. Norwich: The Stationery Office.\n\nDepartment for Children, Schools and Families (2008a) 2007/08 school sport survey.\n\nDepartment for Children, Schools and Families (2008b) The children's plan one year on: a progress report. Nottingham: Department for Children, Schools and Families.\n\nDepartment for Children, Schools and Families (2008c) PE & sport strategy for young people.\n\nDepartment for Children, Schools and Families (2008d) The play strategy. Nottingham: Department for Children, Schools and Families.\n\nDepartment for Children, Schools and Families (2008e) Building brighter futures: next steps for the children's workforce. Nottingham: Department for Children, Schools and Families.\n\nDepartment for Culture, Media and Sport (2002) Game plan: a strategy for delivering government's sport and physical activity objectives. London: Cabinet Office.\n\nDepartment for Culture, Media and Sport (2004) Getting serious about play. London: Department for Culture, Media and Sport.\n\nDepartment for Culture, Media and Sport (2006) Time for play. London: Department for Culture, Media and Sport.\n\nDepartment for Culture, Media and Sport (2008a) Playing to win: a new era for sport. London: Department for Culture, Media and Sport.\n\nDepartment for Culture, Media and Sport (2008b) Before, during and after: making the most of the London 2012 games. London: Department for Culture, Media and Sport.\n\nDepartment for Education and Skills (2004) Every child matters: change for children. London: The Stationery Office.\n\nDepartment for Education and Skills (2006a) Sustainable schools for pupils, communities and the environment. An action plan for the DfES. Nottingham: Department for Education and Skills.\n\nDepartment for Education and Skills (2006b) Sustainable schools for pupils, communities and the environment. Nottingham: Department for Education and Skills.\n\nDepartment for Transport (2005a) Travelling to school initiative: report on the findings of the initial evaluation.\n\nDepartment for Transport (2005b) Home zones. Challenging the future of our streets. London: Department for Transport.\n\nDepartment for Transport (2008) Travel to school personal travel factsheet.\n\nDepartment of Health (2003) Health survey for England 2002. London: Department of Health.\n\nDepartment of Health (2004) At least five a week: evidence on the impact of physical activity and its relationship to health. London: Department of Health.\n\nDepartment of Health (2005) Choosing activity: a physical activity action plan. London: Department of Health.\n\nDepartment of Health (2006) Health challenge England. London: Department of Health.\n\nDepartment of Health and Department for Children, Schools and Families (2007) Introduction to the national healthy schools programme. London: Department of Health.\n\nDepartment of Health (2008a) Department of Health (2008a) Change4Life.\n\nDepartment of Health (2008b) Healthy weight. Healthy lives. A cross-government strategy for England. London: Department of Health.\n\nDepartment of Health (2008c) Child health promotion programme. London: Department of Health.\n\nDepartment of Health (2009) The physical activity plan. London: Department of Health.\n\nHM Government (2006) Education and Inspections Act 2006. London: The Stationery Office.\n\nHM Treasury (2008a) Public service agreement 12 2005–2008.\n\nHM Treasury (2008b) Public service agreement 22 2008–2011.\n\nNational Playing Fields Association, Children's Play Council and PLAY LINK (2000) Best play. London: National Playing Fields Association.\n\nRiddoch CJ, Mattocks C, Deere K et al. (2007) Objective measurement of levels and patterns of physical activity. Archives of Disease in Childhood 92: 963–969.\n\nSport England (2008) Sport England strategy 2008–2011. London: Sport England.\n\nSustainable Development Commission (2007) Every child's future matters. London: Sustainable Development Commission.\n\nThe Information Centre (2008a) Health survey for England 2007. Leeds: The Information Centre.\n\nThe Information Centre (2008b) Health survey for England 2006. Leeds: The Information Centre.", 'Appendix B: Summary of the methods used to develop this guidance': "# Introduction\n\nThe reports of the reviews and economic appraisal include full details of the methods used to select the evidence (including search strategies), assess its quality and summarise it. The minutes of the PDG meetings provide further detail about the Group's interpretation of the evidence and development of the recommendations.\n\nAll supporting documents are listed in appendix E.\n\n# Key questions\n\nThe key questions were established as part of the scope. They formed the starting point for the reviews of evidence and facilitated the development of recommendations by the PDG. The overarching questions were:\n\n. Which strategies, policies, campaigns, interventions and approaches are effective and cost effective in helping children of different ages (with low levels of physical activity) to become more physically active?\n\n. What are the barriers and facilitators to children's participation in physical activity?\n\n. Which physical activity strategies, policies, campaigns, interventions and approaches are effective and cost effective in reducing health inequalities among pre-school and school-age children?\n\nThese questions were refined further in relation to the topic of each review (see reviews for further details).\n\n# Reviewing the evidence\n\nA total of eight reviews were conducted.\n\n## Identifying the evidence\n\nSearches were conducted for studies published from January 1990 to April 2007 (except where stated).\n\nThe following databases were searched for reviews 2, 4, 5, 6, and 7. Additional searches for these reviews and details for the other reviews are listed separately.\n\nApplied Social Sciences Index and Abstracts\n\nArticleFirst\n\nCambridge Scientific Abstract\n\nCINAHL\n\nCochrane Library\n\nCSA Environmental Sciences\n\nEMBASE\n\nERIC\n\nGeobase\n\nGlobal Health\n\nISI Social Science Citation Index\n\nMEDLINE\n\nPubMed\n\nPsycINFO\n\nScience Citation Index\n\nSIGLE\n\nSociological Abstracts\n\nSPORTDiscus\n\nTRIS online\n\nWeb of Science.\n\nThe following databases were searched from 2001 for longitudinal or cohort studies:\n\nMEDLINE\n\nMetalib (including ArticleFirst, Physical Education Index, PSYCinfo, SPORTDiscus, Web of Science, Zetoc)\n\nPubMed.\n\nWeb searches were also conducted: a key source was a briefing paper on obesity produced by the NHS.\n\nIn addition to searching the main databases from 2000 to April 2007, manual searches were conducted of the following key peer-reviewed journals:\n\n'International journal of behavioural nutrition and physical activity'\n\n'Journal of physical activity & health'\n\n'Obesity reviews'\n\n'Pediatric exercise science'\n\n'Preventive medicine'\n\n'Sports medicine'.\n\nPrimary research articles, reviews and book chapters, as well as research team members' files were also searched. In addition, the websites of four UK and US organisations involved in commissioning, undertaking or cataloguing research on physical activity and young people were searched for 'grey' literature. These were:\n\nPlay England\n\nSustrans\n\nActive Living Research (US)\n\nInstitute of Education, University of London\n\nThe following databases were searched to identify non-intervention qualitative studies published since 1990:\n\nCINAHL\n\nCSA Environmental Sciences\n\nEMBASE\n\nEnvironmental Sciences and Pollution Management\n\nERIC\n\nIndex to Thesis\n\nPsycINFO\n\nScience Citation Index and SSCI\n\nSIGLE (ends 2005)\n\nSPORTDiscus\n\nTRIS online.\n\nIn addition, the websites of four UK and US organisations involved in commissioning, undertaking or cataloguing research on physical activity and young people were searched for 'grey' literature. These were:\n\nPlay England\n\nSustrans\n\nActive Living Research (US)\n\nInstitute of Education, University of London\n\nIn addition to the main database search, the following were also searched:\n\nEnvironline\n\nEPPI Centre Databases\n\nHMIC\n\nNRR\n\nTRANSPORT\n\nThe 'Journal of physical activity and health'.\n\nTwo PDG members helped to identify a list of relevant references, based on an iterative search of material in the Children's Play Information Service at the National Children's Bureau. This was supplemented by web searches and re-interrogation of the search results from the other reviews. References were screened for relevance by two reviewers.\n\n# Selection criteria\n\nInclusion and exclusion criteria for each review varied. However, in general studies were included as follows.\n\nReview 1: Studies conducted in England or the UK (as long as they included England) that questioned children and young people on physical activity in childhood and adulthood.\n\nReview 2: Studies classified as review papers and using systematic methodologies, if they looked at the association between quantitatively measured variables and children or adolescents' (<19 years old) physical activity.\n\nReview 3: Studies which explored children's, adolescents' (<19 years old) or carers' experiences of sport, play and active travel. Methods and results had to be clearly reported and the study had to be relevant to the UK.\n\nReviews 4, 5, 6 and 7: Intervention studies on children under eight, active travel, adolescent girls, and family and communities, if they reported on physical activity or physical skills. See the reviews for further details.\n\nReview 8: Material directly applicable to the UK. It was not limited by quality or study design, but needed to illustrate or describe the opinions and experiences of children, parents and practitioners about how to stimulate – or help stimulate – active play.\n\nStudies were excluded if:\n\nthey focused on treating obesity\n\nthey were from less economically developed countries\n\nthey were studies about ethnic groups that do not have large populations in England\n\nthe intervention involved the school curriculum/physical education\n\nthe study involved a change to the built or natural environment.\n\n## Quality appraisal\n\nFor reviews 3–7, included papers were assessed for methodological rigour and quality using the NICE methodology checklist, as set out in the NICE technical manual 'Methods for development of NICE public health guidance' (see appendix E). Each study was described by study type and graded (++, +, -) to reflect the risk of potential bias arising from its design and execution.\n\nMeta-analyses, systematic reviews of randomised controlled trials (RCTs) or RCTs (including cluster RCTs).\n\nSystematic reviews of, or individual, non-randomised controlled trials, case-control studies, cohort studies, controlled before-and-after (CBA) studies, interrupted time series (ITS) studies, correlation studies.\n\nNon-analytical studies (for example, case reports, case series).\n\nExpert opinion, formal consensus.\n\n++ All or most of the criteria have been fulfilled. Where they have not been fulfilled the conclusions are thought very unlikely to alter.\n\n+ Some criteria have been fulfilled. Those criteria that have not been fulfilled or not adequately described are thought unlikely to alter the conclusions.\n\n- Few or no criteria fulfilled. The conclusions of the study are thought likely or very likely to alter.\n\nThe studies were also assessed for their applicability to the UK.\n\n## Summarising the evidence and making evidence statements\n\nThe review data was summarised in evidence tables (see full reviews).\n\nThe findings from the included papers in each review were synthesised and used as the basis for a number of evidence statements relating to each review question. The evidence statements reflect the strength (quantity, type and quality) of evidence and its applicability to the populations and settings in the scope.\n\n# Economic analysis\n\nThe economic appraisal consisted of a review of economic evaluations and a cost-effectiveness analysis.\n\n## Review of economic evaluations: 'A rapid review of economic literature related to the promotion of physical activity, play and sport for pre-school and school age children in family, pre-school, school and community settings'\n\nThe following databases were searched for economic literature that had not been identified through the search of the effectiveness reviews:\n\nEconLIT\n\nHealth Economic Evaluation Database (HEED)\n\nNHS Economic Evaluation Database (NHS EED).\n\nRelevant websites were searched (for example, Sport England and Department for Transport). Other sources included papers identified from the personal libraries or collections of members of the health economics team.\n\nStudies were included if they were:\n\nbased in economically developed countries and considered the promotion of physical activity, play and sport for children\n\neconomic evaluations or contained cost, resource use or outcomes data which could be used to inform the economic modelling.\n\n## Cost-effectiveness analysis: 'A cost-effectiveness scenario analysis of four interventions to increase child and adolescent physical activity: the case of walking buses, free swimming, dance classes and community sports'\n\nAn economic model was constructed to incorporate data from the reviews of effectiveness (reviews 4,5,6,7) and cost effectiveness.\n\n# Fieldwork\n\nFieldwork was carried out to evaluate how relevant and useful NICE's recommendations are for practitioners and how feasible it would be to put them into practice. It was conducted with practitioners and commissioners who are involved in providing physical activity services for children and young people. They included those working in the NHS, education, local authorities and the voluntary and community sector.\n\nThe fieldwork comprised three studies conducted by Greenstreet Berman:\n\nTen workshops carried out in Birmingham, Liverpool, London, Newcastle with representatives from a variety of professional groups. These included: local authority sports, health and play promotion/development services and children's services; primary care trusts (health improvement representatives), county sports partnerships, Play England, Youth Sport Trust and Sport England.\n\nThirty-two telephone interviews with representatives from education, parent/carer associations, pre-school organisations and local clubs and associations. Each interview covered five of the draft recommendations.\n\n\n\nLocal clubs: draft recommendations 4, 6, 7, 8, 9,10, 12, 13, 14\n\nParents and carers: draft recommendations 6, 9, 10, 11, 12, 13, 14, 15\n\nEducation: draft recommendations 4, 6, 7, 8, 9, 10, 11, 12.\n\n\n\nAn online survey of schools, covering the eight draft recommendations that were directly relevant to them (4, 6, 7, 8, 9, 10, 11, 12).\n\nThe three studies were commissioned to ensure there was ample geographical and sector coverage. The main issues arising are set out in appendix C fieldwork findings. The full fieldwork report is 'Fieldwork on the promotion of physical activity, active play and sport for pre-school and school age children in family, pre-school, school and community setting'.\n\n# How the PDG formulated the recommendations\n\nAt its meetings in 2007/2008, the PDG considered the evidence to determine:\n\nwhether there was sufficient evidence (in terms of quantity, quality and applicability) to form a judgement\n\nwhether, on balance, the evidence demonstrates that the intervention is effective or ineffective, or whether it is equivocal\n\nwhere there is an effect, the typical size of effect.\n\nThe PDG developed draft recommendations through informal consensus, based on the following criteria:\n\nStrength (quality and quantity) of evidence of effectiveness and its applicability to the populations/settings referred to in the scope.\n\nEffect size and potential impact on population health and/or reducing inequalities in health.\n\nCost effectiveness (for the NHS and other public sector organisations).\n\nBalance of risks and benefits.\n\nEase of implementation and the anticipated extent of change in practice that would be required.\n\nThe PDG also considered whether a recommendation should only be implemented as part of a research programme where evidence was lacking.\n\nWhere possible, recommendations were linked to evidence statements (see appendix C for details of evidence statements). Where a recommendation was inferred from the evidence, this was indicated by the reference 'IDE' (inference derived from the evidence).\n\nThe draft guidance, including the recommendations, was released for consultation in August 2008. At its meeting in October 2008, the PDG amended the guidance in light of comments from stakeholders and experts and the fieldwork. The guidance was signed off by the NICE Guidance Executive in December 2008.", 'Appendix C: The evidence': "This appendix sets out the evidence statements taken from eight reviews provided by external contractors/public health collaborating centres (see appendix A for details of the external contractors and collaborating centres ) and links them to the relevant recommendations (see appendix B for the key to study types and quality assessments). The evidence statements are presented here without references – these can be found in the full review (see appendix E for details of the full review). It also sets out a brief summary of findings from the economic appraisal and the fieldwork.\n\nThe eight reviews are:\n\nReview 1: 'Descriptive epidemiology'\n\nReview 2: 'Correlates of physical activity in children: a review of quantitative systematic reviews'\n\nReview 3: 'The views of children on the barriers and facilitators to participation in physical activity: a review of qualitative studies'\n\nReview 4: 'Intervention review: under eights'\n\nReview 5: 'Intervention review: children and active travel'\n\nReview 6: 'Intervention review: adolescent girls'\n\nReview 7: 'Intervention review: family and community'\n\nReview 8: 'Review of learning from practice: children and active play'.\n\nEvidence statement number 2.4 indicates that the linked statement is numbered 4 in review 2 'Correlates of physical activity in children: a review of quantitative systematic reviews'. Evidence statement 4.1 indicates that the linked statement is numbered 1 in review 4 'Intervention review: under eights'.\n\nSee the reviews and the economic appraisal. Where a recommendation is not directly taken from the evidence statements, but is inferred from the evidence, this is indicated by IDE (inference derived from the evidence).\n\nRecommendation 1: evidence statements 2.4, 3.1, 3.2, 3.3, 3.4, 7.1b, 7.6, 8.4\n\nRecommendation 2: evidence statements 3.1, 3.2, 7.5\n\nRecommendation 3: evidence statements 3.1, 3.2, 3.3, 3.4\n\nRecommendation 4: evidence statements 2.5, 8.1\n\nRecommendation 5: evidence statements 5.1, 5.2, 5.3, 5.4\n\nRecommendation 6: evidence statements 3.1, 3.2, 3.4\n\nRecommendation 7: evidence statement 3.2\n\nRecommendation 8: evidence statements 3.1, 8.1\n\nRecommendation 9: evidence statement 7.5\n\nRecommendation 10: evidence statements 3.2, 4.3, 8.4\n\nRecommendation 11: evidence statement 3.1, 6.1\n\nRecommendation 12: evidence statements 2.4, 3.3, 5.1, 5.2, 5.3, 5.4\n\nRecommendation 13: evidence statements 3.2, 4.3\n\nRecommendation 14: evidence statements 3.1\n\nRecommendation 15: evidence statements 2.4, 3.2, 7.1a, 7.5, 8.5\n\n# Evidence statements\n\n## Evidence statement 2.4\n\nThere is evidence from four systematic reviews of observational studies that: there is a large positive association between parental and social support and physical activity in young people.\n\n## Evidence statement 2.5\n\nThere is evidence from four systematic reviews of observational studies that there is a:\n\nsmall-to-moderate positive association between access to facilities and participation in physical activity in young people\n\nmoderate negative association between distance from home to school and physical activity in young people\n\nmoderate-to-strong positive association between time spent outside and physical activity in young people\n\nsmall negative association between local crime and physical activity in young people.\n\n## Evidence statement 3.1\n\nThere is evidence from 15 UK qualitative studies of adolescent girls (reported in 16 papers) (two [++]; six [+] and eight [-]) that the main barriers to being physically active were:\n\nsocial pressure to conform, (for example, wanting to fit in)\n\nnegative experience of the school environment (for example, inappropriate school PE kit and discomfort about sharing showers, changing rooms)\n\nnegative experiences of sports facilities (for example, public spaces such as gyms or exercise classes were intimidating to teenage girls)\n\nhaving to perform in public (for example, being forced to perform a skill in front of peers)\n\nfear of forced competition (one study [++] reported that creating a supportive environment for the delivery of a curricula focused on participation rather than competition and empowering students led to non-active student becoming more active)\n\nfear of sexual or racial harassment (for example, Asian girls described needing escorting by family member to places to participate in sports).\n\nThe main facilitators to being physically active were:\n\nsocial and family influences (for example, social sanctioning of activities by peers provided opportunities to gain social standing and was likely to encourage continued or increased participation; having active siblings and supportive parents)\n\nenjoyment (for example, enjoyment and fun during sport and physical activity; enjoyment might outweigh the impact of negative peer pressure not to participate)\n\nsocialisation (for example, sport provides the opportunity to socialise with friends and extend friendship networks beyond school)\n\nintrinsic and extrinsic rewards (for example, wanting to participate in sport as a means to achieve a socially desirable body type; receiving praise and encouragement from PE teachers helped with self confidence and a positive self identity).\n\n## Evidence statement 3.2\n\nThere is evidence from five UK qualitative studies of children aged 8 and under (three [+] and two [-]) that: there were far fewer barriers to physical activity and sport compared with other age groups. Barriers were:\n\ndislike of a focus on team sports (for example, team sport focus in primary schools)\n\ngender and cultural stereotyping about appropriateness of some sports for particular genders by parents and peers for example, parent viewing boys more active than girls; some sports were more 'appropriate' for boys to play than girls; boys not allowing girls to play 'boys games')\n\ncosts of participation in organised sports (for example, cost in terms of time and money in participating)\n\ndislike of physical activities becoming less fun and more technical and performance-orientated (for example, girls stopped participating in ballet as it became more technical and less fun-orientated).\n\nThe main facilitators for children aged 8 and under were:\n\nenjoyment (for example, creative and fun activities; participating in their favourite sports or activities; older children involving younger children)\n\nparental and peer support (for example, physical activity was healthy; girls and boys enjoyed playing sports more if they had started at a younger age)\n\nparticipation in age appropriate activities (for example, fun-based dance activities at younger ages; parent seeing a progression from fun to more structured activity as children became older).\n\n## Evidence statement 3.3\n\nThere is evidence from three UK qualitative studies of children and active travel that the main barriers to active travel were:\n\nchildren and parents' fear of traffic (for example, children feeling unsafe when playing and walking outside, particularly after school)\n\nparental restrictions on independent movement (for example, parental restrictions on a child's range [distance], plus place and destinations)\n\nschool influence over cycling policy and storage facilities (for example, absence of any school provision of facilities reflecting a lack of support for cycling)\n\nlimited play destinations locally (for example, too far to travel to independently; access dangers due to traffic; play equipment unsuitable)\n\nadult disapproval of children playing outside (for example, children told off for cycling or playing in streets by adults).\n\nOnly one study reported any facilitators for walking and cycling. These included:\n\nproviding personal freedom (for example, reported that walking and cycling increased their personal freedom and independence)\n\nenjoyment and fun with friends (for example, older children enjoyed walking to school because they could mix with their friends)\n\nthe opportunity to explore local surroundings (for example, gave them the chance to explore local neighbourhoods with their friends and/or alone).\n\n## Evidence statement 3.4\n\nThere is evidence from two UK studies and two international qualitative studies (both Australian), of families and community that barriers to physical activity and sport were related to personal safety of children while playing outside unsupervised. Common issues were:\n\nperceived stranger danger (for example, both parents and children independently reported fear of strangers)\n\nrisk of personal accidents (for example, both parents and children independently reported risk of accidents or getting hurt)\n\nintimidation from older children (for example, both parents and children independently reported the risk of intimidation or bullying by older children; fear of rival gangs for different areas)\n\npoor quality of places to play (for example, presence of drug taking equipment (like syringes) in play areas; poorly maintained toilets, shaded areas and lighting).\n\nFacilitators were that children:\n\nvalued opportunities for independent outdoor play (for example, the chance to play away from adult supervision with friends; parents preferring these places for independent play to be courtyards or cul-de-sacs rather than through roads)\n\npreferred activities that emphasised fun, play and enjoyment rather than skills practice (for example, older children attending athletics club liked playing with friends).\n\n## Evidence statement 4.3\n\nThere is evidence from one cluster randomised controlled trial in the UK (+), one controlled non-randomised trial in Greece (+) and one controlled before-and-after trial in the USA (-) that supervised physical activity interventions conducted in the pre-school setting can be effective in improving core physical skills such as: running, galloping, hopping, sliding, leaping, skipping and general motor agility.\n\n## Evidence statement 5.1\n\nThere is evidence from five UK studies (all uncontrolled before-and-after studies [+]) that cycling promotion projects, targeting primary and secondary school children can lead to large self-reported increases in cycling both at 9 to 11\xa0months and over 20 to 23\xa0months. Characteristics of successful interventions included the involvement of external agencies to facilitate schools to promote and maintain cycling, with the support of parents and the local community.\n\nThere is evidence from two studies (uncontrolled before-and-after studies [+]), where cycling infrastructure was commonly part of the local transport infrastructure or children were encouraged to cycle to curriculum-related events or sports fixtures, that self-reported levels of walking declined over 20 and 23\xa0months, implying that some of the increase in cycling may have been offset by a decrease in walking. The evidence is applicable to the UK.\n\n## Evidence statement 5.2\n\nThere is evidence from one UK study (randomised controlled trial [++]) to suggest that the introduction of school travel plans and direct support from a school travel plan adviser at primary schools did not lead to increases in self-reported levels of walking and cycling at 12\xa0months.\n\nThere is evidence from one US and one UK study (uncontrolled before-and after-study [+]) to suggest that a mix of promotional measures including curriculum, parental and community promotions (for example, mapping safe routes to school, walk and bike to school days) can increase self-reported walking and cycling at 24\xa0months. In the UK study, this activity was in support of a travel plan. The evidence is applicable to the UK.\n\n## Evidence statement 5.3\n\nThere is evidence from three UK studies (uncontrolled before-and-after studies [+]) to suggest that walking buses (volunteer-led walking groups supported by parents and teachers plus the involvement of the local highways or transport authority) led to increases in self-reported walking among 5 to 11\xa0year olds, and reduced car use for children's' journeys to and from school at 10\xa0weeks and 14 to 30\xa0months.\n\nThere is evidence from one study (uncontrolled before-and-after study [-]) to suggest that the provision of a walking bus may in itself not be sufficient to stem a more general decline in walking to and from school. Retaining volunteers to act as coordinators for these schemes appears to be a key factor in the sustainability of walking buses.\n\nCurrently walking buses are found to be commonly delivered in the UK, however evidence for their applicability remains uncertain (as they may be applicable only to the specific populations or settings included in the studies).\n\n## Evidence statement 5.4\n\nThere is evidence from one UK study (controlled before-and-after study [+]), and two UK (uncontrolled before-and-after studies [+]) and one Australian studies (uncontrolled before-and-after study [+])to suggest that walking promotion schemes, involving promotional materials, incentives and rewards (such as travel diaries for children and parents and provision of 'park and walk' parking areas close to school and restriction of parking outside of schools), can lead to increases in self-reported walking to school among 4 to 11\xa0year olds, and reduced car use for children's' journeys to and from school at 4 to 10\xa0weeks and 41 to 48\xa0months.\n\nThere is evidence from one UK study (controlled before-and-after study [+]) to suggest that walking campaign packs alone, including promotion materials for children and parents, did not lead to increases in walking among 4 to 11\xa0year olds at 4\xa0weeks.\n\nThere is evidence from two UK and one Australia study (uncontrolled before-and-after study [+]) to suggest that targeting children and parents who live a short distance to school (1\xa0mile or less) may support interventions to encourage increase walking levels for the school journey.\n\nThe evidence mainly comes from UK studies and so is directly applicable only to populations or settings included in the studies (primary school settings). The success of broader application is uncertain.\n\n## Evidence statement 6.1\n\nThere is evidence from three cluster randomised controlled trials (one each in Australia [+], France [+], and Ireland [+]), and one controlled non-randomised trial in the USA (-), that school-based interventions outside of physical education lessons, targeting the single behaviour of physical activity, can lead to moderate-to-large increases in physical activity in adolescent girls for up to 6\xa0months. One randomised controlled trial (++) and one cluster randomised controlled trial (+) (both from the USA), failed to show an effect. Characteristics of successful interventions were not consistent across studies, although three of the four successful trials targeted girls only. Successful interventions included self-monitoring techniques, stage-matched counselling, teacher-led extra-curricula physical activity, and multi-level programming targeting psychological, social and environmental correlates.\n\nThe evidence is drawn from non-UK studies and therefore the applicability to the UK is limited.\n\n## Evidence statement 7.1a\n\nThere is evidence from two randomised controlled trials in the USA (one [++] and one [+]) that family-based physical activity interventions targeting overweight/obese children and/or those at risk for overweight/obesity, can lead to increases in physical activity in young people. However, two randomised controlled trials in the USA (both [+]) failed to show an effect in the same target group. Characteristics of successful interventions included being located in the home and therefore not involving attendance at external sites and focused on small, specific lifestyle changes (2000 more steps per day and a single dietary target). In contrast, unsuccessful interventions required regular attendance at sites external to the home for education and/or physical activity sessions, broader physical activity and dietary behaviour change, and were with 8 to 9\xa0year old African-American girls.\n\n## Evidence statement 7.1b\n\nThere is evidence from one randomised controlled trial in the USA (+), one randomised non-controlled trial in the USA (+), one controlled non-randomised trial (+) and one uncontrolled before-and-after study (-) that family-based interventions, targeting physical activity, can lead to increases in physical activity in young people. One randomised controlled trial in the USA (++) and one uncontrolled before-and-after study in the USA (-) failed to show an effect. One randomised controlled trial in the USA (-) showed a negative effect. Successful interventions were located mostly in the home and predominantly involved information packs. Two of the successful interventions involved either mothers and daughters or grandmothers, mothers, and daughters exercising together. Unsuccessful interventions all involved regular attendance at physical activity and education sessions outside of the home. Other differences between successful and unsuccessful interventions were not consistent.\n\n## Evidence statement 7.5\n\nThere is evidence from two cluster randomised controlled trials in Belgium and France (both [+]) and three controlled non-randomised trials in the Netherlands, Greece and the USA (one [+] and two [-]) that interventions involving both the school and family and/or community agencies lead to positive changes in physical activity in boys and girls aged 13 or under. These positive outcomes may include an actual increase in physical activity or less of a decline in physical activity relative to controls. Successful interventions had multiple components. At the school level this included computer-tailored advice, changes to the school environment, classroom sessions, physical activity sessions, and physical education. Family components included facilitating social support for physical activity, education on creating a supportive home environment, homework activities involving parents, and community sport information. One cluster randomised controlled trial in the USA (+) and one uncontrolled before-and-after study in the USA (-) failed to show an effect. The characteristics of these unsuccessful interventions were not consistently different from those of successful interventions.\n\n## Evidence statement 7.6\n\nThere is evidence from one controlled non-randomised trial in the USA (+) that social marketing interventions can increase levels of free-time physical activity in children and adolescents (9 to 15\xa0year olds). The social marketing campaign employed engaging messages (primarily via TV advertisements) and promoted opportunities to incorporate physical activity into daily lives. The sustained nature of the campaign (2\xa0years) was considered important to its success. Behavioural changes were seen in the activities targeted by the campaign (for example, free-time activities) and there were no effects on participation in organised sport.\n\n## Evidence statement 8.1\n\nThere is strong support for the principle of ensuring that children in the foundation stage are given the opportunity for regular outdoor play as part of the school day. Outdoor play should provide opportunities for movement and challenge, and opportunities to play safely with natural elements.\n\nChildren's play in outdoor space can be optimised through a number of practical measures such as: seeing the indoor and outdoor spaces as one environment; providing materials specifically for physically active play; making links to the curriculum; provide for diverse active activities; planning to take account of issues such as weather, light, wind direction.\n\nThe indoor environment can also be optimised for active play, through providing sufficient space; allowing freedom to move from one area to another; providing good opportunities for energetic physical movement; dividing space into active and quiet zones.\n\nAdults can help to facilitate active play through: creating the right context for play in which children feel secure and still have the necessary freedom and autonomy to explore through free play; observing play and understanding children's interests, in order to guide the provision of resources and environments for play; interacting appropriately and intervening only when necessary; creating the right environment for play including materials and resources for play, as well as the actual place to play.\n\nPractitioners may limit the amount of outdoor play offered to children due to a number of assumptions: that the outside is dangerous; that higher adult/child ratios are needed outside; that educators are merely supervisors outdoors, and that no learning happens outside; that the weather is a barrier; and that being outside is somehow less healthy. All of these assumptions can be tackled to increase active play outdoors.\n\nThere appears to be a strong consensus among practitioners that there should be much more out of hours use of school grounds.\n\nFor older children, play facilities are most valued when they are close at hand. If a facility is more than a few hundred metres away, regular use declines dramatically.\n\n## Evidence statement 8.4\n\nIt is well acknowledged that physical education contributes to the development of core skills. However, there appears to be much less consensus on the role of play in developing core skills.\n\nCore skills can be developed through natural active play, especially when the play is determined by the children themselves.\n\nThe role of the play practitioner may be less about planning complex programmes to focus on core skill development, but instead facilitating active play.\n\n## Evidence statement 8.5\n\nThere is often reluctance by parents and professional carers to also go outside and supervise children playing outdoors in poor weather.\n\nIt appears that practitioners are put off by the weather more than children.\n\nThere are many examples of ways that this has been tackled, through encouraging children to spend time outside independently or under supervision in all weathers; encouraging parents and carers to allow their children to be outside; and encouraging nursery and teaching staff to spend time outside with children as part of their formal and informal activities.\n\nThere is a great deal of experience of a positive approach to bad weather, much of which has been incorporated into the UK Forest Schools movement, building on its origins in Sweden.\n\n# Cost-effectiveness evidence\n\nFor this guidance the economic appraisal consisted of a review of economic evaluations and a cost-effectiveness analysis.\n\n'A rapid review of economic literature related to the promotion of physical activity, play and sport for pre-school and school age children in family, pre-school, school and community settings'.\n\n'A cost-effectiveness scenario analysis of four interventions to increase child and adolescent physical activity: the case of walking buses, free swimming, dance classes and community sports'.\n\n## Review of economic evaluations\n\nOverall, the rapid review found that there was very limited economic evidence with respect to the promotion of physical activity, play and sport in the four core areas identified. Only two economic evaluations were appraised on the strength of their evidence, both were from the USA and considered interventions to modify the behaviour of obese children, while one study also considered the behaviour of their obese parents. However, these studies were considered not to be relevant to the development of the guidance due their targeting of only obese children.\n\n## Cost-effectiveness analysis\n\nA case study or scenario analysis approach was taken to model four different physical activity programmes and consider the cost effectiveness of each as far as was practical with the available data. The programmes considered were:\n\nwalking buses\n\nfree swimming\n\ndance classes\n\ncommunity sports.\n\nThe analysis sought to estimate the additional minutes of physical exercise derived from the interventions, and these minutes of exercise per year were used to derive the short-term quality of life improvements for children.\n\nHowever, there was uncertainty associated with the cost-effectiveness results as, due to the limitations of the evidence, it was necessary to make a number of unverified assumptions within the analyses. The results were also shown to be sensitive to changes in these assumptions.\n\nOnly walking buses were estimated to be cost effective. This was assuming a cost-effectiveness threshold of £20,000 per QALY and because of their relatively low cost and that children benefited by being engaged in the activity on a regular basis over time. However, due to the number of assumptions made producing the cost-effectiveness estimates, the PDG was cautious in drawing conclusions.\n\n# Fieldwork findings\n\nFieldwork aimed to test the relevance, usefulness and feasibility of putting the recommendations into practice. The PDG considered the findings when developing the final recommendations. For details, see the fieldwork section in appendix B and the final fieldwork report.\n\nParticipants with a direct or indirect role in promoting physical activity, play and sport with children were very positive about the recommendations and their potential to help promote physical activity.\n\nMany participants stated that the recommendations would be both useful and relevant and that, if successfully implemented, would have a significant impact on policy and service provision. Potentially, they could address inconsistencies in the provision and quality of physical activity initiatives.\n\nFor service providers and practitioners who are not doing much work in this area, the recommendations were seen to provide useful guidance to help develop new policies. For those already heavily involved in physical activity work, they served to provide reassurance and weight to that work. They were also seen to reinforce aspects of the 'Early years' foundation stage framework, particularly in relation to the provision of safe, secure and challenging environments for physical activity.\n\nPractitioners said the recommendations did not offer a new approach but agreed that the measures had not been implemented universally.\n\nFeedback suggests that many of the stakeholders who should be involved in implementing the recommendations may not be aware that guidance published by NICE would directly impact on their work. They believed wider and more systematic implementation would be achieved if there was an awareness-raising campaign.", 'Appendix D: Gaps in the evidence': "The PDG identified a number of gaps in the evidence related to the programmes under examination, based on an assessment of the evidence in the various reviews. These gaps are set out below.\n\nThe qualitative literature mainly focuses on school and sport. There is little evidence on formal or informal activities outside school such as yoga, dance, aerobics and play, or activities in social settings. Provision of non-competitive recreational physical activities has rarely been compared with more traditional school sporting activities (in or outside normal school hours). Comparisons between recreational physical activities organised with groups of friends – or with groups of a similar ability – are also lacking.\n\nThere is limited evidence about what prevents children and young people from being physically active – or what encourages them. Lack of detail in the intervention descriptions means it is unclear whether the barriers or facilitators identified in the qualitative literature were addressed.\n\nFew studies report on all physical activities that the participant is involved in. Most only report changes in the activity targeted by the intervention. Whether or not one type of physical activity will displace another – and the factors affecting any such displacement – are not identified.\n\nFew studies have investigated the relationship between children's and parents' physical activity over time. There is little evidence about what encourages families to be physically active (either together or split into adult–child groups). There is also little evidence about how families manage competing priorities when planning such activities.\n\nLittle is known about how children and young people view travel involving physical activity (such as walking and cycling) and how to promote it to them. The exception relates to journeys to and from school.\n\nThere is little evidence on how to sustain 'active' travel initiatives. For example, little is known about how best to recruit and retain walking bus leaders and local champions, or how effective it is to use pedometers to promote walking among children and young people. In addition, the effect of the environment on uptake (that is, urban versus rural settings and flat versus hilly terrain) has not been properly considered.\n\nThe intervention literature has methodological limitations. Descriptions of the interventions and evaluation methods used are limited (which may, to some extent, reflect publishing restrictions). In addition, implementation fidelity is rarely assessed and few studies have long-term follow-up. Often studies do not take potential mediator variables into account and do not use objective measures of overall physical activity when measuring effectiveness.\n\nMuch of the evidence comes from urban settings and its relevance to children from rural areas needs to be considered.\n\nNo studies were identified that measured the use of rewards to increase participation in – and enjoyment of – organised physical activity.\n\nNo studies were found which evaluated UK-based, multi-component interventions.\n\nEvidence is scarce on how to encourage groups of children and young people who are least likely to be physically active. They include: those with disabilities (or from families where someone else is disabled), those with special educational needs and those from certain minority ethnic groups or traveller and refugee communities.\n\nThere is a lack of evidence on the effectiveness of private or community-based physical activity provision.\n\nThere is little evidence of what works to encourage young children to be physically active. For example, the mediating role of parents and practitioners has not been explored. In addition, the evidence about whether or not play initiatives encourage pre-school children to be active is contradictory.\n\nThere is virtually no evidence on the cost-effectiveness of interventions to increase children and young people's physical activity levels. Many studies use weak measurements of effectiveness (as noted above). As a result, the opportunities to use modelling methods to estimate cost-effectiveness were limited.\n\nFew longitudinal studies track the relationship between physical activity and health outcomes. Likewise, few interventions have been well-evaluated over the longer term.\n\nThe Group made 5 recommendations for research.", 'Appendix E: Supporting documents': "Supporting documents include:\n\nReviews:\n\n\n\nReview 1: 'Descriptive epidemiology'\n\nReview 2: 'Correlates of physical activity in children: a review of quantitative systematic reviews'\n\nReview 3: 'The views of children on the barriers and facilitators to participation in physical activity: a review of qualitative studies'\n\nReview 4: 'Intervention review: under eights'\n\nReview 5: 'Intervention review: children and active travel'\n\nReview 6: 'Intervention review: adolescent girls'\n\nReview 7: 'Intervention review: family and community'\n\nReview 8: 'Review of learning from practice: children and active play'.\n\n\n\nEconomic analysis:\n\n\n\nReview of economic evaluations: 'A rapid review of economic literature related to the promotion of physical activity, play and sport for pre-school and school age children in family, pre-school, school and community settings'\n\nCost-effectiveness analysis: 'A cost effectiveness scenario analysis of four interventions to increase child and adolescent physical activity: the case of walking buses, free swimming, dance classes and community sports'.\n\n\n\nFieldwork report: 'Fieldwork on the promotion of physical activity, active play and sport for pre-school and school age children in family, pre-school, school and community setting'.", 'Finding more information ': "You can see everything NICE says on this topic in the NICE Pathway on physical activity.\n\nTo find NICE guidance on related topics, including guidance in development, see our topic page for physical activity.\n\nFor full details of the evidence and the guideline committee's discussions, see the evidence reviews. You can also find information about how the guideline was developed.\n\nNICE has produced tools and resources to help you put this guideline into practice. For general help and advice on putting NICE guidelines into practice, see resources to help you put guidance into practice."}	https://www.nice.org.uk/guidance/ph17	This guideline covers promoting physical activity for children and young people aged under 18 at home, preschool, school and in the community. It includes raising awareness of the benefits of physical activity, listening to what children and young people want, planning and providing spaces and facilities, and helping families build physical activity into their daily lives.
e52098ba8d753f387d60ef029ce37a51b3c0d45b	nice	Medicines adherence: involving patients in decisions about prescribed medicines and supporting adherence	Medicines adherence: involving patients in decisions about prescribed medicines and supporting adherence This guideline covers medicines adherence in people aged 18 and over. It recommends how to encourage adherence to medicines by supporting and involving people in decisions about their prescribed medicines. It aims to ensure that a person’s decision to use a medicine is an informed choice. # Introduction It is thought that between a third and a half of all medicines prescribed for long‑term conditions are not taken as recommended. If the prescription is appropriate, then this may represent a loss to patients, the healthcare system and society. The costs are both personal and economic. In this guideline 'medicines' is used as a general term to refer to prescribed medicines that are self-administered and includes tablets, syrups, ointments, eyedrops and suppositories. Adherence presumes an agreement between prescriber and patient about the prescriber's recommendations. Adherence to medicines is defined as the extent to which the patient's action matches the agreed recommendations. Non‑adherence may limit the benefits of medicines, resulting in lack of improvement, or deterioration, in health. The economic costs are not limited to wasted medicines but also include the knock‑on costs arising from increased demands for healthcare if health deteriorates. Non‑adherence should not be seen as the patient's problem. It represents a fundamental limitation in the delivery of healthcare, often because of a failure to fully agree the prescription in the first place or to identify and provide the support that patients need later on. Addressing non‑adherence is not about getting patients to take more medicines per se. Rather, it starts with an exploration of patients' perspectives of medicines and the reasons why they may not want or are unable to use them. Healthcare professionals have a duty to help patients make informed decisions about treatment and use appropriately prescribed medicines to best effect. There are many causes of non˗adherence but they fall into two overlapping categories: intentional and unintentional. Unintentional non˗adherence occurs when the patient wants to follow the agreed treatment but is prevented from doing so by barriers that are beyond their control. Examples include poor recall or difficulties in understanding the instructions, problems with using the treatment, inability to pay for the treatment, or simply forgetting to take it. Intentional non˗adherence occurs when the patient decides not to follow the treatment recommendations. This is best understood in terms of the beliefs and preferences that influence the person's perceptions of the treatment and their motivation to start and continue with it. It follows that to understand adherence to treatment we need to consider the perceptual factors (for example, beliefs and preferences) that influence motivation to start and continue with treatment, as well as the practical factors that influence patients' ability to adhere to the agreed treatment. Applying this approach in practice requires: a frank and open approach which recognises that non˗adherence may be the norm (or is at least very common) and takes a no˗blame approach, encouraging patients to discuss non˗adherence and any doubts or concerns they have about treatment a patient˗centred approach that encourages informed adherence identification of specific perceptual and practical barriers to adherence for each individual, both at the time of prescribing and during regular review, because perceptions, practical problems and adherence may change over time. This guideline makes recommendations about how healthcare professionals can help patients to make informed decisions by facilitating the involvement of patients in the decision to prescribe, and how they can support patients to adhere to the prescribed medicine. We have not made separate recommendations for carers and families. The principal relationship is between patient and healthcare professional, and the patient has a right to decide who should be involved in their care. With the patient's consent, carers should have access to appropriate levels of information and support. An increasing number of healthcare professionals are now involved in the prescribing, dispensing and reviewing of medicines. It is not within the remit of a guideline to recommend which healthcare professional carries out these roles. All healthcare professionals should be aware of and work within legal and professional codes.# Key principles Healthcare professionals should adapt their consultation style to the needs of individual patients so that all patients have the opportunity to be involved in decisions about their medicines at the level they wish. Establish the most effective way of communicating with each patient and, if necessary, consider ways of making information accessible and understandable (for example, using pictures, symbols, large print, different languages, an interpreter or a patient advocate). Offer all patients the opportunity to be involved in making decisions about prescribed medicines. Establish what level of involvement in decision˗making the patient would like. Be aware that increasing patient involvement may mean that the patient decides not to take or to stop taking a medicine. If in the healthcare professional's view this could have an adverse effect, then the information provided to the patient on risks and benefits and the patient's decision should be recorded. Accept that the patient has the right to decide not to take a medicine, even if you do not agree with the decision, as long as the patient has the capacity to make an informed decision and has been provided with the information needed to make such a decision. Be aware that patients' concerns about medicines, and whether they believe they need them, affect how and whether they take their prescribed medicines. Offer patients information that is relevant to their condition, possible treatments and personal circumstances, and that is easy to understand and free from jargon. Recognise that non˗adherence is common and that most patients are non˗adherent sometimes. Routinely assess adherence in a non˗judgemental way whenever you prescribe, dispense and review medicines. Be aware that although adherence can be improved, no specific intervention can be recommended for all patients. Tailor any intervention to increase adherence to the specific difficulties with adherence the patient is experiencing. Review patient knowledge, understanding and concerns about medicines, and a patient's view of their need for medicine at intervals agreed with the patient, because these may change over time. Offer repeat information and review to patients, especially when treating long˗term conditions with multiple medicines.# Guidance People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care. Making decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding. The following guidance is based on the best available evidence. The full guideline gives details of the methods and the evidence used to develop the guidance. Recommendation 1.4.2 has been replaced by recommendations in the NICE guideline on medicines optimisation. These recommendations apply to all healthcare professionals who prescribe, dispense or review medicines or who have a role in making decisions about medicines with patients. Healthcare professionals are reminded of their duty under the Equality Act (2010) to make reasonable adjustments to ensure that all people have the same opportunity for health. # Patient involvement in decisions about medicines Communication Good communication between healthcare professionals and patients is needed for involvement of patients in decisions about medicines and for supporting adherence. Some patients may find it easier to communicate with their healthcare professional than others. Healthcare professionals should adapt their consultation style to the needs of individual patients so that all patients have the opportunity to be involved in decisions about their medicines at the level they wish. Consider any factors such as physical or learning disabilities, sight or hearing problems and difficulties with reading or speaking English, which may affect the patient's involvement in the consultation. Establish the most effective way of communicating with each patient and, if necessary, consider ways of making information accessible and understandable (for example, using pictures, symbols, large print, different languages, an interpreter or a patient advocate). Encourage patients to ask about their condition and treatment. Ask patients open˗ended questions because these are more likely to uncover patients' concerns. Be aware that the consultation skills needed for increasing patient involvement can be improved. Increasing patient involvement Patient involvement in the decision˗making process requires that healthcare professionals acknowledge patients' views about their condition and its treatment, and that both healthcare professional and patient have a role in making decisions about treatment. Simple interventions to increase patient involvement do not necessarily increase the overall length of consultation and may be justified by benefits, particularly over the course of a long˗term condition. Offer all patients the opportunity to be involved in making decisions about prescribed medicines. Establish what level of involvement in decision-making the patient would like. Discuss with the patient why they might benefit from the treatment. Clearly explain the disease or condition and how the medicine will influence this. Explain the medical aims of the treatment to patients and openly discuss the pros and cons of proposed medicines. The discussion should be at the level preferred by the patient. Clarify what the patient hopes the treatment will achieve. Avoid making assumptions about patient preferences about treatment. Talk to the patient to find out their preferences, and note any non˗verbal cues that may indicate you need to explore the patient's perspective further. Healthcare professionals have a duty to help patients to make decisions about their treatment based on an understanding of the likely benefits and risks rather than on misconceptions. Accept that patients may have different views from healthcare professionals about the balance of risks, benefits and side effects of medicines. Be aware that increasing patient involvement may mean that the patient decides not to take or to stop taking a medicine. If in the healthcare professional's view this could have an adverse effect, then the information provided to the patient on risks and benefits and the patient's decision should be recorded. Accept that the patient has the right to decide not to take a medicine, even if you do not agree with the decision, as long as the patient has the capacity to make an informed decision and has been provided with the information needed to make such a decision. Assess the patient's capacity to make each decision using the principles in the Mental Capacity Act 2005. To lack capacity patients must: (a) have an impairment of or disturbance or malfunction of brain and mind, and (b) demonstrate lack of capacity to: understand the information relevant to the decision retain information for long enough to use it in the decision use or weigh information as part of the process of making the decision communicate the decision (whether by talking, using sign language or any other means). More information is available in NICE's guideline on decision-making and mental capacity. If the patient has specific concerns, record a summary of the discussion, because this may be helpful in future consultations. Encourage and support patients, families and carers to keep an up˗to˗date list of all medicines the patient is taking. The list should include the names and dosages of prescription and non˗prescription medicines and herbal and nutritional supplements. If the patient has any allergic or adverse reactions to medicines, these should be noted. Understanding the patient's knowledge, beliefs and concerns about medicines There is evidence that patients make decisions about medicines based on their understanding of their condition and the possible treatments, their view of their own need for the medicine and their concerns about the medicine. Be aware that patients' concerns about medicines, and whether they believe they need them, affect how and whether they take their prescribed medicines. Ask patients what they know, believe and understand about medicines before prescribing new treatments and when reviewing medicines. Ask if the patient has any specific concerns about their medicines, whenever you prescribe, dispense or review medicines. These may include concerns about becoming dependent on medicines and concerns about adverse effects. Address these concerns. Be aware that patients may wish to minimise how much medicine they take. Be aware that patients may wish to discuss: what will happen if they do not take the medicine suggested by their healthcare professional non˗pharmacological alternatives to medicines how to reduce and stop medicines they may have been taking for a long time, particularly those known to be associated with withdrawal symptoms how to fit taking the medicine into their daily routine how to make a choice between medicines if they believe they are taking too many medicines. Providing information Patients need information about their condition and possible treatments if they are to be involved in making informed decisions about medicines. The format and content of the information provided should meet the needs of individual patients. Offer patients information about medicines before the medicines are prescribed. Offer patients information that is relevant to their condition, possible treatments and personal circumstances, and that is easy to understand and free from jargon. Check that patients have any information they wish about medicines when the medicines are dispensed. Discuss information on medicines with the patient rather than just presenting it. The discussion should take into account what the patient understands and believes about the condition and treatment. Do not assume that the patient information leaflets (PILs) that patients receive with their medicines will meet each patient's needs. Address concerns that patients may have after reading the standard PILs.PILs contain information for patients on how medicines should be used. It is a legal requirement that this information is included on the label or within the packaging of a medicine. Patients differ in the type and amount of information they need and want. Therefore, the provision of information should be individualised and is likely to include, but not be limited to: what the medicine is how the medicine is likely to affect their condition (that is, its benefits) likely or significant adverse effects and what to do if they think they are experiencing them how to use the medicine what to do if they miss a dose whether further courses of the medicine will be needed after the first prescription how to get further supplies of medicines. Be careful not to make assumptions about a patient's ability to understand the information provided. Check with the patient that they have understood the information. Information for patients should be clear and logical and, if possible, tailored to the needs of the individual patient. Suggest where patients might find reliable information and support after the consultation: for example, by providing written information or directing them to other resources (for example, the NHS website). Provide inpatients with the same information as patients in other settings. Information should include: what the medicine is how the medicine is likely to affect their condition (that is, its benefits) likely or significant adverse effects and what to do if they think they are experiencing them how to use the medicine what to do if they miss a dose whether further courses of the medicine will be needed after the first prescription how to get further supply after discharge. # Supporting adherence Assessing adherence Patients do not always take their medicines exactly as prescribed, and healthcare professionals are often unaware of how patients take their medicines. The purpose of assessing adherence is not to monitor patients but rather to find out whether patients need more information and support. Recognise that non˗adherence is common and that most patients are non˗adherent sometimes. Routinely assess adherence in a non˗judgemental way whenever you prescribe, dispense and review medicines. Consider assessing non-adherence by asking the patient if they have missed any doses of medicine recently. Make it easier for them to report non˗adherence by: asking the question in a way that does not apportion blame explaining why you are asking the question mentioning a specific time period such as 'in the past week' asking about medicine-taking behaviours such as reducing the dose, stopping and starting medicines. Consider using records of prescription re˗ordering, pharmacy patient medication records and return of unused medicines to identify potential non˗adherence and patients needing additional support. Interventions to increase adherence Patients may need support to help them make the most effective use of their medicines. This support may take the form of further information and discussion, or involve practical changes to the type of medicine or the regimen. Any interventions to support adherence should be considered on a case˗by˗case basis and should address the concerns and needs of individual patients. If a patient is not taking their medicines, discuss with them whether this is because of beliefs and concerns or problems about the medicines (intentional non˗adherence) or because of practical problems (unintentional non˗adherence). Be aware that although adherence can be improved, no specific intervention can be recommended for all patients. Tailor any intervention to increase adherence to the specific difficulties with adherence the patient is experiencing. Find out what form of support the patient would prefer to increase their adherence to medicines. Together, you and your patient should consider options for support. Address any beliefs and concerns that patients have that result in reduced adherence. Because evidence supporting interventions to increase adherence is inconclusive, only use interventions to overcome practical problems associated with non˗adherence if a specific need is identified. Target the intervention to the need. Interventions might include: suggesting that patients record their medicine˗taking encouraging patients to monitor their condition simplifying the dosing regimen using alternative packaging for the medicine using a multi˗compartment medicines system. Side effects can be a problem for some patients. If this is the case you should: discuss how the patient would like to deal with side effects discuss the benefits, side effects and long˗term effects with the patient to allow them to make an informed choice consider adjusting the dosage consider switching to another medicine with a different risk of side effects consider what other strategies might be used (for example, timing of medicines). Ask patients if prescriptions charges are a problem for them. If they are, consider possible options to reduce costs. # Reviewing medicines Patients may use medicines long term. The initial decision to prescribe medicines, the patient's experience of using the medicines and the patient's needs for adherence support should be reviewed regularly. The patient's own list of medicines may be a useful aid in a medicines review. Review patient knowledge, understanding and concerns about medicines, and a patient's view of their need for medicine at intervals agreed with the patient, because these may change over time. Offer repeat information and review to patients, especially when treating long˗term conditions with multiple medicines. Review at regular intervals the decision to prescribe medicines, according to patient choice and need. Enquire about adherence when reviewing medicines. If non˗adherence is identified, clarify possible causes and agree any action with the patient. Any plan should include a date for a follow˗up review. Be aware that patients sometimes evaluate prescribed medicines using their own criteria such as their understanding of their condition or the symptoms most troubling to them. They may, for example, stop and start the medicine or alter the dose and check how this affects their symptoms. Ask the patient whether they have done this. # Communication between healthcare professionals Patients may be under the care of healthcare professionals from different disciplines and specialties at the same time; responsibility for patients' care may be transferred between healthcare professionals, and medicines reviews may be carried out by healthcare professionals other than the prescriber. Therefore good communication between healthcare professionals is required to ensure that fragmentation of care does not occur. Healthcare professionals involved in prescribing, dispensing or reviewing medicines should ensure that there are robust processes for communicating with other healthcare professionals involved in the patient's care. This recommendation has been replaced by recommendations in section 1.2 in the NICE guideline on medicines optimisation. Healthcare professionals involved in reviewing medicines should inform the prescriber of the review and its outcome. This is particularly important if the review involves discussion of difficulties with adherence and further review is necessary.# Research recommendations The Guideline Development Group has made the following recommendations for research, based on its review of evidence, to improve NICE guidance and patient care in the future. The Guideline Development Group's full set of research recommendations is detailed in the full guideline (see section 5). # Developing effective, equitable interventions to support adherence to appropriate prescriptions What are the most clinically effective and cost˗effective methods for identifying and addressing the perceptual barriers (such as beliefs and concerns about medicines) that influence motivation to start and continue with treatment, and the practical barriers (such as limitations in personal capacity and resources) that limit an individual's ability to implement intentions to adhere to medicines? Why this is important The Guideline Development Group identified a priority for the systematic development of effective, realisable, efficient and equitable interventions to facilitate informed choice and optimal adherence to appropriately prescribed medicines. Systematic reviews of adherence interventions show that although adherence can be improved, the effects were generally modest and there is considerable room for improvement. Few previous interventions have been developed systematically using appropriate theoretical models, and they have not been modelled and piloted with assessment of process variables as well as outcomes. Interventions should be developed using an appropriate theoretical framework with a phased approach to testing that includes assessment of process (that is, the things that are targeted for change) as well as outcomes and a need for an individual approach. (Campbell NC, Murray E, Darbyshire J et al. 2007) # Informed choice and shared decision-making What are the most clinically effective and cost˗effective ways of communicating the potential benefits and risks of medicines to promote informed choice and optimal adherence? Why this is important The principles of informed choice and shared decision˗making have largely been developed from theoretical and conceptual models. The competencies listed for shared decision-making consist of a number of different skills, and patients have shown that they may value different aspects of shared decision˗making. Although the right of patients to be involved in decision˗making in regard to their own healthcare is accepted, the practice of shared decision-making may mean that healthcare professionals and patients play different roles than they have to date in healthcare consultations. This may have implications for legal and professional responsibility and accountability. Patients and professionals enter decision˗making with very different levels of knowledge and access to information. Improving patient knowledge and information may require structural changes to health services and their delivery. Patient˗reported outcomes also need to be included. # Support processes: prescribing˗related consultations and medicines review How can practitioners and patients be supported to improve the quality of prescribing-related consultations and medicines reviews so that they facilitate informed choice and optimal adherence to medicines? What are the effects of medicines reviews by healthcare professionals other than the prescriber on patients, prescribers and outcomes? How can the process of medicines review be enhanced or improved to address issues of informed choice and adherence? Why this is important Non˗adherence is often a hidden problem. Many patients are reluctant to express doubts and concerns about medicines because they fear that it will displease the healthcare professional. We need better methods for overcoming this problem and promoting honest and open discussions about medicines and adherence. There are an increasing number of non˗medical prescribers (such as pharmacists and nurses) This is a key context issue and there are a range of questions relating to patient perspectives on new prescribers and to new and existing prescribers' perceptions and skills. The effects of new prescribers on patient adherence to medicines should be included in any studies designed to evaluate new prescribers. The inclusion of formal procedures for medicines review within the Pharmacy Contract in England provides an opportunity for improved support for patients. We need a better understanding of the effects of non˗prescriber reviews on medicines usage and outcomes, and how reviews might be improved to benefit patients and society.	{'Introduction': "It is thought that between a third and a half of all medicines prescribed for long‑term conditions are not taken as recommended. If the prescription is appropriate, then this may represent a loss to patients, the healthcare system and society. The costs are both personal and economic. In this guideline 'medicines' is used as a general term to refer to prescribed medicines that are self-administered and includes tablets, syrups, ointments, eyedrops and suppositories.\n\nAdherence presumes an agreement between prescriber and patient about the prescriber's recommendations. Adherence to medicines is defined as the extent to which the patient's action matches the agreed recommendations. Non‑adherence may limit the benefits of medicines, resulting in lack of improvement, or deterioration, in health. The economic costs are not limited to wasted medicines but also include the knock‑on costs arising from increased demands for healthcare if health deteriorates.\n\nNon‑adherence should not be seen as the patient's problem. It represents a fundamental limitation in the delivery of healthcare, often because of a failure to fully agree the prescription in the first place or to identify and provide the support that patients need later on.\n\nAddressing non‑adherence is not about getting patients to take more medicines per se. Rather, it starts with an exploration of patients' perspectives of medicines and the reasons why they may not want or are unable to use them. Healthcare professionals have a duty to help patients make informed decisions about treatment and use appropriately prescribed medicines to best effect.\n\nThere are many causes of non˗adherence but they fall into two overlapping categories: intentional and unintentional. Unintentional non˗adherence occurs when the patient wants to follow the agreed treatment but is prevented from doing so by barriers that are beyond their control. Examples include poor recall or difficulties in understanding the instructions, problems with using the treatment, inability to pay for the treatment, or simply forgetting to take it. Intentional non˗adherence occurs when the patient decides not to follow the treatment recommendations. This is best understood in terms of the beliefs and preferences that influence the person's perceptions of the treatment and their motivation to start and continue with it. It follows that to understand adherence to treatment we need to consider the perceptual factors (for example, beliefs and preferences) that influence motivation to start and continue with treatment, as well as the practical factors that influence patients' ability to adhere to the agreed treatment.\n\nApplying this approach in practice requires:\n\na frank and open approach which recognises that non˗adherence may be the norm (or is at least very common) and takes a no˗blame approach, encouraging patients to discuss non˗adherence and any doubts or concerns they have about treatment\n\na patient˗centred approach that encourages informed adherence\n\nidentification of specific perceptual and practical barriers to adherence for each individual, both at the time of prescribing and during regular review, because perceptions, practical problems and adherence may change over time.\n\nThis guideline makes recommendations about how healthcare professionals can help patients to make informed decisions by facilitating the involvement of patients in the decision to prescribe, and how they can support patients to adhere to the prescribed medicine. We have not made separate recommendations for carers and families. The principal relationship is between patient and healthcare professional, and the patient has a right to decide who should be involved in their care. With the patient's consent, carers should have access to appropriate levels of information and support.\n\nAn increasing number of healthcare professionals are now involved in the prescribing, dispensing and reviewing of medicines. It is not within the remit of a guideline to recommend which healthcare professional carries out these roles. All healthcare professionals should be aware of and work within legal and professional codes.", 'Key principles': "Healthcare professionals should adapt their consultation style to the needs of individual patients so that all patients have the opportunity to be involved in decisions about their medicines at the level they wish.\n\nEstablish the most effective way of communicating with each patient and, if necessary, consider ways of making information accessible and understandable (for example, using pictures, symbols, large print, different languages, an interpreter or a patient advocate).\n\nOffer all patients the opportunity to be involved in making decisions about prescribed medicines. Establish what level of involvement in decision˗making the patient would like.\n\nBe aware that increasing patient involvement may mean that the patient decides not to take or to stop taking a medicine. If in the healthcare professional's view this could have an adverse effect, then the information provided to the patient on risks and benefits and the patient's decision should be recorded.\n\nAccept that the patient has the right to decide not to take a medicine, even if you do not agree with the decision, as long as the patient has the capacity to make an informed decision and has been provided with the information needed to make such a decision.\n\nBe aware that patients' concerns about medicines, and whether they believe they need them, affect how and whether they take their prescribed medicines.\n\nOffer patients information that is relevant to their condition, possible treatments and personal circumstances, and that is easy to understand and free from jargon.\n\nRecognise that non˗adherence is common and that most patients are non˗adherent sometimes. Routinely assess adherence in a non˗judgemental way whenever you prescribe, dispense and review medicines.\n\nBe aware that although adherence can be improved, no specific intervention can be recommended for all patients. Tailor any intervention to increase adherence to the specific difficulties with adherence the patient is experiencing.\n\nReview patient knowledge, understanding and concerns about medicines, and a patient's view of their need for medicine at intervals agreed with the patient, because these may change over time. Offer repeat information and review to patients, especially when treating long˗term conditions with multiple medicines.", 'Guidance': "People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.\n\nMaking decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.\n\nThe following guidance is based on the best available evidence. The full guideline gives details of the methods and the evidence used to develop the guidance.\n\nRecommendation 1.4.2 has been replaced by recommendations in the NICE guideline on medicines optimisation.\n\nThese recommendations apply to all healthcare professionals who prescribe, dispense or review medicines or who have a role in making decisions about medicines with patients. Healthcare professionals are reminded of their duty under the Equality Act (2010) to make reasonable adjustments to ensure that all people have the same opportunity for health.\n\n# Patient involvement in decisions about medicines\n\nCommunication\n\nGood communication between healthcare professionals and patients is needed for involvement of patients in decisions about medicines and for supporting adherence. Some patients may find it easier to communicate with their healthcare professional than others.\n\nHealthcare professionals should adapt their consultation style to the needs of individual patients so that all patients have the opportunity to be involved in decisions about their medicines at the level they wish.\n\nConsider any factors such as physical or learning disabilities, sight or hearing problems and difficulties with reading or speaking English, which may affect the patient's involvement in the consultation.\n\nEstablish the most effective way of communicating with each patient and, if necessary, consider ways of making information accessible and understandable (for example, using pictures, symbols, large print, different languages, an interpreter or a patient advocate).\n\nEncourage patients to ask about their condition and treatment.\n\nAsk patients open˗ended questions because these are more likely to uncover patients' concerns.\n\nBe aware that the consultation skills needed for increasing patient involvement can be improved.\n\nIncreasing patient involvement\n\nPatient involvement in the decision˗making process requires that healthcare professionals acknowledge patients' views about their condition and its treatment, and that both healthcare professional and patient have a role in making decisions about treatment. Simple interventions to increase patient involvement do not necessarily increase the overall length of consultation and may be justified by benefits, particularly over the course of a long˗term condition.\n\nOffer all patients the opportunity to be involved in making decisions about prescribed medicines. Establish what level of involvement in decision-making the patient would like.\n\nDiscuss with the patient why they might benefit from the treatment. Clearly explain the disease or condition and how the medicine will influence this.\n\nExplain the medical aims of the treatment to patients and openly discuss the pros and cons of proposed medicines. The discussion should be at the level preferred by the patient.\n\nClarify what the patient hopes the treatment will achieve.\n\nAvoid making assumptions about patient preferences about treatment. Talk to the patient to find out their preferences, and note any non˗verbal cues that may indicate you need to explore the patient's perspective further.\n\nHealthcare professionals have a duty to help patients to make decisions about their treatment based on an understanding of the likely benefits and risks rather than on misconceptions.\n\nAccept that patients may have different views from healthcare professionals about the balance of risks, benefits and side effects of medicines.\n\nBe aware that increasing patient involvement may mean that the patient decides not to take or to stop taking a medicine. If in the healthcare professional's view this could have an adverse effect, then the information provided to the patient on risks and benefits and the patient's decision should be recorded.\n\nAccept that the patient has the right to decide not to take a medicine, even if you do not agree with the decision, as long as the patient has the capacity to make an informed decision and has been provided with the information needed to make such a decision.\n\nAssess the patient's capacity to make each decision using the principles in the Mental Capacity Act 2005. To lack capacity patients must: (a) have an impairment of or disturbance or malfunction of brain and mind, and (b) demonstrate lack of capacity to:\n\nunderstand the information relevant to the decision\n\nretain information for long enough to use it in the decision\n\nuse or weigh information as part of the process of making the decision\n\ncommunicate the decision (whether by talking, using sign language or any other means). More information is available in NICE's guideline on decision-making and mental capacity.\n\nIf the patient has specific concerns, record a summary of the discussion, because this may be helpful in future consultations.\n\nEncourage and support patients, families and carers to keep an up˗to˗date list of all medicines the patient is taking. The list should include the names and dosages of prescription and non˗prescription medicines and herbal and nutritional supplements. If the patient has any allergic or adverse reactions to medicines, these should be noted.\n\nUnderstanding the patient's knowledge, beliefs and concerns about medicines\n\nThere is evidence that patients make decisions about medicines based on their understanding of their condition and the possible treatments, their view of their own need for the medicine and their concerns about the medicine.\n\nBe aware that patients' concerns about medicines, and whether they believe they need them, affect how and whether they take their prescribed medicines.\n\nAsk patients what they know, believe and understand about medicines before prescribing new treatments and when reviewing medicines.\n\nAsk if the patient has any specific concerns about their medicines, whenever you prescribe, dispense or review medicines. These may include concerns about becoming dependent on medicines and concerns about adverse effects. Address these concerns.\n\nBe aware that patients may wish to minimise how much medicine they take.\n\nBe aware that patients may wish to discuss:\n\nwhat will happen if they do not take the medicine suggested by their healthcare professional\n\nnon˗pharmacological alternatives to medicines\n\nhow to reduce and stop medicines they may have been taking for a long time, particularly those known to be associated with withdrawal symptoms\n\nhow to fit taking the medicine into their daily routine\n\nhow to make a choice between medicines if they believe they are taking too many medicines.\n\nProviding information\n\nPatients need information about their condition and possible treatments if they are to be involved in making informed decisions about medicines. The format and content of the information provided should meet the needs of individual patients.\n\nOffer patients information about medicines before the medicines are prescribed.\n\nOffer patients information that is relevant to their condition, possible treatments and personal circumstances, and that is easy to understand and free from jargon.\n\nCheck that patients have any information they wish about medicines when the medicines are dispensed.\n\nDiscuss information on medicines with the patient rather than just presenting it. The discussion should take into account what the patient understands and believes about the condition and treatment.\n\nDo not assume that the patient information leaflets (PILs) that patients receive with their medicines will meet each patient's needs. Address concerns that patients may have after reading the standard PILs.PILs contain information for patients on how medicines should be used. It is a legal requirement that this information is included on the label or within the packaging of a medicine.\n\nPatients differ in the type and amount of information they need and want. Therefore, the provision of information should be individualised and is likely to include, but not be limited to:\n\nwhat the medicine is\n\nhow the medicine is likely to affect their condition (that is, its benefits)\n\nlikely or significant adverse effects and what to do if they think they are experiencing them\n\nhow to use the medicine\n\nwhat to do if they miss a dose\n\nwhether further courses of the medicine will be needed after the first prescription\n\nhow to get further supplies of medicines.\n\nBe careful not to make assumptions about a patient's ability to understand the information provided. Check with the patient that they have understood the information. Information for patients should be clear and logical and, if possible, tailored to the needs of the individual patient.\n\nSuggest where patients might find reliable information and support after the consultation: for example, by providing written information or directing them to other resources (for example, the NHS website).\n\nProvide inpatients with the same information as patients in other settings. Information should include:\n\nwhat the medicine is\n\nhow the medicine is likely to affect their condition (that is, its benefits)\n\nlikely or significant adverse effects and what to do if they think they are experiencing them\n\nhow to use the medicine\n\nwhat to do if they miss a dose\n\nwhether further courses of the medicine will be needed after the first prescription\n\nhow to get further supply after discharge.\n\n# Supporting adherence\n\nAssessing adherence\n\nPatients do not always take their medicines exactly as prescribed, and healthcare professionals are often unaware of how patients take their medicines. The purpose of assessing adherence is not to monitor patients but rather to find out whether patients need more information and support.\n\nRecognise that non˗adherence is common and that most patients are non˗adherent sometimes. Routinely assess adherence in a non˗judgemental way whenever you prescribe, dispense and review medicines.\n\nConsider assessing non-adherence by asking the patient if they have missed any doses of medicine recently. Make it easier for them to report non˗adherence by:\n\nasking the question in a way that does not apportion blame\n\nexplaining why you are asking the question\n\nmentioning a specific time period such as 'in the past week'\n\nasking about medicine-taking behaviours such as reducing the dose, stopping and starting medicines.\n\nConsider using records of prescription re˗ordering, pharmacy patient medication records and return of unused medicines to identify potential non˗adherence and patients needing additional support.\n\nInterventions to increase adherence\n\nPatients may need support to help them make the most effective use of their medicines. This support may take the form of further information and discussion, or involve practical changes to the type of medicine or the regimen. Any interventions to support adherence should be considered on a case˗by˗case basis and should address the concerns and needs of individual patients.\n\nIf a patient is not taking their medicines, discuss with them whether this is because of beliefs and concerns or problems about the medicines (intentional non˗adherence) or because of practical problems (unintentional non˗adherence).\n\nBe aware that although adherence can be improved, no specific intervention can be recommended for all patients. Tailor any intervention to increase adherence to the specific difficulties with adherence the patient is experiencing.\n\nFind out what form of support the patient would prefer to increase their adherence to medicines. Together, you and your patient should consider options for support.\n\nAddress any beliefs and concerns that patients have that result in reduced adherence.\n\nBecause evidence supporting interventions to increase adherence is inconclusive, only use interventions to overcome practical problems associated with non˗adherence if a specific need is identified. Target the intervention to the need. Interventions might include:\n\nsuggesting that patients record their medicine˗taking\n\nencouraging patients to monitor their condition\n\nsimplifying the dosing regimen\n\nusing alternative packaging for the medicine\n\nusing a multi˗compartment medicines system.\n\nSide effects can be a problem for some patients. If this is the case you should:\n\ndiscuss how the patient would like to deal with side effects\n\ndiscuss the benefits, side effects and long˗term effects with the patient to allow them to make an informed choice\n\nconsider adjusting the dosage\n\nconsider switching to another medicine with a different risk of side effects\n\nconsider what other strategies might be used (for example, timing of medicines).\n\nAsk patients if prescriptions charges are a problem for them. If they are, consider possible options to reduce costs.\n\n# Reviewing medicines\n\nPatients may use medicines long term. The initial decision to prescribe medicines, the patient's experience of using the medicines and the patient's needs for adherence support should be reviewed regularly. The patient's own list of medicines may be a useful aid in a medicines review.\n\nReview patient knowledge, understanding and concerns about medicines, and a patient's view of their need for medicine at intervals agreed with the patient, because these may change over time. Offer repeat information and review to patients, especially when treating long˗term conditions with multiple medicines.\n\nReview at regular intervals the decision to prescribe medicines, according to patient choice and need.\n\nEnquire about adherence when reviewing medicines. If non˗adherence is identified, clarify possible causes and agree any action with the patient. Any plan should include a date for a follow˗up review.\n\nBe aware that patients sometimes evaluate prescribed medicines using their own criteria such as their understanding of their condition or the symptoms most troubling to them. They may, for example, stop and start the medicine or alter the dose and check how this affects their symptoms. Ask the patient whether they have done this.\n\n# Communication between healthcare professionals\n\nPatients may be under the care of healthcare professionals from different disciplines and specialties at the same time; responsibility for patients' care may be transferred between healthcare professionals, and medicines reviews may be carried out by healthcare professionals other than the prescriber. Therefore good communication between healthcare professionals is required to ensure that fragmentation of care does not occur.\n\nHealthcare professionals involved in prescribing, dispensing or reviewing medicines should ensure that there are robust processes for communicating with other healthcare professionals involved in the patient's care.\n\nThis recommendation has been replaced by recommendations in section 1.2 in the NICE guideline on medicines optimisation.\n\nHealthcare professionals involved in reviewing medicines should inform the prescriber of the review and its outcome. This is particularly important if the review involves discussion of difficulties with adherence and further review is necessary.", 'Research recommendations': "The Guideline Development Group has made the following recommendations for research, based on its review of evidence, to improve NICE guidance and patient care in the future. The Guideline Development Group's full set of research recommendations is detailed in the full guideline (see section 5).\n\n# Developing effective, equitable interventions to support adherence to appropriate prescriptions\n\nWhat are the most clinically effective and cost˗effective methods for identifying and addressing the perceptual barriers (such as beliefs and concerns about medicines) that influence motivation to start and continue with treatment, and the practical barriers (such as limitations in personal capacity and resources) that limit an individual's ability to implement intentions to adhere to medicines?\n\nWhy this is important\n\nThe Guideline Development Group identified a priority for the systematic development of effective, realisable, efficient and equitable interventions to facilitate informed choice and optimal adherence to appropriately prescribed medicines.\n\nSystematic reviews of adherence interventions show that although adherence can be improved, the effects were generally modest and there is considerable room for improvement. Few previous interventions have been developed systematically using appropriate theoretical models, and they have not been modelled and piloted with assessment of process variables as well as outcomes.\n\nInterventions should be developed using an appropriate theoretical framework with a phased approach to testing that includes assessment of process (that is, the things that are targeted for change) as well as outcomes and a need for an individual approach. (Campbell NC, Murray E, Darbyshire J et al. 2007)\n\n# Informed choice and shared decision-making\n\nWhat are the most clinically effective and cost˗effective ways of communicating the potential benefits and risks of medicines to promote informed choice and optimal adherence?\n\nWhy this is important\n\nThe principles of informed choice and shared decision˗making have largely been developed from theoretical and conceptual models. The competencies listed for shared decision-making consist of a number of different skills, and patients have shown that they may value different aspects of shared decision˗making. Although the right of patients to be involved in decision˗making in regard to their own healthcare is accepted, the practice of shared decision-making may mean that healthcare professionals and patients play different roles than they have to date in healthcare consultations. This may have implications for legal and professional responsibility and accountability. Patients and professionals enter decision˗making with very different levels of knowledge and access to information. Improving patient knowledge and information may require structural changes to health services and their delivery. Patient˗reported outcomes also need to be included.\n\n# Support processes: prescribing˗related consultations and medicines review\n\nHow can practitioners and patients be supported to improve the quality of prescribing-related consultations and medicines reviews so that they facilitate informed choice and optimal adherence to medicines?\n\nWhat are the effects of medicines reviews by healthcare professionals other than the prescriber on patients, prescribers and outcomes? How can the process of medicines review be enhanced or improved to address issues of informed choice and adherence?\n\nWhy this is important\n\nNon˗adherence is often a hidden problem. Many patients are reluctant to express doubts and concerns about medicines because they fear that it will displease the healthcare professional. We need better methods for overcoming this problem and promoting honest and open discussions about medicines and adherence.\n\nThere are an increasing number of non˗medical prescribers (such as pharmacists and nurses) This is a key context issue and there are a range of questions relating to patient perspectives on new prescribers and to new and existing prescribers' perceptions and skills. The effects of new prescribers on patient adherence to medicines should be included in any studies designed to evaluate new prescribers. The inclusion of formal procedures for medicines review within the Pharmacy Contract in England provides an opportunity for improved support for patients. We need a better understanding of the effects of non˗prescriber reviews on medicines usage and outcomes, and how reviews might be improved to benefit patients and society."}	https://www.nice.org.uk/guidance/cg76	This guideline covers medicines adherence in people aged 18 and over. It recommends how to encourage adherence to medicines by supporting and involving people in decisions about their prescribed medicines. It aims to ensure that a person’s decision to use a medicine is an informed choice.
6c389d1bc6adc4d91ca75be48c660aca62bc4f9d	nice	Borderline personality disorder: recognition and management	Borderline personality disorder: recognition and management This guideline covers recognising and managing borderline personality disorder. It aims to help people with borderline personality disorder to manage feelings of distress, anxiety, worthlessness and anger, and to maintain stable and close relationships with others. # Introduction This guideline makes recommendations for the treatment and management of borderline personality disorder in adults and young people (under the age of 18) who meet criteria for the diagnosis in primary, secondary and tertiary care. The guideline also covers the treatment and management of people diagnosed with emotionally unstable personality disorder based on ICD-10 criteria Borderline personality disorder is characterised by significant instability of interpersonal relationships, self-image and mood, and impulsive behaviour. There is a pattern of sometimes rapid fluctuation from periods of confidence to despair, with fear of abandonment and rejection, and a strong tendency towards suicidal thinking and self-harm. Transient psychotic symptoms, including brief delusions and hallucinations, may also be present. It is also associated with substantial impairment of social, psychological and occupational functioning and quality of life. People with borderline personality disorder are particularly at risk of suicide. The extent of the emotional and behavioural problems experienced by people with borderline personality disorder varies considerably. Some people with borderline personality disorder are able to sustain some relationships and occupational activities. People with more severe forms experience very high levels of emotional distress. They have repeated crises, which can involve self-harm and impulsive aggression. They also have high levels of comorbidity, including other personality disorders, and are frequent users of psychiatric and acute hospital emergency services. While the general principles of management referred to in this guideline are intended for all people with borderline personality disorder, the treatment recommendations are directed primarily at those with more severe forms of the disorder. Borderline personality disorder is present in just under 1% of the population, and is most common in early adulthood. Women present to services more often than men. Borderline personality disorder is often not formally diagnosed before the age of 18, but the features of the disorder can be identified earlier. Its course is variable and although many people recover over time, some people may continue to experience social and interpersonal difficulties. Borderline personality disorder is often comorbid with depression, anxiety, eating disorders, post-traumatic stress disorder, alcohol and drug misuse, and bipolar disorder (the symptoms of which are often confused with borderline personality disorder). This guideline does not cover the separate management of comorbid conditions. People with borderline personality disorder have sometimes been excluded from any health or social care services because of their diagnosis. This may be because staff lack the confidence and skills to work with this group of people. This guideline draws on the best available evidence. However, there are significant limitations to the evidence base, notably, few randomised controlled trials (RCTs) of interventions, which have few outcomes in common. Some of the limitations are addressed in the research recommendations. At the time of publication (January 2009), no drug has UK marketing authorisation for the treatment of borderline personality disorder, but this guideline contains recommendations about the use of drugs to manage crises, comorbid conditions and insomnia. The guideline assumes that prescribers will use a drug's summary of product characteristics to inform their decisions for each person. NICE has developed a guideline on antisocial personality disorder: prevention and management.# Guidance People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care. Making decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding. The following guidance is based on the best available evidence. The full guideline gives details of the methods and evidence used to develop the guidance. # General principles for working with people with borderline personality disorder ## Access to services People with borderline personality disorder should not be excluded from any health or social care service because of their diagnosis or because they have self-harmed. Young people with a diagnosis of borderline personality disorder, or symptoms and behaviour that suggest it, should have access to the full range of treatments and services recommended in this guideline, but within children and adolescent mental health services (CAMHS). Ensure that people with borderline personality disorder from black and minority ethnic groups have equal access to culturally appropriate services based on clinical need. When language is a barrier to accessing or engaging with services for people with borderline personality disorder, provide them with: information in their preferred language and in an accessible format psychological or other interventions in their preferred language independent interpreters. ## Borderline personality disorder and learning disabilities When a person with a mild learning disability presents with symptoms and behaviour that suggest borderline personality disorder, assessment and diagnosis should take place in consultation with a specialist in learning disabilities services. When a person with a mild learning disability has a diagnosis of borderline personality disorder, they should have access to the same services as other people with borderline personality disorder. When care planning for people with a mild learning disability and borderline personality disorder, follow the Care Programme Approach (CPA). Consider consulting a specialist in learning disabilities services when developing care plans and strategies for managing behaviour that challenges. People with a moderate or severe learning disability should not normally be diagnosed with borderline personality disorder. If they show behaviour and symptoms that suggest borderline personality disorder, refer for assessment and treatment by a specialist in learning disabilities services. ## Autonomy and choice Work in partnership with people with borderline personality disorder to develop their autonomy and promote choice by: ensuring they remain actively involved in finding solutions to their problems, including during crises encouraging them to consider the different treatment options and life choices available to them, and the consequences of the choices they make. ## Developing an optimistic and trusting relationship When working with people with borderline personality disorder: explore treatment options in an atmosphere of hope and optimism, explaining that recovery is possible and attainable build a trusting relationship, work in an open, engaging and non-judgemental manner, and be consistent and reliable bear in mind when providing services that many people will have experienced rejection, abuse and trauma, and encountered stigma often associated with self-harm and borderline personality disorder. ## Involving families or carers Ask directly whether the person with borderline personality disorder wants their family or carers to be involved in their care, and, subject to the person's consent and rights to confidentiality: encourage family or carers to be involved ensure that the involvement of families or carers does not lead to withdrawal of, or lack of access to, services inform families or carers about local support groups for families or carers, if these exist. CAMHS professionals working with young people with borderline personality disorder should: balance the developing autonomy and capacity of the young person with the responsibilities of parents or carers be familiar with the legal framework that applies to young people, including the Mental Capacity Act, the Children Acts and the Mental Health Act. ## Principles for assessment When assessing a person with borderline personality disorder: explain clearly the process of assessment use non-technical language whenever possible explain the diagnosis and the use and meaning of the term borderline personality disorder -ffer post-assessment support, particularly if sensitive issues, such as childhood trauma, have been discussed. ## Managing endings and supporting transitions Anticipate that withdrawal and ending of treatments or services, and transition from one service to another, may evoke strong emotions and reactions in people with borderline personality disorder. Ensure that: such changes are discussed carefully beforehand with the person (and their family or carers if appropriate) and are structured and phased the care plan supports effective collaboration with other care providers during endings and transitions, and includes the opportunity to access services in times of crisis when referring a person for assessment in other services (including for psychological treatment), they are supported during the referral period and arrangements for support are agreed beforehand with them. CAMHS and adult healthcare professionals should work collaboratively to minimise any potential negative effect of transferring young people from CAMHS to adult services. They should: time the transfer to suit the young person, even if it takes place after they have reached the age of 18 years continue treatment in CAMHS beyond 18 years if there is a realistic possibility that this may avoid the need for referral to adult mental health services. ## Managing self-harm and attempted suicide Follow the recommendations in the NICE guideline on self-harm in over 8s: short-term management and prevention of recurrence to manage episodes of self-harm or attempted suicide. ## Training, supervision and support Mental health professionals working in secondary care services, including community-based services and teams, CAMHS and inpatient services, should be trained to diagnose borderline personality disorder, assess risk and need, and provide treatment and management in accordance with this guideline. Training should also be provided for primary care healthcare professionals who have significant involvement in the assessment and early treatment of people with borderline personality disorder. Training should be provided by specialist personality disorder teams based in mental health trusts (see recommendation 1.5.1.1 in the section on the role of specialist personality disorder services within trusts ). Mental health professionals working with people with borderline personality disorder should have routine access to supervision and staff support. # Recognition and management in primary care ## Recognition of borderline personality disorder If a person presents in primary care who has repeatedly self-harmed or shown persistent risk-taking behaviour or marked emotional instability, consider referring them to community mental health services for assessment for borderline personality disorder. If the person is younger than 18 years, refer them to CAMHS for assessment. ## Crisis management in primary care When a person with an established diagnosis of borderline personality disorder presents to primary care in a crisis: assess the current level of risk to self or others ask about previous episodes and effective management strategies used in the past help to manage their anxiety by enhancing coping skills and helping them to focus on the current problems encourage them to identify manageable changes that will enable them to deal with the current problems -ffer a follow-up appointment at an agreed time. ## Referral to community mental health services Consider referring a person with diagnosed or suspected borderline personality disorder who is in crisis to a community mental health service when: their levels of distress and/or the risk to self or others are increasing their levels of distress and/or the risk to self or others have not subsided despite attempts to reduce anxiety and improve coping skills they request further help from specialist services. # Assessment and management by community mental health services ## Assessment Community mental health services (community mental health teams, related community-based services, and tier 2 or 3 services in children and adolescent mental health services ) should be responsible for the routine assessment, treatment and management of people with borderline personality disorder. When assessing a person with possible borderline personality disorder in community mental health services, fully assess: psychosocial and occupational functioning, coping strategies, strengths and vulnerabilities comorbid mental disorders and social problems the need for psychological treatment, social care and support, and occupational rehabilitation or development the needs of any dependent children. See Social Care Institute for Excellence's research briefing on experiences of children and young people caring for a parent with a mental health problem. ## Care planning Teams working with people with borderline personality disorder should develop comprehensive multidisciplinary care plans in collaboration with the service user (and their family or carers, where agreed with the person). The care plan should: identify clearly the roles and responsibilities of all health and social care professionals involved identify manageable short-term treatment aims and specify steps that the person and others might take to achieve them identify long-term goals, including those relating to employment and occupation, that the person would like to achieve, which should underpin the overall long-term treatment strategy; these goals should be realistic, and linked to the short-term treatment aims develop a crisis plan that identifies potential triggers that could lead to a crisis, specifies self-management strategies likely to be effective and establishes how to access services (including a list of support numbers for out-of-hours teams and crisis teams) when self-management strategies alone are not enough be shared with the GP and the service user. Teams should use the CPA when people with borderline personality disorder are routinely or frequently in contact with more than one secondary care service. It is particularly important if there are communication difficulties between the service user and healthcare professionals, or between healthcare professionals. ## Risk assessment and management Risk assessment in people with borderline personality disorder should: take place as part of a full assessment of the person's needs differentiate between long-term and more immediate risks identify the risks posed to self and others, including the welfare of any dependent children. Agree explicitly the risks being assessed with the person with borderline personality disorder and develop collaboratively risk management plans that: address both the long-term and more immediate risks relate to the overall long-term treatment strategy take account of changes in personal relationships, including the therapeutic relationship. When managing the risks posed by people with borderline personality disorder in a community mental health service, risks should be managed by the whole multidisciplinary team with good supervision arrangements, especially for less experienced team members. Be particularly cautious when: evaluating risk if the person is not well known to the team there have been frequent suicidal crises. Teams working with people with borderline personality disorder should review regularly the team members' tolerance and sensitivity to people who pose a risk to themselves and others. This should be reviewed annually (or more frequently if a team is regularly working with people with high levels of risk). ## Psychological treatment When considering a psychological treatment for a person with borderline personality disorder, take into account: the choice and preference of the service user the degree of impairment and severity of the disorder the person's willingness to engage with therapy and their motivation to change the person's ability to remain within the boundaries of a therapeutic relationship the availability of personal and professional support. Before offering a psychological treatment for a person with borderline personality disorder or for a comorbid condition, provide the person with written material about the psychological treatment being considered. For people who have reading difficulties, alternative means of presenting the information should be considered, such as video or DVD. So that the person can make an informed choice, there should be an opportunity for them to discuss not only this information but also the evidence for the effectiveness of different types of psychological treatment for borderline personality disorder and any comorbid conditions. When providing psychological treatment for people with borderline personality disorder, especially those with multiple comorbidities and/or severe impairment, the following service characteristics should be in place: an explicit and integrated theoretical approach used by both the treatment team and the therapist, which is shared with the service user structured care in accordance with this guideline provision for therapist supervision.Although the frequency of psychotherapy sessions should be adapted to the person's needs and context of living, twice-weekly sessions may be considered. Do not use brief psychological interventions (of less than 3 months' duration) specifically for borderline personality disorder or for the individual symptoms of the disorder, outside a service that has the characteristics outlined in recommendation 1.3.4.3. For women with borderline personality disorder for whom reducing recurrent self-harm is a priority, consider a comprehensive dialectical behaviour therapy programme. When providing psychological treatment to people with borderline personality disorder as a specific intervention in their overall treatment and care, use the CPA to clarify the roles of different services, professionals providing psychological treatment and other healthcare professionals. When providing psychological treatment to people with borderline personality disorder, monitor the effect of treatment on a broad range of outcomes, including personal functioning, drug and alcohol use, self-harm, depression and the symptoms of borderline personality disorder. ## The role of drug treatment Drug treatment should not be used specifically for borderline personality disorder or for the individual symptoms or behaviour associated with the disorder (for example, repeated self-harm, marked emotional instability, risk-taking behaviour and transient psychotic symptoms). Antipsychotic drugs should not be used for the medium- and long-term treatment of borderline personality disorder. Drug treatment may be considered in the overall treatment of comorbid conditions (see section 1.3.6 on the management of comorbidities). Short-term use of sedative medication may be considered cautiously as part of the overall treatment plan for people with borderline personality disorder in a crisis. Sedative antihistamines are not licensed for this indication and informed consent should be obtained and documented. The duration of treatment should be agreed with them, but should be no longer than 1 week (see section 1.3.7 on the management of crises). When considering drug treatment for any reason for a person with borderline personality disorder, provide the person with written material about the drug being considered. This should include evidence for the drug's effectiveness in the treatment of borderline personality disorder and for any comorbid condition, and potential harm. For people who have reading difficulties, alternative means of presenting the information should be considered, such as video or DVD. So that the person can make an informed choice, there should be an opportunity for the person to discuss the material. Review the treatment of people with borderline personality disorder who do not have a diagnosed comorbid mental or physical illness and who are currently being prescribed drugs, with the aim of reducing and stopping unnecessary drug treatment. ## The management of comorbidities Before starting treatment for a comorbid condition in people with borderline personality disorder, review: the diagnosis of borderline personality disorder and that of the comorbid condition, especially if either diagnosis has been made during a crisis or emergency presentation the effectiveness and tolerability of previous and current treatments; discontinue ineffective treatments. Treat comorbid depression, post-traumatic stress disorder or anxiety within a well-structured treatment programme for borderline personality disorder. Refer people with borderline personality disorder who also have major psychosis, dependence on alcohol or Class A drugs, or a severe eating disorder to an appropriate service. The care coordinator should keep in contact with people being treated for the comorbid condition so that they can continue with treatment for borderline personality disorder when appropriate. When treating a comorbid condition in people with borderline personality disorder, follow the NICE clinical guideline for the comorbid condition (see the NICE topic page on mental health and behavioural conditions). ## The management of crises The following principles and guidance on the management of crises apply to secondary care and specialist services for personality disorder. They may also be of use to GPs with a special interest in the management of borderline personality disorder within primary care. When a person with borderline personality disorder presents during a crisis, consult the crisis plan and: maintain a calm and non-threatening attitude try to understand the crisis from the person's point of view explore the person's reasons for distress use empathic open questioning, including validating statements, to identify the onset and the course of the current problems seek to stimulate reflection about solutions avoid minimising the person's stated reasons for the crisis refrain from offering solutions before receiving full clarification of the problems explore other options before considering admission to a crisis unit or inpatient admission -ffer appropriate follow-up within a time frame agreed with the person. Short-term use of drug treatments may be helpful for people with borderline personality disorder during a crisis. Before starting short-term drug treatments for people with borderline personality disorder during a crisis (see recommendation 1.3.5.4 in the section on the role of drug treatment): ensure that there is consensus among prescribers and other involved professionals about the drug used and that the primary prescriber is identified establish likely risks of prescribing, including alcohol and illicit drug use take account of the psychological role of prescribing (both for the individual and for the prescriber) and the impact that prescribing decisions may have on the therapeutic relationship and the overall care plan, including long-term treatment strategies ensure that a drug is not used in place of other more appropriate interventions use a single drug avoid polypharmacy whenever possible. When prescribing short-term drug treatment for people with borderline personality disorder in a crisis: choose a drug (such as a sedative antihistamine which are not licensed for this indication and informed consent should be obtained and documented) that has a low side-effect profile, low addictive properties, minimum potential for misuse and relative safety in overdose use the minimum effective dose prescribe fewer tablets more frequently if there is a significant risk of overdose agree with the person the target symptoms, monitoring arrangements and anticipated duration of treatment agree with the person a plan for adherence discontinue a drug after a trial period if the target symptoms do not improve consider alternative treatments, including psychological treatments, if target symptoms do not improve or the level of risk does not diminish arrange an appointment to review the overall care plan, including pharmacological and other treatments, after the crisis has subsided. After a crisis has resolved or subsided, ensure that crisis plans, and if necessary the overall care plan, are updated as soon as possible to reflect current concerns and identify which treatment strategies have proved helpful. This should be done in conjunction with the person with borderline personality disorder and their family or carers if possible, and should include: a review of the crisis and its antecedents, taking into account environmental, personal and relationship factors a review of drug treatment, including benefits, side effects, any safety concerns and role in the overall treatment strategy a plan to stop drug treatment begun during a crisis, usually within 1 week a review of psychological treatments, including their role in the overall treatment strategy and their possible role in precipitating the crisis. If drug treatment started during a crisis cannot be stopped within 1 week, there should be a regular review of the drug to monitor effectiveness, side effects, misuse and dependency. The frequency of the review should be agreed with the person and recorded in the overall care plan. ## The management of insomnia Provide people with borderline personality disorder who have sleep problems with general advice about sleep hygiene, including having a bedtime routine, avoiding caffeine, reducing activities likely to defer sleep (such as watching violent or exciting television programmes or films), and employing activities that may encourage sleep. For the further short-term management of insomnia follow the recommendations in the NICE technology appraisal guidance on the use of zaleplon, zolpidem and zopiclone for the short-term management of insomnia. However, be aware of the potential for misuse of many of the drugs used for insomnia and consider other drugs such as sedative antihistamines. For guidance on safe prescribing of Z-drugs (such as zolpidem and zopiclone) and managing withdrawal, see NICE's guideline on medicines associated with dependence or withdrawal symptoms. ## Discharge to primary care When discharging a person with borderline personality disorder from secondary care to primary care, discuss the process with them and, whenever possible, their family or carers beforehand. Agree a care plan that specifies the steps they can take to try to manage their distress, how to cope with future crises and how to re-engage with community mental health services if needed. Inform the GP. # Inpatient services Before considering admission to an acute psychiatric inpatient unit for a person with borderline personality disorder, first refer them to a crisis resolution and home treatment team or other locally available alternative to admission. Only consider people with borderline personality disorder for admission to an acute psychiatric inpatient unit for: the management of crises involving significant risk to self or others that cannot be managed within other services, or detention under the Mental Health Act (for any reason). When considering inpatient care for a person with borderline personality disorder, actively involve them in the decision and: ensure the decision is based on an explicit, joint understanding of the potential benefits and likely harm that may result from admission agree the length and purpose of the admission in advance ensure that when, in extreme circumstances, compulsory treatment is used, management on a voluntary basis is resumed at the earliest opportunity. Arrange a formal CPA review for people with borderline personality disorder who have been admitted twice or more in the previous 6 months. NHS trusts providing CAMHS should ensure that young people with severe borderline personality disorder have access to tier 4 specialist services if required, which may include: inpatient treatment tailored to the needs of young people with borderline personality disorder specialist outpatient programmes home treatment teams. # Organisation and planning of services ## The role of specialist personality disorder services within trusts Mental health trusts should develop multidisciplinary specialist teams and/or services for people with personality disorders. These teams should have specific expertise in the diagnosis and management of borderline personality disorder and should: provide assessment and treatment services for people with borderline personality disorder who have particularly complex needs and/or high levels of risk provide consultation and advice to primary and secondary care services -ffer a diagnostic service when general psychiatric services are in doubt about the diagnosis and/or management of borderline personality disorder develop systems of communication and protocols for information sharing among different services, including those in forensic settings, and collaborate with all relevant agencies within the local community including health, mental health and social services, the criminal justice system, CAMHS and relevant voluntary services be able to provide and/or advise on social and psychological interventions, including access to peer support, and advise on the safe use of drug treatment in crises and for comorbidities and insomnia work with CAMHS to develop local protocols to govern arrangements for the transition of young people from CAMHS to adult services ensure that clear lines of communication between primary and secondary care are established and maintained support, lead and participate in the local and national development of treatments for people with borderline personality disorder, including multi-centre research -versee the implementation of this guideline develop and provide training programmes on the diagnosis and management of borderline personality disorder and the implementation of this guideline (see recommendation 1.5.1.2 in the section on the role of specialist personality disorder services within trusts) monitor the provision of services for minority ethnic groups to ensure equality of service delivery. The size and time commitment of these teams will depend on local circumstances (for example, the size of trust, the population covered and the estimated referral rate for people with borderline personality disorder). Specialist teams should develop and provide training programmes that cover the diagnosis and management of borderline personality disorder and the implementation of this guideline for general mental health, social care, forensic and primary care providers and other professionals who have contact with people with borderline personality disorder. The programmes should also address problems around stigma and discrimination as these apply to people with borderline personality disorder. Specialist personality disorder services should involve people with personality disorders and families or carers in planning service developments, and in developing information about services. With appropriate training and support, people with personality disorders may also provide services, such as training for professionals, education for service users and families or carers, and facilitating peer support groups.# Research recommendations The guideline development gxroup has made the following recommendations for research, based on its review of evidence, to improve NICE guidance and care of service users in the future. # Development of an agreed set of outcomes measures What are the best outcome measures to assess interventions for people with borderline personality disorder? This question should be addressed in a three-stage process using formal consensus methods involving people from a range of backgrounds, including service users, families or carers, clinicians and academics. The outcomes chosen should be valid and reliable for this patient group, and should include measures of quality of life, function and symptoms for both service users and carers. The three-stage process should include: (1) identifying aspects of quality of life, functioning and symptoms that are important for service users and families/carers; (2) matching these to existing outcome measures and highlighting where measures are lacking; (3) generating a shortlist of relevant outcome measures to avoid multiple outcome measures being used in future. Where measures are lacking, further work should be done to develop appropriate outcomes. ## Why this is important Existing research examining the effects of psychological and pharmacological interventions for people with borderline personality disorder has used a wide range of outcomes measures. This makes it difficult to synthesise data from different studies and to compare interventions. Also, outcomes do not always adequately reflect patient experience. Agreeing outcome measures for future studies of interventions for people with borderline personality disorder will make it easier to develop evidence-based treatment guidelines in the future. # Psychological therapy programmes for people with borderline personality disorder What is the relative efficacy of psychological therapy programmes (for example, mentalisation-based therapy, dialectical behaviour therapy or similar approach) delivered within well structured, high quality community-based services (for example, a day hospital setting, or a community mental health team) compared with high-quality community care delivered by general mental health services without the psychological intervention for people with borderline personality disorder? This question should be answered using a randomised controlled design which reports medium-term outcomes (including cost effectiveness outcomes) of at least 18 months' duration. They should pay particular attention to the training and supervision of those providing interventions in order to ensure that systems for delivering them are both robust and generalisable. ## Why this is important Research suggests that psychological therapy programmes, such as dialectical behaviour therapy and mentalisation-based therapy as delivered in the studies reviewed for this guideline, may benefit people with borderline personality disorder. However, trials are relatively small, and research is generally at an early stage of development with studies tending to examine interventions delivered in centres of excellence. In addition, few trials have included large numbers of men. Pragmatic trials comparing psychological therapy programmes with high-quality outpatient follow-up by community mental health services would help to establish the effectiveness, costs and cost effectiveness of these interventions delivered in generalisable settings. The effect of these interventions among men and young people should also be examined. # Outpatient psychosocial interventions What is the efficacy of outpatient psychosocial interventions (such as cognitive analytic therapy, cognitive behavioural therapy, schema-focused therapy, and transference focused therapy) for people with less severe (fewer comorbidities, higher level of social functioning, more able to depend on self-management methods) borderline personality disorder? This question should be answered using randomised controlled trials which report medium-term outcomes (for example, quality of life, psychosocial functioning, employment outcomes and borderline personality disorder symptomatology) of at least 18 months. They should pay particular attention to training and supervision of those delivering interventions. ## Why this is important The evidence base for the effectiveness of psychosocial interventions for people with personality disorder is at an early stage of development. Data collected from cohort studies and case series suggest that a variety of such interventions may help people with borderline personality disorder. Trials of these interventions would help to develop a better understanding of their efficacy. They should examine the process of treatment delivery in an experimental study, and explore logistical and other factors that could have an impact on the likelihood of larger scale experimental evaluations of these interventions succeeding. # Mood stabilisers What is the effectiveness and cost-effectiveness of mood stabilisers on the symptoms of borderline personality disorder? This should be answered by a randomised placebo-controlled trial which should include the medium to long-term impact of such treatment. The study should be sufficiently powered to investigate both the effects and side effects of this treatment. ## Why this is important There is little evidence of the effectiveness of pharmacological treatments for people with personality disorder. However, there have been encouraging findings from small-scale studies of mood stabilisers such as topiramate and lamotrigine, which indicates the need for further research. Emotional instability is a key feature of borderline personality disorder and the effect of these treatments on mood and other key features of this disorder should be studied. The findings of such a study would support the development of future recommendations on the role of pharmacological interventions in the treatment of borderline personality disorder. # Developing a care pathway What is the best care pathway for people with borderline personality disorder? A mixed-methods cohort study examining the care pathway of a representative sample of people with borderline personality disorder should be undertaken. Such a study should include consideration of factors that should guide referral from primary to secondary care services, and examine the role of inpatient treatment. The study should examine the effect that people with borderline personality disorder and service-level factors have on the transfer between different components of care and include collection and analysis of both qualitative and quantitative data. ## Why this is important The development of a care pathway for people with borderline personality disorder would help to ensure that available resources are used effectively and that services are suited to their needs. Service provision for people with borderline personality disorder varies greatly in different parts of the country, and factors that should be considered when deciding the type and intensity of care that people receive are poorly understood. A cohort study in which qualitative and quantitative data from service users and providers are collected at the point of transfer to and from different parts of the care pathway would help to inform the decisions that people with borderline personality disorder and healthcare professionals have to make about the type of services that people receive.	{'Introduction': "This guideline makes recommendations for the treatment and management of borderline personality disorder in adults and young people (under the age of 18) who meet criteria for the diagnosis in primary, secondary and tertiary care. The guideline also covers the treatment and management of people diagnosed with emotionally unstable personality disorder based on ICD-10 criteria\n\nBorderline personality disorder is characterised by significant instability of interpersonal relationships, self-image and mood, and impulsive behaviour. There is a pattern of sometimes rapid fluctuation from periods of confidence to despair, with fear of abandonment and rejection, and a strong tendency towards suicidal thinking and self-harm. Transient psychotic symptoms, including brief delusions and hallucinations, may also be present. It is also associated with substantial impairment of social, psychological and occupational functioning and quality of life. People with borderline personality disorder are particularly at risk of suicide.\n\nThe extent of the emotional and behavioural problems experienced by people with borderline personality disorder varies considerably. Some people with borderline personality disorder are able to sustain some relationships and occupational activities. People with more severe forms experience very high levels of emotional distress. They have repeated crises, which can involve self-harm and impulsive aggression. They also have high levels of comorbidity, including other personality disorders, and are frequent users of psychiatric and acute hospital emergency services. While the general principles of management referred to in this guideline are intended for all people with borderline personality disorder, the treatment recommendations are directed primarily at those with more severe forms of the disorder.\n\nBorderline personality disorder is present in just under 1% of the population, and is most common in early adulthood. Women present to services more often than men. Borderline personality disorder is often not formally diagnosed before the age of 18, but the features of the disorder can be identified earlier. Its course is variable and although many people recover over time, some people may continue to experience social and interpersonal difficulties.\n\nBorderline personality disorder is often comorbid with depression, anxiety, eating disorders, post-traumatic stress disorder, alcohol and drug misuse, and bipolar disorder (the symptoms of which are often confused with borderline personality disorder). This guideline does not cover the separate management of comorbid conditions.\n\nPeople with borderline personality disorder have sometimes been excluded from any health or social care services because of their diagnosis. This may be because staff lack the confidence and skills to work with this group of people.\n\nThis guideline draws on the best available evidence. However, there are significant limitations to the evidence base, notably, few randomised controlled trials (RCTs) of interventions, which have few outcomes in common. Some of the limitations are addressed in the research recommendations.\n\nAt the time of publication (January 2009), no drug has UK marketing authorisation for the treatment of borderline personality disorder, but this guideline contains recommendations about the use of drugs to manage crises, comorbid conditions and insomnia. The guideline assumes that prescribers will use a drug's summary of product characteristics to inform their decisions for each person.\n\nNICE has developed a guideline on antisocial personality disorder: prevention and management.", 'Guidance': "People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.\n\nMaking decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.\n\nThe following guidance is based on the best available evidence. The full guideline gives details of the methods and evidence used to develop the guidance.\n\n# General principles for working with people with borderline personality disorder\n\n## Access to services\n\nPeople with borderline personality disorder should not be excluded from any health or social care service because of their diagnosis or because they have self-harmed.\n\nYoung people with a diagnosis of borderline personality disorder, or symptoms and behaviour that suggest it, should have access to the full range of treatments and services recommended in this guideline, but within children and adolescent mental health services (CAMHS).\n\nEnsure that people with borderline personality disorder from black and minority ethnic groups have equal access to culturally appropriate services based on clinical need.\n\nWhen language is a barrier to accessing or engaging with services for people with borderline personality disorder, provide them with:\n\ninformation in their preferred language and in an accessible format\n\npsychological or other interventions in their preferred language\n\nindependent interpreters.\n\n## Borderline personality disorder and learning disabilities\n\nWhen a person with a mild learning disability presents with symptoms and behaviour that suggest borderline personality disorder, assessment and diagnosis should take place in consultation with a specialist in learning disabilities services.\n\nWhen a person with a mild learning disability has a diagnosis of borderline personality disorder, they should have access to the same services as other people with borderline personality disorder.\n\nWhen care planning for people with a mild learning disability and borderline personality disorder, follow the Care Programme Approach (CPA). Consider consulting a specialist in learning disabilities services when developing care plans and strategies for managing behaviour that challenges.\n\nPeople with a moderate or severe learning disability should not normally be diagnosed with borderline personality disorder. If they show behaviour and symptoms that suggest borderline personality disorder, refer for assessment and treatment by a specialist in learning disabilities services.\n\n## Autonomy and choice\n\nWork in partnership with people with borderline personality disorder to develop their autonomy and promote choice by:\n\nensuring they remain actively involved in finding solutions to their problems, including during crises\n\nencouraging them to consider the different treatment options and life choices available to them, and the consequences of the choices they make.\n\n## Developing an optimistic and trusting relationship\n\nWhen working with people with borderline personality disorder:\n\nexplore treatment options in an atmosphere of hope and optimism, explaining that recovery is possible and attainable\n\nbuild a trusting relationship, work in an open, engaging and non-judgemental manner, and be consistent and reliable\n\nbear in mind when providing services that many people will have experienced rejection, abuse and trauma, and encountered stigma often associated with self-harm and borderline personality disorder.\n\n## Involving families or carers\n\nAsk directly whether the person with borderline personality disorder wants their family or carers to be involved in their care, and, subject to the person's consent and rights to confidentiality:\n\nencourage family or carers to be involved\n\nensure that the involvement of families or carers does not lead to withdrawal of, or lack of access to, services\n\ninform families or carers about local support groups for families or carers, if these exist.\n\nCAMHS professionals working with young people with borderline personality disorder should:\n\nbalance the developing autonomy and capacity of the young person with the responsibilities of parents or carers\n\nbe familiar with the legal framework that applies to young people, including the Mental Capacity Act, the Children Acts and the Mental Health Act.\n\n## Principles for assessment\n\nWhen assessing a person with borderline personality disorder:\n\nexplain clearly the process of assessment\n\nuse non-technical language whenever possible\n\nexplain the diagnosis and the use and meaning of the term borderline personality disorder\n\noffer post-assessment support, particularly if sensitive issues, such as childhood trauma, have been discussed.\n\n## Managing endings and supporting transitions\n\nAnticipate that withdrawal and ending of treatments or services, and transition from one service to another, may evoke strong emotions and reactions in people with borderline personality disorder. Ensure that:\n\nsuch changes are discussed carefully beforehand with the person (and their family or carers if appropriate) and are structured and phased\n\nthe care plan supports effective collaboration with other care providers during endings and transitions, and includes the opportunity to access services in times of crisis\n\nwhen referring a person for assessment in other services (including for psychological treatment), they are supported during the referral period and arrangements for support are agreed beforehand with them.\n\nCAMHS and adult healthcare professionals should work collaboratively to minimise any potential negative effect of transferring young people from CAMHS to adult services. They should:\n\ntime the transfer to suit the young person, even if it takes place after they have reached the age of 18\xa0years\n\ncontinue treatment in CAMHS beyond 18\xa0years if there is a realistic possibility that this may avoid the need for referral to adult mental health services.\n\n## Managing self-harm and attempted suicide\n\nFollow the recommendations in the NICE guideline on self-harm in over 8s: short-term management and prevention of recurrence to manage episodes of self-harm or attempted suicide.\n\n## Training, supervision and support\n\nMental health professionals working in secondary care services, including community-based services and teams, CAMHS and inpatient services, should be trained to diagnose borderline personality disorder, assess risk and need, and provide treatment and management in accordance with this guideline. Training should also be provided for primary care healthcare professionals who have significant involvement in the assessment and early treatment of people with borderline personality disorder. Training should be provided by specialist personality disorder teams based in mental health trusts (see recommendation 1.5.1.1 in the section on the role of specialist personality disorder services within trusts ).\n\nMental health professionals working with people with borderline personality disorder should have routine access to supervision and staff support.\n\n# Recognition and management in primary care\n\n## Recognition of borderline personality disorder\n\nIf a person presents in primary care who has repeatedly self-harmed or shown persistent risk-taking behaviour or marked emotional instability, consider referring them to community mental health services for assessment for borderline personality disorder. If the person is younger than 18\xa0years, refer them to CAMHS for assessment.\n\n## Crisis management in primary care\n\nWhen a person with an established diagnosis of borderline personality disorder presents to primary care in a crisis:\n\nassess the current level of risk to self or others\n\nask about previous episodes and effective management strategies used in the past\n\nhelp to manage their anxiety by enhancing coping skills and helping them to focus on the current problems\n\nencourage them to identify manageable changes that will enable them to deal with the current problems\n\noffer a follow-up appointment at an agreed time.\n\n## Referral to community mental health services\n\nConsider referring a person with diagnosed or suspected borderline personality disorder who is in crisis to a community mental health service when:\n\ntheir levels of distress and/or the risk to self or others are increasing\n\ntheir levels of distress and/or the risk to self or others have not subsided despite attempts to reduce anxiety and improve coping skills\n\nthey request further help from specialist services.\n\n# Assessment and management by community mental health services\n\n## Assessment\n\nCommunity mental health services (community mental health teams, related community-based services, and tier 2 or 3 services in children and adolescent mental health services [CAMHS]) should be responsible for the routine assessment, treatment and management of people with borderline personality disorder.\n\nWhen assessing a person with possible borderline personality disorder in community mental health services, fully assess:\n\npsychosocial and occupational functioning, coping strategies, strengths and vulnerabilities\n\ncomorbid mental disorders and social problems\n\nthe need for psychological treatment, social care and support, and occupational rehabilitation or development\n\nthe needs of any dependent children. See Social Care Institute for Excellence's research briefing on experiences of children and young people caring for a parent with a mental health problem.\n\n## Care planning\n\nTeams working with people with borderline personality disorder should develop comprehensive multidisciplinary care plans in collaboration with the service user (and their family or carers, where agreed with the person). The care plan should:\n\nidentify clearly the roles and responsibilities of all health and social care professionals involved\n\nidentify manageable short-term treatment aims and specify steps that the person and others might take to achieve them\n\nidentify long-term goals, including those relating to employment and occupation, that the person would like to achieve, which should underpin the overall long-term treatment strategy; these goals should be realistic, and linked to the short-term treatment aims\n\ndevelop a crisis plan that identifies potential triggers that could lead to a crisis, specifies self-management strategies likely to be effective and establishes how to access services (including a list of support numbers for out-of-hours teams and crisis teams) when self-management strategies alone are not enough\n\nbe shared with the GP and the service user.\n\nTeams should use the CPA when people with borderline personality disorder are routinely or frequently in contact with more than one secondary care service. It is particularly important if there are communication difficulties between the service user and healthcare professionals, or between healthcare professionals.\n\n## Risk assessment and management\n\nRisk assessment in people with borderline personality disorder should:\n\ntake place as part of a full assessment of the person's needs\n\ndifferentiate between long-term and more immediate risks\n\nidentify the risks posed to self and others, including the welfare of any dependent children.\n\nAgree explicitly the risks being assessed with the person with borderline personality disorder and develop collaboratively risk management plans that:\n\naddress both the long-term and more immediate risks\n\nrelate to the overall long-term treatment strategy\n\ntake account of changes in personal relationships, including the therapeutic relationship.\n\nWhen managing the risks posed by people with borderline personality disorder in a community mental health service, risks should be managed by the whole multidisciplinary team with good supervision arrangements, especially for less experienced team members. Be particularly cautious when:\n\nevaluating risk if the person is not well known to the team\n\nthere have been frequent suicidal crises.\n\nTeams working with people with borderline personality disorder should review regularly the team members' tolerance and sensitivity to people who pose a risk to themselves and others. This should be reviewed annually (or more frequently if a team is regularly working with people with high levels of risk).\n\n## Psychological treatment\n\nWhen considering a psychological treatment for a person with borderline personality disorder, take into account:\n\nthe choice and preference of the service user\n\nthe degree of impairment and severity of the disorder\n\nthe person's willingness to engage with therapy and their motivation to change\n\nthe person's ability to remain within the boundaries of a therapeutic relationship\n\nthe availability of personal and professional support.\n\nBefore offering a psychological treatment for a person with borderline personality disorder or for a comorbid condition, provide the person with written material about the psychological treatment being considered. For people who have reading difficulties, alternative means of presenting the information should be considered, such as video or DVD. So that the person can make an informed choice, there should be an opportunity for them to discuss not only this information but also the evidence for the effectiveness of different types of psychological treatment for borderline personality disorder and any comorbid conditions.\n\nWhen providing psychological treatment for people with borderline personality disorder, especially those with multiple comorbidities and/or severe impairment, the following service characteristics should be in place:\n\nan explicit and integrated theoretical approach used by both the treatment team and the therapist, which is shared with the service user\n\nstructured care in accordance with this guideline\n\nprovision for therapist supervision.Although the frequency of psychotherapy sessions should be adapted to the person's needs and context of living, twice-weekly sessions may be considered.\n\nDo not use brief psychological interventions (of less than 3\xa0months' duration) specifically for borderline personality disorder or for the individual symptoms of the disorder, outside a service that has the characteristics outlined in recommendation\xa01.3.4.3.\n\nFor women with borderline personality disorder for whom reducing recurrent self-harm is a priority, consider a comprehensive dialectical behaviour therapy programme.\n\nWhen providing psychological treatment to people with borderline personality disorder as a specific intervention in their overall treatment and care, use the CPA to clarify the roles of different services, professionals providing psychological treatment and other healthcare professionals.\n\nWhen providing psychological treatment to people with borderline personality disorder, monitor the effect of treatment on a broad range of outcomes, including personal functioning, drug and alcohol use, self-harm, depression and the symptoms of borderline personality disorder.\n\n## The role of drug treatment\n\nDrug treatment should not be used specifically for borderline personality disorder or for the individual symptoms or behaviour associated with the disorder (for example, repeated self-harm, marked emotional instability, risk-taking behaviour and transient psychotic symptoms).\n\nAntipsychotic drugs should not be used for the medium- and long-term treatment of borderline personality disorder.\n\nDrug treatment may be considered in the overall treatment of comorbid conditions (see section\xa01.3.6 on the management of comorbidities).\n\nShort-term use of sedative medication may be considered cautiously as part of the overall treatment plan for people with borderline personality disorder in a crisis. Sedative antihistamines are not licensed for this indication and informed consent should be obtained and documented. The duration of treatment should be agreed with them, but should be no longer than 1\xa0week (see section\xa01.3.7 on the management of crises).\n\nWhen considering drug treatment for any reason for a person with borderline personality disorder, provide the person with written material about the drug being considered. This should include evidence for the drug's effectiveness in the treatment of borderline personality disorder and for any comorbid condition, and potential harm. For people who have reading difficulties, alternative means of presenting the information should be considered, such as video or DVD. So that the person can make an informed choice, there should be an opportunity for the person to discuss the material.\n\nReview the treatment of people with borderline personality disorder who do not have a diagnosed comorbid mental or physical illness and who are currently being prescribed drugs, with the aim of reducing and stopping unnecessary drug treatment.\n\n## The management of comorbidities\n\nBefore starting treatment for a comorbid condition in people with borderline personality disorder, review:\n\nthe diagnosis of borderline personality disorder and that of the comorbid condition, especially if either diagnosis has been made during a crisis or emergency presentation\n\nthe effectiveness and tolerability of previous and current treatments; discontinue ineffective treatments.\n\nTreat comorbid depression, post-traumatic stress disorder or anxiety within a well-structured treatment programme for borderline personality disorder.\n\nRefer people with borderline personality disorder who also have major psychosis, dependence on alcohol or Class A drugs, or a severe eating disorder to an appropriate service. The care coordinator should keep in contact with people being treated for the comorbid condition so that they can continue with treatment for borderline personality disorder when appropriate.\n\nWhen treating a comorbid condition in people with borderline personality disorder, follow the NICE clinical guideline for the comorbid condition (see the NICE topic page on mental health and behavioural conditions).\n\n## The management of crises\n\nThe following principles and guidance on the management of crises apply to secondary care and specialist services for personality disorder. They may also be of use to GPs with a special interest in the management of borderline personality disorder within primary care.\n\nWhen a person with borderline personality disorder presents during a crisis, consult the crisis plan and:\n\nmaintain a calm and non-threatening attitude\n\ntry to understand the crisis from the person's point of view\n\nexplore the person's reasons for distress\n\nuse empathic open questioning, including validating statements, to identify the onset and the course of the current problems\n\nseek to stimulate reflection about solutions\n\navoid minimising the person's stated reasons for the crisis\n\nrefrain from offering solutions before receiving full clarification of the problems\n\nexplore other options before considering admission to a crisis unit or inpatient admission\n\noffer appropriate follow-up within a time frame agreed with the person.\n\nShort-term use of drug treatments may be helpful for people with borderline personality disorder during a crisis.\n\nBefore starting short-term drug treatments for people with borderline personality disorder during a crisis (see recommendation\xa01.3.5.4 in the section on the role of drug treatment):\n\nensure that there is consensus among prescribers and other involved professionals about the drug used and that the primary prescriber is identified\n\nestablish likely risks of prescribing, including alcohol and illicit drug use\n\ntake account of the psychological role of prescribing (both for the individual and for the prescriber) and the impact that prescribing decisions may have on the therapeutic relationship and the overall care plan, including long-term treatment strategies\n\nensure that a drug is not used in place of other more appropriate interventions\n\nuse a single drug\n\navoid polypharmacy whenever possible.\n\nWhen prescribing short-term drug treatment for people with borderline personality disorder in a crisis:\n\nchoose a drug (such as a sedative antihistamine which are not licensed for this indication and informed consent should be obtained and documented) that has a low side-effect profile, low addictive properties, minimum potential for misuse and relative safety in overdose\n\nuse the minimum effective dose\n\nprescribe fewer tablets more frequently if there is a significant risk of overdose\n\nagree with the person the target symptoms, monitoring arrangements and anticipated duration of treatment\n\nagree with the person a plan for adherence\n\ndiscontinue a drug after a trial period if the target symptoms do not improve\n\nconsider alternative treatments, including psychological treatments, if target symptoms do not improve or the level of risk does not diminish\n\narrange an appointment to review the overall care plan, including pharmacological and other treatments, after the crisis has subsided.\n\nAfter a crisis has resolved or subsided, ensure that crisis plans, and if necessary the overall care plan, are updated as soon as possible to reflect current concerns and identify which treatment strategies have proved helpful. This should be done in conjunction with the person with borderline personality disorder and their family or carers if possible, and should include:\n\na review of the crisis and its antecedents, taking into account environmental, personal and relationship factors\n\na review of drug treatment, including benefits, side effects, any safety concerns and role in the overall treatment strategy\n\na plan to stop drug treatment begun during a crisis, usually within 1\xa0week\n\na review of psychological treatments, including their role in the overall treatment strategy and their possible role in precipitating the crisis.\n\nIf drug treatment started during a crisis cannot be stopped within 1\xa0week, there should be a regular review of the drug to monitor effectiveness, side effects, misuse and dependency. The frequency of the review should be agreed with the person and recorded in the overall care plan.\n\n## The management of insomnia\n\nProvide people with borderline personality disorder who have sleep problems with general advice about sleep hygiene, including having a bedtime routine, avoiding caffeine, reducing activities likely to defer sleep (such as watching violent or exciting television programmes or films), and employing activities that may encourage sleep.\n\nFor the further short-term management of insomnia follow the recommendations in the NICE technology appraisal guidance on the use of zaleplon, zolpidem and zopiclone for the short-term management of insomnia. However, be aware of the potential for misuse of many of the drugs used for insomnia and consider other drugs such as sedative antihistamines. For guidance on safe prescribing of Z-drugs (such as zolpidem and zopiclone) and managing withdrawal, see NICE's guideline on medicines associated with dependence or withdrawal symptoms.\n\n## Discharge to primary care\n\nWhen discharging a person with borderline personality disorder from secondary care to primary care, discuss the process with them and, whenever possible, their family or carers beforehand. Agree a care plan that specifies the steps they can take to try to manage their distress, how to cope with future crises and how to re-engage with community mental health services if needed. Inform the GP.\n\n# Inpatient services\n\nBefore considering admission to an acute psychiatric inpatient unit for a person with borderline personality disorder, first refer them to a crisis resolution and home treatment team or other locally available alternative to admission.\n\nOnly consider people with borderline personality disorder for admission to an acute psychiatric inpatient unit for:\n\nthe management of crises involving significant risk to self or others that cannot be managed within other services, or\n\ndetention under the Mental Health Act (for any reason).\n\nWhen considering inpatient care for a person with borderline personality disorder, actively involve them in the decision and:\n\nensure the decision is based on an explicit, joint understanding of the potential benefits and likely harm that may result from admission\n\nagree the length and purpose of the admission in advance\n\nensure that when, in extreme circumstances, compulsory treatment is used, management on a voluntary basis is resumed at the earliest opportunity.\n\nArrange a formal CPA review for people with borderline personality disorder who have been admitted twice or more in the previous 6\xa0months.\n\nNHS trusts providing CAMHS should ensure that young people with severe borderline personality disorder have access to tier 4 specialist services if required, which may include:\n\ninpatient treatment tailored to the needs of young people with borderline personality disorder\n\nspecialist outpatient programmes\n\nhome treatment teams.\n\n# Organisation and planning of services\n\n## The role of specialist personality disorder services within trusts\n\nMental health trusts should develop multidisciplinary specialist teams and/or services for people with personality disorders. These teams should have specific expertise in the diagnosis and management of borderline personality disorder and should:\n\nprovide assessment and treatment services for people with borderline personality disorder who have particularly complex needs and/or high levels of risk\n\nprovide consultation and advice to primary and secondary care services\n\noffer a diagnostic service when general psychiatric services are in doubt about the diagnosis and/or management of borderline personality disorder\n\ndevelop systems of communication and protocols for information sharing among different services, including those in forensic settings, and collaborate with all relevant agencies within the local community including health, mental health and social services, the criminal justice system, CAMHS and relevant voluntary services\n\nbe able to provide and/or advise on social and psychological interventions, including access to peer support, and advise on the safe use of drug treatment in crises and for comorbidities and insomnia\n\nwork with CAMHS to develop local protocols to govern arrangements for the transition of young people from CAMHS to adult services\n\nensure that clear lines of communication between primary and secondary care are established and maintained\n\nsupport, lead and participate in the local and national development of treatments for people with borderline personality disorder, including multi-centre research\n\noversee the implementation of this guideline\n\ndevelop and provide training programmes on the diagnosis and management of borderline personality disorder and the implementation of this guideline (see recommendation\xa01.5.1.2 in the section on the role of specialist personality disorder services within trusts)\n\nmonitor the provision of services for minority ethnic groups to ensure equality of service delivery. The size and time commitment of these teams will depend on local circumstances (for example, the size of trust, the population covered and the estimated referral rate for people with borderline personality disorder).\n\nSpecialist teams should develop and provide training programmes that cover the diagnosis and management of borderline personality disorder and the implementation of this guideline for general mental health, social care, forensic and primary care providers and other professionals who have contact with people with borderline personality disorder. The programmes should also address problems around stigma and discrimination as these apply to people with borderline personality disorder.\n\nSpecialist personality disorder services should involve people with personality disorders and families or carers in planning service developments, and in developing information about services. With appropriate training and support, people with personality disorders may also provide services, such as training for professionals, education for service users and families or carers, and facilitating peer support groups.", 'Research recommendations': "The guideline development gxroup has made the following recommendations for research, based on its review of evidence, to improve NICE guidance and care of service users in the future.\n\n# Development of an agreed set of outcomes measures\n\nWhat are the best outcome measures to assess interventions for people with borderline personality disorder? This question should be addressed in a three-stage process using formal consensus methods involving people from a range of backgrounds, including service users, families or carers, clinicians and academics. The outcomes chosen should be valid and reliable for this patient group, and should include measures of quality of life, function and symptoms for both service users and carers.\n\nThe three-stage process should include: (1) identifying aspects of quality of life, functioning and symptoms that are important for service users and families/carers; (2) matching these to existing outcome measures and highlighting where measures are lacking; (3) generating a shortlist of relevant outcome measures to avoid multiple outcome measures being used in future. Where measures are lacking, further work should be done to develop appropriate outcomes.\n\n## Why this is important\n\nExisting research examining the effects of psychological and pharmacological interventions for people with borderline personality disorder has used a wide range of outcomes measures. This makes it difficult to synthesise data from different studies and to compare interventions. Also, outcomes do not always adequately reflect patient experience. Agreeing outcome measures for future studies of interventions for people with borderline personality disorder will make it easier to develop evidence-based treatment guidelines in the future.\n\n# Psychological therapy programmes for people with borderline personality disorder\n\nWhat is the relative efficacy of psychological therapy programmes (for example, mentalisation-based therapy, dialectical behaviour therapy or similar approach) delivered within well structured, high quality community-based services (for example, a day hospital setting, or a community mental health team) compared with high-quality community care delivered by general mental health services without the psychological intervention for people with borderline personality disorder?\n\nThis question should be answered using a randomised controlled design which reports medium-term outcomes (including cost effectiveness outcomes) of at least 18 months' duration. They should pay particular attention to the training and supervision of those providing interventions in order to ensure that systems for delivering them are both robust and generalisable.\n\n## Why this is important\n\nResearch suggests that psychological therapy programmes, such as dialectical behaviour therapy and mentalisation-based therapy as delivered in the studies reviewed for this guideline, may benefit people with borderline personality disorder. However, trials are relatively small, and research is generally at an early stage of development with studies tending to examine interventions delivered in centres of excellence. In addition, few trials have included large numbers of men. Pragmatic trials comparing psychological therapy programmes with high-quality outpatient follow-up by community mental health services would help to establish the effectiveness, costs and cost effectiveness of these interventions delivered in generalisable settings. The effect of these interventions among men and young people should also be examined.\n\n# Outpatient psychosocial interventions\n\nWhat is the efficacy of outpatient psychosocial interventions (such as cognitive analytic therapy, cognitive behavioural therapy, schema-focused therapy, and transference focused therapy) for people with less severe (fewer comorbidities, higher level of social functioning, more able to depend on self-management methods) borderline personality disorder? This question should be answered using randomised controlled trials which report medium-term outcomes (for example, quality of life, psychosocial functioning, employment outcomes and borderline personality disorder symptomatology) of at least 18\xa0months. They should pay particular attention to training and supervision of those delivering interventions.\n\n## Why this is important\n\nThe evidence base for the effectiveness of psychosocial interventions for people with personality disorder is at an early stage of development. Data collected from cohort studies and case series suggest that a variety of such interventions may help people with borderline personality disorder. Trials of these interventions would help to develop a better understanding of their efficacy. They should examine the process of treatment delivery in an experimental study, and explore logistical and other factors that could have an impact on the likelihood of larger scale experimental evaluations of these interventions succeeding.\n\n# Mood stabilisers\n\nWhat is the effectiveness and cost-effectiveness of mood stabilisers on the symptoms of borderline personality disorder? This should be answered by a randomised placebo-controlled trial which should include the medium to long-term impact of such treatment. The study should be sufficiently powered to investigate both the effects and side effects of this treatment.\n\n## Why this is important\n\nThere is little evidence of the effectiveness of pharmacological treatments for people with personality disorder. However, there have been encouraging findings from small-scale studies of mood stabilisers such as topiramate and lamotrigine, which indicates the need for further research. Emotional instability is a key feature of borderline personality disorder and the effect of these treatments on mood and other key features of this disorder should be studied. The findings of such a study would support the development of future recommendations on the role of pharmacological interventions in the treatment of borderline personality disorder.\n\n# Developing a care pathway\n\nWhat is the best care pathway for people with borderline personality disorder? A mixed-methods cohort study examining the care pathway of a representative sample of people with borderline personality disorder should be undertaken. Such a study should include consideration of factors that should guide referral from primary to secondary care services, and examine the role of inpatient treatment. The study should examine the effect that people with borderline personality disorder and service-level factors have on the transfer between different components of care and include collection and analysis of both qualitative and quantitative data.\n\n## Why this is important\n\nThe development of a care pathway for people with borderline personality disorder would help to ensure that available resources are used effectively and that services are suited to their needs. Service provision for people with borderline personality disorder varies greatly in different parts of the country, and factors that should be considered when deciding the type and intensity of care that people receive are poorly understood. A cohort study in which qualitative and quantitative data from service users and providers are collected at the point of transfer to and from different parts of the care pathway would help to inform the decisions that people with borderline personality disorder and healthcare professionals have to make about the type of services that people receive."}	https://www.nice.org.uk/guidance/cg78	This guideline covers recognising and managing borderline personality disorder. It aims to help people with borderline personality disorder to manage feelings of distress, anxiety, worthlessness and anger, and to maintain stable and close relationships with others.
3dfaa2b8d57e905864c5c76799cda17ae837c88f	nice	Machine perfusion systems and cold static storage of kidneys from deceased donors	Machine perfusion systems and cold static storage of kidneys from deceased donors Evidence-based recommendations on machine perfusion systems and cold static storage of kidneys from deceased donors. # Guidance This technology appraisal covers the available methods of storing kidneys from deceased donors – that is, LifePort kidney transporter, Belzer University of Wisconsin (Belzer UW) storage solution and Marshall's hypertonic citrate solution. No cost data were available to the Committee to allow recommendations to be made for the RM3 renal preservation system. Machine perfusion using the LifePort kidney transporter and cold static storage using Belzer UW storage solution or Marshall's hypertonic citrate solution are recommended as options for the storage of kidneys from deceased donors. The choice of storage method should take into account clinical and logistical factors in both the retrieval teams and transplant centres. In situations where different storage methods are considered equally appropriate, then the least costly should be used.# Clinical need and practice End-stage renal disease, or established renal failure, is defined as an irreversible decline in kidney function that is severe enough to be fatal without renal replacement therapy. The most common causes of chronic renal damage leading to established renal failure are diabetes mellitus, arteriosclerosis, hypertension, glomerulonephritis and microscopic vasculitis. Acute renal failure from traumatic injury or infection may also lead to established renal failure. In children, it is usually caused by congenital structural abnormalities, but may be genetic or the result of glomerulonephritis. People with established renal failure can become tired and nauseated and lose their appetite, leading to weight loss. Pruritus may also occur. Signs of established renal failure include fluid retention, pallor and raised blood pressure, which are accompanied by lowered haemoglobin levels and abnormal levels of biochemical markers. Established renal failure leads to death unless renal replacement therapy is provided, through haemodialysis, peritoneal dialysis or a kidney transplant. In the UK in 2005 there were 41,776 adults and 748 children (younger than 18 years) on renal replacement therapy. This is a 28% increase in patient numbers since 2000. In the UK in 2005, the median age at which people started renal replacement therapy was 65 years. Survival in the 1st year after starting renal replacement therapy for all patients regardless of age was 79%. Five-year survival rates varied depending on age. In people aged 18–34 years 58% were alive 5 years after starting renal replacement therapy, and 12% in people aged 75 years or older. Kidney transplantation, which involves implanting a kidney from a donor, is the preferred therapeutic option where it is possible. Kidneys for transplantation may come from living donors or deceased organ donors. Deceased organ donors may be certified as dead either by brainstem criteria (deceased heart-beating donors) or after cardiac arrest (non-heart-beating donors). The availability of kidneys from deceased heart-beating donors has decreased by about 20% in the last decade. Kidneys from deceased heart-beating donors are allocated nationally; kidneys from non-heart-beating donors are allocated locally. Non-heart-beating donors are categorised according to the Maastricht criteria, and described as controlled (where cardiac death is expected, but the criteria for brainstem death are not fulfilled) or uncontrolled (where cardiac death is unexpected). Kidneys from non-heart-beating donors (particularly those categorised as uncontrolled) may have long periods of warm ischaemic time, that is, the time that the organ spends deprived of oxygen before it is cooled and retrieved. As a result, kidneys from non-heart-beating donors can have higher rates of delayed graft function (the graft does not function immediately) or primary non-function (the graft never functions) than those from heart-beating donors. Primary non-function and early graft failure are associated with an increased risk of death in the ensuing months. Kidney function is also affected by cold ischaemic time (the duration of storage in cold conditions between retrieval and transplantation), but cooling the organ reduces the metabolic rate and thereby decreases the rate of damage to the organs compared with warm ischaemia. Kidneys from 'extended criteria' deceased heart-beating donors may also be used to expand the donor pool. These are kidneys from donors who are aged over 60 years, or are over 50 years and have two or more of: a history of hypertension, a history of cerebral vascular accident, or terminal creatinine levels greater than 133 micromoles/litre. Like kidneys from non-heart-beating donors, kidneys from extended criteria donors are also associated with higher rates of delayed graft function and primary non-function than those from non-extended criteria donors. Successful kidney transplantation removes the need for dialysis, but immunosuppressant drugs are needed permanently to prevent rejection of the graft. Complications of immunosuppression include increased risk of infections and malignancy, especially skin cancer and lymphoproliferative disorders. Nephrotoxicity is a particular complication of some immunosuppressive regimens. Post-transplantation diabetes mellitus is a potentially serious side-effect of treatment. Other treatment side-effects, depending on the drugs used, may include hirsutism, alopecia, tremors, mood swings or gastrointestinal intolerance. In the UK in 2005, 76% of people accepted for renal replacement therapy started treatment with haemodialysis and 21% started treatment with peritoneal dialysis. Only 3% of patients received a kidney transplant before they started dialysis. There is increasing demand for kidney transplants; the waiting list has increased by 48% since 1998. Demand for kidneys outstrips supply. In the UK in 2006, 1403 kidneys from deceased donors were transplanted (from 765 deceased kidney donors); 6384 people were awaiting transplantation. Therefore, there is a need to increase kidney donation and to make donated kidneys function in the best possible way.# The technologies Kidneys need to be preserved before transplantation to allow time to match kidney to recipient, to transport and prepare the recipient and kidney, and to implant the kidney. It is important that the kidney is cooled and prepared as quickly as possible to minimise damage caused by warm ischaemia. There are two established methods of preservation: cold static storage and hypothermic machine perfusion. # Cold static storage solutions In cold static storage, the kidney is flushed through with a sterile preservation solution and is kept on ice in a box before transplantation. Two preservation solutions are widely used in the NHS for cold storage: Marshall's hypertonic citrate (Soltran, Baxter Healthcare) and Belzer UW (Viaspan, Bristol Myers Squibb). Marshall's hypertonic citrate solution has a marketing authorisation for use in the preservation of human kidneys before transplantation. The summary of product characteristics (SPC) states that approximately 2–3 litres of solution should be delivered to each kidney and lists no adverse events or contraindications. The cost of 1 litre of Marshall's hypertonic citrate solution is £9.60 (obtained from the Baxter Healthcare e-catalogue, 20 October 2008). It is sold in packs of ten 1-litre bags. Costs may vary in different settings because of negotiated procurement discounts. Belzer UW storage solution is not classified as a device or a medicine. The manufacturer was advised by the Medicines and Healthcare Products Regulatory Agency that it is therefore not covered by relevant legislation and does not require a marketing authorisation or CE mark. The solution does have a marketing authorisation in some European Union countries and is indicated for the preservation of kidney, liver and pancreas. It is not recommended for continuous machine perfusion. The cost of 1 litre of Belzer UW storage solution is £116 (obtained from the manufacturer, 23 April 2008). It is sold in packs of six 1-litre bags. Costs may vary in different settings because of negotiated procurement discounts. The submission from the British Transplantation Society indicates that in the UK from 2000 to 2007 about 74% of kidneys from deceased donors were stored with Marshall's hypertonic citrate solution and most of the remainder (23%) with Belzer UW storage solution. For the subset of kidneys from non-heart-beating donors, 42% were stored using Belzer UW storage solution and 48% with Marshall's hypertonic citrate solution. # Machine perfusion systems Machine perfusion systems continuously pump cold preservation solution through the kidney. The solution provides nutrients and sometimes oxygen, carries away toxic metabolites and reduces build-up of lactic acid. In machine perfusion the kidney is attached to the machine via the renal artery. Further surgical preparation of the kidney is then required to make the seal airtight. The LifePort kidney transporter (Organ Recovery Systems) is a portable machine perfusion system which can perfuse a single kidney and can run without supervision. The system requires a solution to perfuse the kidney; University of Wisconsin machine preservation solution is sold as KPS-1 by Organ Recovery Systems for use with the LifePort kidney transporter. The LifePort kidney transporter is CE marked for the continuous hypothermic machine perfusion of kidneys for preservation, transportation and eventual transplantation into a recipient. The cost of the LifePort kidney transporter is £10,700 (obtained from the manufacturer). They are normally purchased in pairs, one for each kidney. Costs may vary in different settings because of negotiated procurement discounts. The RM3 renal preservation system is a non-portable system that can perfuse two kidneys simultaneously under supervision. It is CE marked for the hypothermic pulsatile perfusion of kidneys. No further information is available. There are 21 kidney transplant centres in England and Wales, eight of which use LifePort kidney transporters as well as cold static storage. These centres have non-heart-beating donor programmes. The RM3 system is not used in any centres in the UK. The submission from the British Transplantation Society indicates that in the UK from 2000 to 2007 about 2% of kidneys from deceased donors were stored using machine perfusion (excluding cases where method of storage was not reported). For the subset of kidneys from non-heart-beating donors this increased to 20% (excluding cases where method of storage was not reported). However, the data for the subset may not be accurate because only 50% of records for kidneys from non-heart-beating donors included information on how the kidney was stored. Transplant arrangements limit the use of machine perfusion. Perfusion systems are the property of individual NHS trusts and have to be returned to the transplant centre that owns the machine. This means that they tend to be used only in the local transplant region, which is not compatible with the national allocation of kidneys from deceased heart-beating donors. Therefore, perfusion systems are used mainly to preserve kidneys from non-heart-beating donors, which are allocated only on a local basis. A recent report from the Department of Health's Organ Donation Taskforce has indicated that the organisation of transplantation services may become national in the future.# Evidence and interpretation The Appraisal Committee (appendix A) considered evidence from a number of sources (appendix B). # Clinical effectiveness The Assessment Group identified seven studies that compared at least two of: the RM3 renal preservation system, the LifePort kidney transporter, Belzer UW storage solution and Marshall's hypertonic citrate solution. Two of these studies, which were both retrospective record reviews, compared the two machines. Three of the studies compared the LifePort kidney transporter with Belzer UW storage solution (two ongoing randomised controlled trials and one retrospective review) and one cohort study compared the LifePort kidney transporter with Marshall's storage solution. One study compared the two different storage solutions. No studies were identified that compared the RM3 renal preservation system with either of the storage solutions. Two retrospective record reviews (reported as abstracts) compared the two machine preservation systems. One study (744 kidneys transplanted) was a review over a 5-year period that included a change in practice from the use of the RM3 renal preservation system to the LifePort kidney transporter. The kidneys included in this study were from extended criteria deceased heart-beating donors (78%) or non-heart-beating donors (22%). The second study (89 kidneys transplanted) reviewed transplant records over a 22-month period and included kidneys mainly from deceased heart-beating donors (98%). Reporting in both studies was insufficient for a thorough assessment of quality. The relative risks were calculated by the Assessment Group. In the larger study, rates of primary non-function were reported as 3% and 2% in the RM3 and LifePort groups, respectively (relative risk 1.44; 95% confidence interval 0.59 to 3.54; p = 0.42). Rates of delayed graft function were reported as 24% and 32% in the RM3 and LifePort groups, respectively (RR 0.76; 95% CI 0.62 to 0.94; p < 0.01). Patient survival and graft survival were both reported as 97% and 93% in the RM3 and LifePort groups, respectively (RR 1.05; 95% CI 1.01 to 1.08; p < 0.01). The smaller study reported graft survival at a different follow-up point. At 30 days this was 97% and 94% in the RM3 and LifePort groups, respectively (RR 0.97; 95% CI 0.89 to 1.06; p = 0.49), and at 90 days 97% and 90% (RR 0.93; 95% CI 0.83 to 1.04; p = 0.21). Two ongoing randomised controlled trials and one retrospective record review compared Belzer UW storage solution with the LifePort kidney transporter. One study (the Machine Preservation Trial, 672 kidneys transplanted) included mainly kidneys from deceased heart-beating donors but also some from non-heart-beating donors. The other study (the PPART study, 90 kidneys transplanted) included only kidneys from non-heart-beating donors. The primary outcome in both studies was rate of delayed graft function. The retrospective record review (36 kidneys transplanted) included kidneys from non-heart-beating donors. The primary outcome for this study was immediate graft function. The Machine Preservation Trial study reported a small statistically significant benefit in terms of graft survival favouring the use of machine perfusion. Further detailed results of the Machine Preservation Trial study were provided as academic-in-confidence and are not included in this document. The PPART study reported no statistically significant differences between the LifePort kidney transporter and Belzer UW storage solution at 3-month follow-up. Rates of primary non-function were reported as 2% and 0% in the LifePort kidney transporter and Belzer UW storage solution groups, respectively (RR 3.00; 95% CI 0.13 to 71.74; p = not reported). Rates of delayed graft function were reported as 58% and 56% in the LifePort kidney transporter and Belzer UW storage solution groups, respectively (RR 1.04; 95% CI 0.73 to 1.49; p = 0.99). Patient survival was reported as 98% and 100% in the LifePort kidney transporter and Belzer UW storage solution groups, respectively (RR 0.98; 95% CI 0.92 to 1.04; p = 0.32). Rates of graft survival were reported as 96% and 100% in the LifePort kidney transporter and Belzer UW storage solution groups, respectively (RR 0.96; 95% CI 0.89 to 1.03; p = 0.16). The retrospective record review reported statistically significant results favouring the use of the LifePort kidney transporter compared with Belzer UW storage solution. Delayed graft function was reported as 28% and 89% in the LifePort kidney transporter and Belzer UW storage solution groups, respectively (RR 0.31; 95% CI 0.15 to 0.67; p < 0.001). One sequential cohort study (60 kidneys transplanted) compared Marshall's hypertonic citrate solution with the LifePort kidney transporter. This study included kidneys from non-heart-beating donors, where death was controlled. For the first 2 years of the study all kidneys were stored using the solution, after this point they were stored using the perfusion machine. The significance tests reported were calculated by the Assessment Group. This study reported that no kidneys suffered from primary non-function. Rates of delayed graft function were reported as 53% and 87% in the LifePort kidney transporter and Marshall's hypertonic citrate solution groups, respectively (RR 0.64; 95% CI 0.43 to 0.93; p = 0.012). The rates of patient survival and graft survival were reported as the same. After 1 year of follow-up survival rates were reported as 100% and 93% in the LifePort kidney transporter and Marshall's hypertonic citrate solution groups, respectively (RR 1.07; 95% CI 0.96 to 1.20; p = 0.24); 2-year survival rates were 97% and 90%, respectively (RR 1.07; 95% CI 0.94 to 1.23; p = 0.30). One retrospective record review (58,607 kidneys transplanted) of kidneys from deceased donors included in the Collaborative Transplant Study database included data for kidneys stored using either Belzer UW storage solution (53,560 kidneys) or Marshall's hypertonic citrate solution (5047 kidneys). This study specifically considered differences in graft survival of kidneys that had undergone different durations of cold ischaemia. The Assessment Group's analysis of the data from the study suggests no statistically significant differences between the two solutions. The 3-year graft survival rates in kidneys that had had up to 18 hours of cold ischaemic time were 81% and 80% in the Belzer UW storage solution and Marshall's storage solution groups, respectively (RR 1.02; 95% CI 0.99 to 1.04; p=0.13). The 3-year graft survival rates in kidneys that had had more than 36 hours of cold ischaemic time were 75% and 73% in the Belzer UW storage solution and Marshall's storage solution groups, respectively (RR 1.03; 95% CI 0.96 to 1.11; p = 0.45). Comparing different durations of cold ischaemic time, the study suggests that the incidence of graft failure increases as cold ischaemic time increases. # Cost effectiveness The manufacturers of the technologies did not submit economic analyses. The Assessment Group identified two published economic analyses, one from the UK and another from Canada, both using a healthcare system perspective. The UK study reported cost per quality-adjusted life year (QALY), while the Canadian study reported cost per delayed-graft-function event avoided. Both studies reported that machine perfusion was associated with lower costs and greater benefits than cold static storage. Both economic analyses were completed before the most recent data from the PPART and Machine Preservation Trial studies became available. The Assessment Group developed an economic model that made three comparisons. First, LifePort machine perfusion was compared with Belzer UW storage solution. This comparison was completed in two different populations: kidneys from non-heart-beating donors using data from the PPART study and kidneys mainly from deceased heart-beating donors using data from the Machine Preservation Trial study. Second, LifePort machine perfusion was compared with Marshall's hypertonic citrate solution using data from a cohort study. Third, Belzer UW storage solution was compared with Marshall's hypertonic citrate using data from a retrospective record review. The Assessment Group was unable to do any cost-effectiveness analyses that included the RM3 machine perfusion system because cost data, although requested, were not made available. The model was a Markov state transition model that included the health states immediate graft function, delayed graft function, transplant failure, explantation and a return to dialysis, and subsequent transplantation. The characteristics of the cohort modelled were chosen to be consistent with data obtained from UK Transplant and The Renal Registry. The cohort was followed up until almost all patients (97%) had died. The Assessment Group developed a standard data set for use in the model which was modified to reflect the comparisons described above. Cost data for machine perfusion were annualised and it was assumed that perfusion machines were used for 10 years with no resale value afterwards. The estimated number of kidneys stored by each machine per year was calculated based on the total number of transplantations per year divided by the number of transplant centres. This estimate was 61 kidneys per year for analyses using data from the Machine Preservation Trial and 16 kidneys per year for analyses using data from the PPART study. The costs for machine perfusion also included an annual maintenance contract and the costs of the perfusion kit and solution used in the machine. This resulted in a cost per kidney stored of £544 for the analyses using data from Machine Preservation Trial and £737 for the analyses using data from PPART. The costs of storing a kidney using cold static storage included the costs of the solution and the box required to store the kidney. This was calculated to be £262.53 per kidney with Belzer UW storage solution and £49.73 per kidney with Marshall's solution. Utility data were derived from published literature. The utility of living with a transplanted kidney varied according to age and was 0.83 for people aged 18–34 years, decreasing to 0.66 for people aged 65 years and older. The reduction in utility of living with dialysis was 0.12. Therefore, a person aged 18–34 years on dialysis had a utility of 0.71 and a person aged 65 years and older had a utility of 0.54. Renal registry data were used to model patient survival on dialysis and with a transplant; this rate was also varied according to age. Data from the PPART study were used to model the cost effectiveness of LifePort compared with Belzer UW storage solution for the preservation of kidneys from non-heart-beating donors. The results of the deterministic analyses suggested that the LifePort kidney transporter was associated with greater cost than Belzer UW storage solution (£141,319 versus £139,205) and fewer QALYs (9.13 versus 9.19). Probabilistic sensitivity analyses predicted that over a range of willingness-to-pay levels (£0–£100,000) the probability of LifePort being cost effective was about 40%. Data from the Machine Preservation Trial study were used to model the cost effectiveness of LifePort compared with Belzer UW storage solution for the preservation of kidneys mainly from deceased heart-beating donors. The results of the deterministic analyses suggested that Belzer UW storage solution was associated with greater cost than the LifePort kidney transporter (£142,805 versus £139,100) and fewer QALYs (9.58 versus 9.79). Probabilistic sensitivity analyses predicted that over a range of willingness-to-pay levels (£0–£100,000) the probability of LifePort being cost effective was 80%. Data from the cohort study (described in section 4.1.8) were used to model the cost effectiveness of LifePort compared with Marshall's hypertonic citrate for the preservation of kidneys from controlled non-heart-beating donors. The results of the deterministic analyses suggested that Marshall's hypertonic citrate solution was associated with greater cost than the LifePort kidney transporter (£144,332 versus £132,953) and fewer QALYs (8.55 versus 9.54). Probabilistic sensitivity analyses predicted that over a range of willingness-to-pay levels (£0–£100,000) the probability of LifePort being cost effective was 95%. Data from the retrospective record review (described in section 4.1.10) were used to model the cost effectiveness of Marshall's hypertonic citrate compared with Belzer UW storage solution for the preservation of kidneys from deceased donors. This study analysed kidneys by duration of cold ischaemia. The cost-effectiveness analyses were based on kidneys that had 19–24 hours of cold ischaemic time. For these kidneys graft survival at 3 years was reported as 79.5% and 77.7% in the Belzer UW storage solution and Marshall's hypertonic citrate solution groups, respectively. The results of the deterministic analyses suggested that Marshall's hypertonic citrate solution was associated with greater cost than Belzer UW storage solution (£151,826 versus £151,001) and fewer QALYs (8.57 versus 8.62). Probabilistic sensitivity analyses predicted that over a range of willingness-to-pay levels (£0–£100,000) the probability of Marshall's storage solution being cost effective was 40%. # Consideration of the evidence The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of machine perfusion systems and cold static storage of donated kidneys, having considered evidence on the nature of the condition and the value placed on the benefits of improvements in access to viable kidneys for transplantation by people with established renal failure, those who represent them, and clinical specialists. It was also mindful of the need to take account of the effective use of NHS resources. The Committee considered the process of retrieving donated organs and the methods for their storage. The Committee was aware that it was important to minimise the length of ischaemic time regardless of the storage method used, in order to reduce the detrimental impact of ischaemia on the donated kidney. It also recognised that kidneys could be obtained from different types of donors and that type of donor is associated with differences in rates of delayed graft function and overall graft survival. The Committee understood that minimising primary non-function and early and late graft loss was important. Unsuccessful transplantation has a significant physical and psychological effect on the recipient of the kidney and could reduce the chance of successful reimplant because of exposure to antigens. The Committee understood that kidneys from brainstem-dead (that is, deceased heart-beating) donors are allocated nationally and that kidneys from non-heart-beating donors are allocated locally. However, it was aware that transplant services may be reorganised as a result of recent recommendations to the government from the Organ Donation Taskforce. The Committee concluded that kidneys from different types of donor needed to be considered separately and that the mechanism for allocating kidneys could influence the choice of storage method. The Committee considered the different machine perfusion systems. It was aware that the RM3 is not portable and therefore does not replace cold static storage if transportation is needed. The Committee noted that although clinical effectiveness evidence comparing the RM3 with the LifePort kidney transporter was available, it had methodological limitations because it was based on retrospective record reviews rather than prospective studies. The Committee recognised that the Assessment Group had been unable to complete any cost-effectiveness analyses that included the RM3 because no cost data were made available by the manufacturer. The Committee concluded that it could only issue recommendations for storage methods whose cost is known. The Committee specifically considered the use of machine perfusion to assess the viability of kidneys before implant. The Committee heard from clinical specialists that there was no clear experimental evidence to support testing the viability of the kidney using the machine, but that they considered viability testing to be potentially important. The Committee heard that clinical experience of machine perfusion systems, and knowledge of kidney function after transplantation, may enable clinicians to identify factors associated with poor viability. The Committee was aware that a retrospective analysis had been proposed as part of the Machine Preservation Trial study but had not yet been completed. The Committee concluded that although viability testing is potentially important, currently there is insufficient evidence to make this a deciding factor in choice of storage methods. The Committee considered the differences in clinical effectiveness between the two cold static storage solutions. The Committee noted that the analysis by the Assessment Group suggested no statistically significant differences between the two solutions. The Committee noted that Marshall's hypertonic citrate solution is used to store kidneys in a large proportion of centres, although choice of solution may depend on several factors. The Committee heard from clinical specialists that there are differences in viscosity between Marshall's hypertonic citrate solution and Belzer UW storage solution, which affected the choice of solution in some cases. The Committee additionally heard that for multiorgan donation that included the pancreas, Marshall's hypertonic citrate solution was not considered suitable for cooling of the organs in situ. The Committee also heard that where a longer cold ischaemic time is anticipated, clinicians consider Belzer UW storage solution to be more suitable than Marshall's hypertonic citrate solution. However, cold ischaemic times greater than 24 hours are generally avoided in the UK, unless an organ is reallocated, or national allocation means that the kidney has a long transport time. These factors are, however, difficult to predict beforehand. The Committee concluded that the clinical effectiveness evidence did not support a general preference for one storage solution over another but that both these clinical and logistical considerations need to be taken into account when choosing between storage solutions. The Committee considered the clinical effectiveness evidence for the use of the LifePort kidney transporter for the storage of kidneys from deceased heart-beating donors. In considering the clinical effectiveness evidence, the Committee was mindful of comments from a consultee about the additional time required to attach the donated kidney to the LifePort kidney transporter, and the impact that this may have on the retrieval process for the kidneys and other organs. The Committee noted the results of the Machine Preservation Trial study. The Committee was aware that this study included mainly kidneys from deceased heart-beating donors, which does not reflect the type of kidneys for which the machines are usually used in the NHS. The Committee considered that this study suggested a small statistically significant benefit in terms of graft survival favouring the use of machine perfusion. The Committee heard from clinical specialists that these small benefits in rates of graft survival are important, but that factors such as discard rates before implant are also important. The Committee heard clinical specialists express concern about the exclusion of a large number of kidneys from the statistical analysis in the Machine Preservation Trial study, and the effect that these exclusions may have had on results. The Committee also heard from clinical specialists that the potential advantages of machine perfusion are not necessarily considered greater for the storage of kidneys from deceased heart-beating donors because success rates with cold storage solutions are already high. The Committee concluded that machine perfusion may be marginally more clinically effective than Belzer UW storage solution for the storage of kidneys from deceased heart-beating donors. However, it was mindful of possible clinical considerations for choosing between machine perfusion and cold static storage and also the clinical specialists' comments that further evidence was required before the benefits of the LifePort kidney transporter over cold static storage can be fully demonstrated. The Committee considered the clinical effectiveness evidence for the use of the LifePort kidney transporter for the storage of kidneys from non-heart-beating donors. The Committee noted that the PPART study had shown no statistically significant differences between the LifePort kidney transporter and cold static storage using Belzer UW storage solution. The Committee heard from clinical specialists that the results of the PPART study were not consistent with clinical opinion or practice for storing this type of kidney. The Committee also noted comments from a consultee about possible limitations in the reproducibility of the results of this study. The Committee was mindful of the preliminary nature of the data from the PPART study and considered whether the availability of longer term data would change the conclusions. The Committee heard from clinical specialists that they did not think that the overall conclusion of the PPART study would change as more data become available. The Committee noted that the Machine Preservation Trial study reported results from a subgroup of kidneys from non-heart-beating donors in whom death was controlled. The Committee recognised that preliminary analyses suggested benefits to delayed graft function, but did not yet suggest differences in primary non-function and graft survival. The Committee was also aware that a cohort study had compared the LifePort kidney transporter and Marshall's hypertonic citrate solution for the storage of kidneys from non-heart-beating donors where cardiac death had been expected. The Committee noted that this study had shown a statistically significant difference that favoured the LifePort kidney transporter for rate of delayed graft function, but that there were methodological limitations with the design of the study. The Committee concluded that the clinical effectiveness evidence did not allow it to distinguish between the LifePort kidney transporter and cold static storage for the storage of kidneys from non-heart-beating donors. The Committee considered the economic modelling carried out by the Assessment Group and noted the assumptions about the costs of the different storage methods. The Committee heard from clinical specialists that clinicians may use different quantities of the storage solution, varying between 2 and 8 litres per kidney. The Committee noted that the Assessment Group had assumed that two LifePort kidney transporters were required for each transplant centre, but that in clinical practice more machines may be required to ensure that a machine is readily available. The Committee also noted comments from a consultee that in some locations an extra person was employed to supervise the LifePort kidney transporter, and that consumables would be wasted if kidneys were prepared for machine perfusion and then found not to be suitable. However, the Committee was persuaded that the upfront costs of storage are much smaller than the costs of dialysis for failed grafts used in the model and that differences in the costs of storage for different methods would have little effect on the results of cost-effectiveness analysis. The Committee concluded that while specific methods of storing kidneys may differ between centres, which would affect the cost of the technologies, this would not change the results of the cost-effectiveness analyses. The Committee considered the cost-effectiveness evidence for the use of the different methods of kidney storage. The Committee understood that the cost-effectiveness results were driven by differences in the rate of graft survival between storage methods, because better graft survival led to fewer people on dialysis, which reduced costs and improved health-related quality of life. The Committee noted that the results of the cost-effectiveness analyses suggested that Marshall's hypertonic citrate solution is associated with greater cost and fewer QALYs than Belzer UW storage solution. However, the Committee noted that the data suggested small differences in clinical effect between the two solutions, which led to small differences in both costs and QALYs. The Committee concluded that no robust differences in clinical effectiveness had been shown. It recommended that the cheapest solution be used if the solutions are otherwise considered equally suitable, bearing in mind the clinical considerations that might affect the choice (described in 4.3.5). The Committee considered the cost-effectiveness evidence for the LifePort kidney transporter compared with cold static storage solutions. The Committee noted that the results of the cost-effectiveness analyses suggested that Belzer UW storage solution was associated with lower costs and more QALYs, when using data from PPART. However, using data from the Machine Preservation Trial study, the LifePort kidney transporter was associated with lower costs and more QALYs. The Committee noted these results were also based on small differences in costs and QALYs. Taking into consideration the testimony of clinical specialists and the clinical effectiveness evidence, the Committee was not persuaded that the LifePort kidney transporter could be preferentially recommended for the storage of kidneys from deceased donors over other forms of storage. Given that the overall costs and benefits associated with kidney transplantation using either machine perfusion or cold static storage were similar, the Committee recommended that the LifePort kidney transporter be considered as an alternative to cold static storage solutions and that the choice of which to use would depend on clinical and logistical factors within both the retrieval team and transplant centres.# Recommendations for further research The PPART study is ongoing and the Machine Preservation Trial study is analysing subgroup data of kidneys from non-heart-beating donors and extended criteria donors. Both studies are collecting resource-use data. The Committee considered that it was important for transplant centres to collect standardised and comprehensive data that follow up the outcomes for kidneys stored using different methods.# Related NICE guidance There is no related guidance for these technologies.# Review of guidance The review date for a technology appraisal refers to the month and year in which the Guidance Executive will consider whether the technology should be reviewed. This decision will be taken in the light of information gathered by the Institute, and in consultation with consultees and commentators. The guidance on this technology will be considered for review in August 2010. This date is to allow completion and follow up of the PPART and Machine Preservation Trial studies and to assess the implication of the implementation of the recommendations in the organ donation taskforce report. Andrew DillonChief ExecutiveJanuary 2009# Changes after publication February 2014: implementation section updated to clarify that machine perfusion and cold static storage are recommended as options for the storage of kidneys from deceased donors. Additional minor maintenance update also carried out. March 2012: minor maintenance# About this guidance NICE technology appraisal guidance is about the use of new and existing medicines and treatments in the NHS in England and Wales. This guidance was developed using the NICE multiple technology appraisal process. The recommendations from this guideline have been incorporated into a NICE Pathway. We have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available. Your responsibility This guidance represents the views of NICE and was arrived at after careful consideration of the evidence available. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. However, the guidance does not override the individual responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or guardian or carer. Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties. Copyright © National Institute for Health and Clinical Excellence 2009. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.	{'Guidance': "This technology appraisal covers the available methods of storing kidneys from deceased donors – that is, LifePort kidney transporter, Belzer University of Wisconsin (Belzer UW) storage solution and Marshall's hypertonic citrate solution. No cost data were available to the Committee to allow recommendations to be made for the RM3 renal preservation system.\n\nMachine perfusion using the LifePort kidney transporter and cold static storage using Belzer UW storage solution or Marshall's hypertonic citrate solution are recommended as options for the storage of kidneys from deceased donors.\n\nThe choice of storage method should take into account clinical and logistical factors in both the retrieval teams and transplant centres. In situations where different storage methods are considered equally appropriate, then the least costly should be used.", 'Clinical need and practice': "End-stage renal disease, or established renal failure, is defined as an irreversible decline in kidney function that is severe enough to be fatal without renal replacement therapy. The most common causes of chronic renal damage leading to established renal failure are diabetes mellitus, arteriosclerosis, hypertension, glomerulonephritis and microscopic vasculitis. Acute renal failure from traumatic injury or infection may also lead to established renal failure. In children, it is usually caused by congenital structural abnormalities, but may be genetic or the result of glomerulonephritis.\n\nPeople with established renal failure can become tired and nauseated and lose their appetite, leading to weight loss. Pruritus may also occur. Signs of established renal failure include fluid retention, pallor and raised blood pressure, which are accompanied by lowered haemoglobin levels and abnormal levels of biochemical markers. Established renal failure leads to death unless renal replacement therapy is provided, through haemodialysis, peritoneal dialysis or a kidney transplant.\n\nIn the UK in 2005 there were 41,776 adults and 748 children (younger than 18\xa0years) on renal replacement therapy. This is a 28% increase in patient numbers since 2000. In the UK in 2005, the median age at which people started renal replacement therapy was 65\xa0years. Survival in the 1st year after starting renal replacement therapy for all patients regardless of age was 79%. Five-year survival rates varied depending on age. In people aged 18–34\xa0years 58% were alive 5\xa0years after starting renal replacement therapy, and 12% in people aged 75\xa0years or older.\n\nKidney transplantation, which involves implanting a kidney from a donor, is the preferred therapeutic option where it is possible. Kidneys for transplantation may come from living donors or deceased organ donors. Deceased organ donors may be certified as dead either by brainstem criteria (deceased heart-beating donors) or after cardiac arrest (non-heart-beating donors). The availability of kidneys from deceased heart-beating donors has decreased by about 20% in the last decade. Kidneys from deceased heart-beating donors are allocated nationally; kidneys from non-heart-beating donors are allocated locally.\n\nNon-heart-beating donors are categorised according to the Maastricht criteria, and described as controlled (where cardiac death is expected, but the criteria for brainstem death are not fulfilled) or uncontrolled (where cardiac death is unexpected). Kidneys from non-heart-beating donors (particularly those categorised as uncontrolled) may have long periods of warm ischaemic time, that is, the time that the organ spends deprived of oxygen before it is cooled and retrieved. As a result, kidneys from non-heart-beating donors can have higher rates of delayed graft function (the graft does not function immediately) or primary non-function (the graft never functions) than those from heart-beating donors. Primary non-function and early graft failure are associated with an increased risk of death in the ensuing months. Kidney function is also affected by cold ischaemic time (the duration of storage in cold conditions between retrieval and transplantation), but cooling the organ reduces the metabolic rate and thereby decreases the rate of damage to the organs compared with warm ischaemia.\n\nKidneys from 'extended criteria' deceased heart-beating donors may also be used to expand the donor pool. These are kidneys from donors who are aged over 60\xa0years, or are over 50\xa0years and have two or more of: a history of hypertension, a history of cerebral vascular accident, or terminal creatinine levels greater than 133\xa0micromoles/litre. Like kidneys from non-heart-beating donors, kidneys from extended criteria donors are also associated with higher rates of delayed graft function and primary non-function than those from non-extended criteria donors.\n\nSuccessful kidney transplantation removes the need for dialysis, but immunosuppressant drugs are needed permanently to prevent rejection of the graft. Complications of immunosuppression include increased risk of infections and malignancy, especially skin cancer and lymphoproliferative disorders. Nephrotoxicity is a particular complication of some immunosuppressive regimens. Post-transplantation diabetes mellitus is a potentially serious side-effect of treatment. Other treatment side-effects, depending on the drugs used, may include hirsutism, alopecia, tremors, mood swings or gastrointestinal intolerance.\n\nIn the UK in 2005, 76% of people accepted for renal replacement therapy started treatment with haemodialysis and 21% started treatment with peritoneal dialysis. Only 3% of patients received a kidney transplant before they started dialysis. There is increasing demand for kidney transplants; the waiting list has increased by 48% since 1998. Demand for kidneys outstrips supply. In the UK in 2006, 1403 kidneys from deceased donors were transplanted (from 765 deceased kidney donors); 6384 people were awaiting transplantation. Therefore, there is a need to increase kidney donation and to make donated kidneys function in the best possible way.", 'The technologies': "Kidneys need to be preserved before transplantation to allow time to match kidney to recipient, to transport and prepare the recipient and kidney, and to implant the kidney. It is important that the kidney is cooled and prepared as quickly as possible to minimise damage caused by warm ischaemia. There are two established methods of preservation: cold static storage and hypothermic machine perfusion.\n\n# Cold static storage solutions\n\nIn cold static storage, the kidney is flushed through with a sterile preservation solution and is kept on ice in a box before transplantation. Two preservation solutions are widely used in the NHS for cold storage: Marshall's hypertonic citrate (Soltran, Baxter Healthcare) and Belzer UW (Viaspan, Bristol Myers Squibb).\n\nMarshall's hypertonic citrate solution has a marketing authorisation for use in the preservation of human kidneys before transplantation. The summary of product characteristics (SPC) states that approximately 2–3\xa0litres of solution should be delivered to each kidney and lists no adverse events or contraindications. The cost of 1\xa0litre of Marshall's hypertonic citrate solution is £9.60 (obtained from the Baxter Healthcare e-catalogue, 20 October 2008). It is sold in packs of ten 1-litre bags. Costs may vary in different settings because of negotiated procurement discounts.\n\nBelzer UW storage solution is not classified as a device or a medicine. The manufacturer was advised by the Medicines and Healthcare Products Regulatory Agency that it is therefore not covered by relevant legislation and does not require a marketing authorisation or CE mark. The solution does have a marketing authorisation in some European Union countries and is indicated for the preservation of kidney, liver and pancreas. It is not recommended for continuous machine perfusion. The cost of 1\xa0litre of Belzer UW storage solution is £116 (obtained from the manufacturer, 23 April 2008). It is sold in packs of six 1-litre bags. Costs may vary in different settings because of negotiated procurement discounts.\n\nThe submission from the British Transplantation Society indicates that in the UK from 2000 to 2007 about 74% of kidneys from deceased donors were stored with Marshall's hypertonic citrate solution and most of the remainder (23%) with Belzer UW storage solution. For the subset of kidneys from non-heart-beating donors, 42% were stored using Belzer UW storage solution and 48% with Marshall's hypertonic citrate solution.\n\n# Machine perfusion systems\n\nMachine perfusion systems continuously pump cold preservation solution through the kidney. The solution provides nutrients and sometimes oxygen, carries away toxic metabolites and reduces build-up of lactic acid. In machine perfusion the kidney is attached to the machine via the renal artery. Further surgical preparation of the kidney is then required to make the seal airtight.\n\nThe LifePort kidney transporter (Organ Recovery Systems) is a portable machine perfusion system which can perfuse a single kidney and can run without supervision. The system requires a solution to perfuse the kidney; University of Wisconsin machine preservation solution is sold as KPS-1 by Organ Recovery Systems for use with the LifePort kidney transporter. The LifePort kidney transporter is CE marked for the continuous hypothermic machine perfusion of kidneys for preservation, transportation and eventual transplantation into a recipient. The cost of the LifePort kidney transporter is £10,700 (obtained from the manufacturer). They are normally purchased in pairs, one for each kidney. Costs may vary in different settings because of negotiated procurement discounts.\n\nThe RM3 renal preservation system is a non-portable system that can perfuse two kidneys simultaneously under supervision. It is CE marked for the hypothermic pulsatile perfusion of kidneys. No further information is available.\n\nThere are 21 kidney transplant centres in England and Wales, eight of which use LifePort kidney transporters as well as cold static storage. These centres have non-heart-beating donor programmes. The RM3 system is not used in any centres in the UK. The submission from the British Transplantation Society indicates that in the UK from 2000 to 2007 about 2% of kidneys from deceased donors were stored using machine perfusion (excluding cases where method of storage was not reported). For the subset of kidneys from non-heart-beating donors this increased to 20% (excluding cases where method of storage was not reported). However, the data for the subset may not be accurate because only 50% of records for kidneys from non-heart-beating donors included information on how the kidney was stored.\n\nTransplant arrangements limit the use of machine perfusion. Perfusion systems are the property of individual NHS trusts and have to be returned to the transplant centre that owns the machine. This means that they tend to be used only in the local transplant region, which is not compatible with the national allocation of kidneys from deceased heart-beating donors. Therefore, perfusion systems are used mainly to preserve kidneys from non-heart-beating donors, which are allocated only on a local basis. A recent report from the Department of Health's Organ Donation Taskforce has indicated that the organisation of transplantation services may become national in the future.", 'Evidence and interpretation': "The Appraisal Committee (appendix A) considered evidence from a number of sources (appendix B).\n\n# Clinical effectiveness\n\nThe Assessment Group identified seven studies that compared at least two of: the RM3 renal preservation system, the LifePort kidney transporter, Belzer UW storage solution and Marshall's hypertonic citrate solution. Two of these studies, which were both retrospective record reviews, compared the two machines. Three of the studies compared the LifePort kidney transporter with Belzer UW storage solution (two ongoing randomised controlled trials and one retrospective review) and one cohort study compared the LifePort kidney transporter with Marshall's storage solution. One study compared the two different storage solutions. No studies were identified that compared the RM3 renal preservation system with either of the storage solutions.\n\nTwo retrospective record reviews (reported as abstracts) compared the two machine preservation systems. One study (744 kidneys transplanted) was a review over a 5-year period that included a change in practice from the use of the RM3 renal preservation system to the LifePort kidney transporter. The kidneys included in this study were from extended criteria deceased heart-beating donors (78%) or non-heart-beating donors (22%). The second study (89 kidneys transplanted) reviewed transplant records over a 22-month period and included kidneys mainly from deceased heart-beating donors (98%). Reporting in both studies was insufficient for a thorough assessment of quality. The relative risks were calculated by the Assessment Group.\n\nIn the larger study, rates of primary non-function were reported as 3% and 2% in the RM3 and LifePort groups, respectively (relative risk [RR] 1.44; 95% confidence interval [CI] 0.59 to 3.54; p\xa0=\xa00.42). Rates of delayed graft function were reported as 24% and 32% in the RM3 and LifePort groups, respectively (RR 0.76; 95% CI 0.62 to 0.94; p\xa0<\xa00.01). Patient survival and graft survival were both reported as 97% and 93% in the RM3 and LifePort groups, respectively (RR 1.05; 95% CI 1.01 to 1.08; p\xa0<\xa00.01). The smaller study reported graft survival at a different follow-up point. At 30\xa0days this was 97% and 94% in the RM3 and LifePort groups, respectively (RR 0.97; 95% CI 0.89 to 1.06; p\xa0=\xa00.49), and at 90\xa0days 97% and 90% (RR 0.93; 95% CI 0.83 to 1.04; p\xa0=\xa00.21).\n\nTwo ongoing randomised controlled trials and one retrospective record review compared Belzer UW storage solution with the LifePort kidney transporter. One study (the Machine Preservation Trial, 672 kidneys transplanted) included mainly kidneys from deceased heart-beating donors but also some from non-heart-beating donors. The other study (the PPART study, 90 kidneys transplanted) included only kidneys from non-heart-beating donors. The primary outcome in both studies was rate of delayed graft function. The retrospective record review (36 kidneys transplanted) included kidneys from non-heart-beating donors. The primary outcome for this study was immediate graft function.\n\nThe Machine Preservation Trial study reported a small statistically significant benefit in terms of graft survival favouring the use of machine perfusion. Further detailed results of the Machine Preservation Trial study were provided as academic-in-confidence and are not included in this document.\n\nThe PPART study reported no statistically significant differences between the LifePort kidney transporter and Belzer UW storage solution at 3-month follow-up. Rates of primary non-function were reported as 2% and 0% in the LifePort kidney transporter and Belzer UW storage solution groups, respectively (RR 3.00; 95% CI 0.13 to 71.74; p\xa0=\xa0not reported). Rates of delayed graft function were reported as 58% and 56% in the LifePort kidney transporter and Belzer UW storage solution groups, respectively (RR 1.04; 95% CI 0.73 to 1.49; p\xa0=\xa00.99). Patient survival was reported as 98% and 100% in the LifePort kidney transporter and Belzer UW storage solution groups, respectively (RR 0.98; 95% CI 0.92 to 1.04; p\xa0=\xa00.32). Rates of graft survival were reported as 96% and 100% in the LifePort kidney transporter and Belzer UW storage solution groups, respectively (RR 0.96; 95% CI 0.89 to 1.03; p\xa0=\xa00.16).\n\nThe retrospective record review reported statistically significant results favouring the use of the LifePort kidney transporter compared with Belzer UW storage solution. Delayed graft function was reported as 28% and 89% in the LifePort kidney transporter and Belzer UW storage solution groups, respectively (RR 0.31; 95% CI 0.15 to 0.67; p\xa0<\xa00.001).\n\nOne sequential cohort study (60 kidneys transplanted) compared Marshall's hypertonic citrate solution with the LifePort kidney transporter. This study included kidneys from non-heart-beating donors, where death was controlled. For the first 2\xa0years of the study all kidneys were stored using the solution, after this point they were stored using the perfusion machine. The significance tests reported were calculated by the Assessment Group.\n\nThis study reported that no kidneys suffered from primary non-function. Rates of delayed graft function were reported as 53% and 87% in the LifePort kidney transporter and Marshall's hypertonic citrate solution groups, respectively (RR 0.64; 95% CI 0.43 to 0.93; p\xa0=\xa00.012). The rates of patient survival and graft survival were reported as the same. After 1\xa0year of follow-up survival rates were reported as 100% and 93% in the LifePort kidney transporter and Marshall's hypertonic citrate solution groups, respectively (RR 1.07; 95% CI 0.96 to 1.20; p\xa0=\xa00.24); 2-year survival rates were 97% and 90%, respectively (RR 1.07; 95% CI 0.94 to 1.23; p\xa0=\xa00.30).\n\nOne retrospective record review (58,607 kidneys transplanted) of kidneys from deceased donors included in the Collaborative Transplant Study database included data for kidneys stored using either Belzer UW storage solution (53,560 kidneys) or Marshall's hypertonic citrate solution (5047 kidneys). This study specifically considered differences in graft survival of kidneys that had undergone different durations of cold ischaemia.\n\nThe Assessment Group's analysis of the data from the study suggests no statistically significant differences between the two solutions. The 3-year graft survival rates in kidneys that had had up to 18\xa0hours of cold ischaemic time were 81% and 80% in the Belzer UW storage solution and Marshall's storage solution groups, respectively (RR 1.02; 95% CI 0.99 to 1.04; p=0.13). The 3-year graft survival rates in kidneys that had had more than 36\xa0hours of cold ischaemic time were 75% and 73% in the Belzer UW storage solution and Marshall's storage solution groups, respectively (RR\xa01.03; 95% CI 0.96 to 1.11; p\xa0=\xa00.45). Comparing different durations of cold ischaemic time, the study suggests that the incidence of graft failure increases as cold ischaemic time increases.\n\n# Cost effectiveness\n\nThe manufacturers of the technologies did not submit economic analyses. The Assessment Group identified two published economic analyses, one from the UK and another from Canada, both using a healthcare system perspective. The UK study reported cost per quality-adjusted life year (QALY), while the Canadian study reported cost per delayed-graft-function event avoided. Both studies reported that machine perfusion was associated with lower costs and greater benefits than cold static storage. Both economic analyses were completed before the most recent data from the PPART and Machine Preservation Trial studies became available.\n\nThe Assessment Group developed an economic model that made three comparisons. First, LifePort machine perfusion was compared with Belzer UW storage solution. This comparison was completed in two different populations: kidneys from non-heart-beating donors using data from the PPART study and kidneys mainly from deceased heart-beating donors using data from the Machine Preservation Trial study. Second, LifePort machine perfusion was compared with Marshall's hypertonic citrate solution using data from a cohort study. Third, Belzer UW storage solution was compared with Marshall's hypertonic citrate using data from a retrospective record review.\n\nThe Assessment Group was unable to do any cost-effectiveness analyses that included the RM3 machine perfusion system because cost data, although requested, were not made available.\n\nThe model was a Markov state transition model that included the health states immediate graft function, delayed graft function, transplant failure, explantation and a return to dialysis, and subsequent transplantation. The characteristics of the cohort modelled were chosen to be consistent with data obtained from UK Transplant and The Renal Registry. The cohort was followed up until almost all patients (97%) had died. The Assessment Group developed a standard data set for use in the model which was modified to reflect the comparisons described above.\n\nCost data for machine perfusion were annualised and it was assumed that perfusion machines were used for 10\xa0years with no resale value afterwards. The estimated number of kidneys stored by each machine per year was calculated based on the total number of transplantations per year divided by the number of transplant centres. This estimate was 61 kidneys per year for analyses using data from the Machine Preservation Trial and 16\xa0kidneys per year for analyses using data from the PPART study. The costs for machine perfusion also included an annual maintenance contract and the costs of the perfusion kit and solution used in the machine. This resulted in a cost per kidney stored of £544 for the analyses using data from Machine Preservation Trial and £737 for the analyses using data from PPART. The costs of storing a kidney using cold static storage included the costs of the solution and the box required to store the kidney. This was calculated to be £262.53 per kidney with Belzer UW storage solution and £49.73 per kidney with Marshall's solution.\n\nUtility data were derived from published literature. The utility of living with a transplanted kidney varied according to age and was 0.83 for people aged 18–34\xa0years, decreasing to 0.66 for people aged 65\xa0years and older. The reduction in utility of living with dialysis was 0.12. Therefore, a person aged 18–34\xa0years on dialysis had a utility of 0.71 and a person aged 65\xa0years and older had a utility of 0.54. Renal registry data were used to model patient survival on dialysis and with a transplant; this rate was also varied according to age.\n\nData from the PPART study were used to model the cost effectiveness of LifePort compared with Belzer UW storage solution for the preservation of kidneys from non-heart-beating donors. The results of the deterministic analyses suggested that the LifePort kidney transporter was associated with greater cost than Belzer UW storage solution (£141,319 versus £139,205) and fewer QALYs (9.13 versus 9.19). Probabilistic sensitivity analyses predicted that over a range of willingness-to-pay levels (£0–£100,000) the probability of LifePort being cost effective was about 40%.\n\nData from the Machine Preservation Trial study were used to model the cost effectiveness of LifePort compared with Belzer UW storage solution for the preservation of kidneys mainly from deceased heart-beating donors. The results of the deterministic analyses suggested that Belzer UW storage solution was associated with greater cost than the LifePort kidney transporter (£142,805 versus £139,100) and fewer QALYs (9.58 versus 9.79). Probabilistic sensitivity analyses predicted that over a range of willingness-to-pay levels (£0–£100,000) the probability of LifePort being cost effective was 80%.\n\nData from the cohort study (described in section 4.1.8) were used to model the cost effectiveness of LifePort compared with Marshall's hypertonic citrate for the preservation of kidneys from controlled non-heart-beating donors. The results of the deterministic analyses suggested that Marshall's hypertonic citrate solution was associated with greater cost than the LifePort kidney transporter (£144,332 versus £132,953) and fewer QALYs (8.55 versus 9.54). Probabilistic sensitivity analyses predicted that over a range of willingness-to-pay levels (£0–£100,000) the probability of LifePort being cost effective was 95%.\n\nData from the retrospective record review (described in section\xa04.1.10) were used to model the cost effectiveness of Marshall's hypertonic citrate compared with Belzer UW storage solution for the preservation of kidneys from deceased donors. This study analysed kidneys by duration of cold ischaemia. The cost-effectiveness analyses were based on kidneys that had 19–24\xa0hours of cold ischaemic time. For these kidneys graft survival at 3\xa0years was reported as 79.5% and 77.7% in the Belzer UW storage solution and Marshall's hypertonic citrate solution groups, respectively. The results of the deterministic analyses suggested that Marshall's hypertonic citrate solution was associated with greater cost than Belzer UW storage solution (£151,826 versus £151,001) and fewer QALYs (8.57 versus 8.62). Probabilistic sensitivity analyses predicted that over a range of willingness-to-pay levels (£0–£100,000) the probability of Marshall's storage solution being cost effective was 40%.\n\n# Consideration of the evidence\n\nThe Appraisal Committee reviewed the data available on the clinical and cost effectiveness of machine perfusion systems and cold static storage of donated kidneys, having considered evidence on the nature of the condition and the value placed on the benefits of improvements in access to viable kidneys for transplantation by people with established renal failure, those who represent them, and clinical specialists. It was also mindful of the need to take account of the effective use of NHS resources.\n\nThe Committee considered the process of retrieving donated organs and the methods for their storage. The Committee was aware that it was important to minimise the length of ischaemic time regardless of the storage method used, in order to reduce the detrimental impact of ischaemia on the donated kidney. It also recognised that kidneys could be obtained from different types of donors and that type of donor is associated with differences in rates of delayed graft function and overall graft survival. The Committee understood that minimising primary non-function and early and late graft loss was important. Unsuccessful transplantation has a significant physical and psychological effect on the recipient of the kidney and could reduce the chance of successful reimplant because of exposure to antigens. The Committee understood that kidneys from brainstem-dead (that is, deceased heart-beating) donors are allocated nationally and that kidneys from non-heart-beating donors are allocated locally. However, it was aware that transplant services may be reorganised as a result of recent recommendations to the government from the Organ Donation Taskforce. The Committee concluded that kidneys from different types of donor needed to be considered separately and that the mechanism for allocating kidneys could influence the choice of storage method.\n\nThe Committee considered the different machine perfusion systems. It was aware that the RM3 is not portable and therefore does not replace cold static storage if transportation is needed. The Committee noted that although clinical effectiveness evidence comparing the RM3 with the LifePort kidney transporter was available, it had methodological limitations because it was based on retrospective record reviews rather than prospective studies. The Committee recognised that the Assessment Group had been unable to complete any cost-effectiveness analyses that included the RM3 because no cost data were made available by the manufacturer. The Committee concluded that it could only issue recommendations for storage methods whose cost is known.\n\nThe Committee specifically considered the use of machine perfusion to assess the viability of kidneys before implant. The Committee heard from clinical specialists that there was no clear experimental evidence to support testing the viability of the kidney using the machine, but that they considered viability testing to be potentially important. The Committee heard that clinical experience of machine perfusion systems, and knowledge of kidney function after transplantation, may enable clinicians to identify factors associated with poor viability. The Committee was aware that a retrospective analysis had been proposed as part of the Machine Preservation Trial study but had not yet been completed. The Committee concluded that although viability testing is potentially important, currently there is insufficient evidence to make this a deciding factor in choice of storage methods.\n\nThe Committee considered the differences in clinical effectiveness between the two cold static storage solutions. The Committee noted that the analysis by the Assessment Group suggested no statistically significant differences between the two solutions. The Committee noted that Marshall's hypertonic citrate solution is used to store kidneys in a large proportion of centres, although choice of solution may depend on several factors. The Committee heard from clinical specialists that there are differences in viscosity between Marshall's hypertonic citrate solution and Belzer UW storage solution, which affected the choice of solution in some cases. The Committee additionally heard that for multiorgan donation that included the pancreas, Marshall's hypertonic citrate solution was not considered suitable for cooling of the organs in situ. The Committee also heard that where a longer cold ischaemic time is anticipated, clinicians consider Belzer UW storage solution to be more suitable than Marshall's hypertonic citrate solution. However, cold ischaemic times greater than 24\xa0hours are generally avoided in the UK, unless an organ is reallocated, or national allocation means that the kidney has a long transport time. These factors are, however, difficult to predict beforehand. The Committee concluded that the clinical effectiveness evidence did not support a general preference for one storage solution over another but that both these clinical and logistical considerations need to be taken into account when choosing between storage solutions.\n\nThe Committee considered the clinical effectiveness evidence for the use of the LifePort kidney transporter for the storage of kidneys from deceased heart-beating donors. In considering the clinical effectiveness evidence, the Committee was mindful of comments from a consultee about the additional time required to attach the donated kidney to the LifePort kidney transporter, and the impact that this may have on the retrieval process for the kidneys and other organs. The Committee noted the results of the Machine Preservation Trial study. The Committee was aware that this study included mainly kidneys from deceased heart-beating donors, which does not reflect the type of kidneys for which the machines are usually used in the NHS. The Committee considered that this study suggested a small statistically significant benefit in terms of graft survival favouring the use of machine perfusion. The Committee heard from clinical specialists that these small benefits in rates of graft survival are important, but that factors such as discard rates before implant are also important. The Committee heard clinical specialists express concern about the exclusion of a large number of kidneys from the statistical analysis in the Machine Preservation Trial study, and the effect that these exclusions may have had on results. The Committee also heard from clinical specialists that the potential advantages of machine perfusion are not necessarily considered greater for the storage of kidneys from deceased heart-beating donors because success rates with cold storage solutions are already high. The Committee concluded that machine perfusion may be marginally more clinically effective than Belzer UW storage solution for the storage of kidneys from deceased heart-beating donors. However, it was mindful of possible clinical considerations for choosing between machine perfusion and cold static storage and also the clinical specialists' comments that further evidence was required before the benefits of the LifePort kidney transporter over cold static storage can be fully demonstrated.\n\nThe Committee considered the clinical effectiveness evidence for the use of the LifePort kidney transporter for the storage of kidneys from non-heart-beating donors. The Committee noted that the PPART study had shown no statistically significant differences between the LifePort kidney transporter and cold static storage using Belzer UW storage solution. The Committee heard from clinical specialists that the results of the PPART study were not consistent with clinical opinion or practice for storing this type of kidney. The Committee also noted comments from a consultee about possible limitations in the reproducibility of the results of this study. The Committee was mindful of the preliminary nature of the data from the PPART study and considered whether the availability of longer term data would change the conclusions. The Committee heard from clinical specialists that they did not think that the overall conclusion of the PPART study would change as more data become available. The Committee noted that the Machine Preservation Trial study reported results from a subgroup of kidneys from non-heart-beating donors in whom death was controlled. The Committee recognised that preliminary analyses suggested benefits to delayed graft function, but did not yet suggest differences in primary non-function and graft survival. The Committee was also aware that a cohort study had compared the LifePort kidney transporter and Marshall's hypertonic citrate solution for the storage of kidneys from non-heart-beating donors where cardiac death had been expected. The Committee noted that this study had shown a statistically significant difference that favoured the LifePort kidney transporter for rate of delayed graft function, but that there were methodological limitations with the design of the study. The Committee concluded that the clinical effectiveness evidence did not allow it to distinguish between the LifePort kidney transporter and cold static storage for the storage of kidneys from non-heart-beating donors.\n\nThe Committee considered the economic modelling carried out by the Assessment Group and noted the assumptions about the costs of the different storage methods. The Committee heard from clinical specialists that clinicians may use different quantities of the storage solution, varying between 2 and 8\xa0litres per kidney. The Committee noted that the Assessment Group had assumed that two LifePort kidney transporters were required for each transplant centre, but that in clinical practice more machines may be required to ensure that a machine is readily available. The Committee also noted comments from a consultee that in some locations an extra person was employed to supervise the LifePort kidney transporter, and that consumables would be wasted if kidneys were prepared for machine perfusion and then found not to be suitable. However, the Committee was persuaded that the upfront costs of storage are much smaller than the costs of dialysis for failed grafts used in the model and that differences in the costs of storage for different methods would have little effect on the results of cost-effectiveness analysis. The Committee concluded that while specific methods of storing kidneys may differ between centres, which would affect the cost of the technologies, this would not change the results of the cost-effectiveness analyses.\n\nThe Committee considered the cost-effectiveness evidence for the use of the different methods of kidney storage. The Committee understood that the cost-effectiveness results were driven by differences in the rate of graft survival between storage methods, because better graft survival led to fewer people on dialysis, which reduced costs and improved health-related quality of life.\n\nThe Committee noted that the results of the cost-effectiveness analyses suggested that Marshall's hypertonic citrate solution is associated with greater cost and fewer QALYs than Belzer UW storage solution. However, the Committee noted that the data suggested small differences in clinical effect between the two solutions, which led to small differences in both costs and QALYs. The Committee concluded that no robust differences in clinical effectiveness had been shown. It recommended that the cheapest solution be used if the solutions are otherwise considered equally suitable, bearing in mind the clinical considerations that might affect the choice (described in 4.3.5).\n\nThe Committee considered the cost-effectiveness evidence for the LifePort kidney transporter compared with cold static storage solutions. The Committee noted that the results of the cost-effectiveness analyses suggested that Belzer UW storage solution was associated with lower costs and more QALYs, when using data from PPART. However, using data from the Machine Preservation Trial study, the LifePort kidney transporter was associated with lower costs and more QALYs. The Committee noted these results were also based on small differences in costs and QALYs. Taking into consideration the testimony of clinical specialists and the clinical effectiveness evidence, the Committee was not persuaded that the LifePort kidney transporter could be preferentially recommended for the storage of kidneys from deceased donors over other forms of storage. Given that the overall costs and benefits associated with kidney transplantation using either machine perfusion or cold static storage were similar, the Committee recommended that the LifePort kidney transporter be considered as an alternative to cold static storage solutions and that the choice of which to use would depend on clinical and logistical factors within both the retrieval team and transplant centres.", 'Recommendations for further research ': 'The PPART study is ongoing and the Machine Preservation Trial study is analysing subgroup data of kidneys from non-heart-beating donors and extended criteria donors. Both studies are collecting resource-use data.\n\nThe Committee considered that it was important for transplant centres to collect standardised and comprehensive data that follow up the outcomes for kidneys stored using different methods.', 'Related NICE guidance': 'There is no related guidance for these technologies.', 'Review of guidance': 'The review date for a technology appraisal refers to the month and year in which the Guidance Executive will consider whether the technology should be reviewed. This decision will be taken in the light of information gathered by the Institute, and in consultation with consultees and commentators.\n\nThe guidance on this technology will be considered for review in August 2010. This date is to allow completion and follow up of the PPART and Machine Preservation Trial studies and to assess the implication of the implementation of the recommendations in the organ donation taskforce report.\n\nAndrew DillonChief ExecutiveJanuary 2009', 'Changes after publication': 'February 2014: implementation section updated to clarify that machine perfusion and cold static storage are recommended as options for the storage of kidneys from deceased donors. Additional minor maintenance update also carried out.\n\nMarch 2012: minor maintenance', 'About this guidance': 'NICE technology appraisal guidance is about the use of new and existing medicines and treatments in the NHS in England and Wales.\n\nThis guidance was developed using the NICE multiple technology appraisal process.\n\nThe recommendations from this guideline have been incorporated into a NICE Pathway. We have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available.\n\nYour responsibility\n\nThis guidance represents the views of NICE and was arrived at after careful consideration of the evidence available. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. However, the guidance does not override the individual responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.\n\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.\n\nCopyright\n\n© National Institute for Health and Clinical Excellence 2009. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.'}	https://www.nice.org.uk/guidance/ta165	Evidence-based recommendations on machine perfusion systems and cold static storage of kidneys from deceased donors.
bf9fe7e7d40a76168c603e9fa472268e072bf2a8	nice	Functional electrical stimulation for drop foot of central neurological origin	Functional electrical stimulation for drop foot of central neurological origin # Guidance Current evidence on the safety and efficacy (in terms of improving gait) of functional electrical stimulation (FES) for drop foot of central neurological origin appears adequate to support the use of this procedure provided that normal arrangements are in place for clinical governance, consent and audit. Patient selection for implantable FES for drop foot of central neurological origin should involve a multidisciplinary team specialising in rehabilitation. Further publication on the efficacy of FES would be useful, specifically including patient-reported outcomes, such as quality of life and activities of daily living, and these outcomes should be examined in different ethnic and socioeconomic groups.# The procedure # Indications and current treatments Drop foot can be caused by upper or lower motor neurone lesions. Functional electrical stimulation is used to treat the effects of upper motor neurone lesions that can result from conditions such as stroke, cerebral palsy, multiple sclerosis or spinal cord injury but may occur in other conditions. Symptoms and signs of upper motor neurone lesions include muscle weakness in a pyramidal distribution (an imbalance causing arm flexion and leg extension), hypertonicity, exaggerated reflexes, clonus and an extensor plantar response. Functional electrical stimulation is not normally suitable for patients with lower motor neurone lesions. Treatment options include physiotherapy or an ankle-foot orthosis to align the lower leg and control the motion of the ankle and foot, providing stability and improving gait. Medical therapy includes oral administration of muscle relaxant drugs or botulinum toxin type A injections. Surgery (usually reserved for refractory cases) includes selective tendon release of muscles. # Outline of the procedure Functional electrical stimulation aims to produce muscle contractions that mimic normal voluntary gait movement (lifting the foot and achieving correct placement on the ground) by applying electrical pulses to the common peroneal nerve through skin surface or implanted electrodes. Various devices can be used for this procedure. Implanted FES electrodes are usually inserted into the epineurium of the peroneal nerve under general anaesthesia. The electrodes are either percutaneous (passed through the skin and connected to an external pulse generator) or fully implanted (operated by radiofrequency waves). In skin surface FES, electrodes placed over the nerve are connected by leads to a stimulator unit and controlled with a foot switch. Patients may also use ankle-foot orthosis. Sections 2.3 and 2.4 describe efficacy and safety outcomes which were available in the published literature and which the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview. # Efficacy A meta-analysis (including three controlled studies) of 71 patients with stroke reported a mean increase of 0.18 metres/second (95% confidence interval 0.08 to 0.28) in gait speed in 36 patients treated by skin surface FES compared with 35 patients treated by conventional therapy (absolute numbers not given). A case series including 111 patients with stroke treated by skin surface FES reported a mean increase in walking speed of 27% (p < 0.01) and a reduction in effort of 31% (p < 0.01), assessed with stimulation at 18 weeks. Corresponding improvements in speed and effort without stimulation were 14% (p < 0.01) and 19% (p < 0.01) respectively. A randomised controlled trial (RCT) of 29 patients with stroke reported a 23% improvement in walking speed (during daily activity) in the 14 patients treated by implanted FES (assessed with stimulation), compared with 3% in the 15 patients who had conventional therapy (follow-up: 26 weeks; p = 0.010). A second RCT of 29 patients with stroke, of whom 14 were treated by implanted FES over 12 weeks, reported subjective achievement of functional milestones (such as 'prepared dinner', 'walked outside') in 53 instances in the FES group and 11 instances in the conventional therapy group (assessed by bimonthly questionnaires; follow-up not stated). The Specialist Advisers considered key efficacy outcomes to include improved gait, reduction in effort when walking, reduction in pain and discomfort, reduction in falls, return to work and other quality of life outcomes. # Safety In an RCT of 29 patients with stroke, 14 of whom received implanted electrodes (percutaneous), there were four reports of skin erythema. In a case series of 17 patients who all received implanted electrodes (percutaneous), 14 cases of skin erythema were reported in 6 patients (1 of the 6 required electrode removal). A case series of 15 patients who received implanted electrodes (radiofrequency) reported wound infection in 2 patients. The second RCT of 29 stroke patients (14 of whom had implanted electrodes ) reported one instance of device malfunction after 10 weeks. The Specialist Advisers noted anecdotal adverse events included an increase in seizure incidence among patients with epilepsy, autonomic dysreflexia in patients with spinal cord injuries, problems with computed tomography (CT) or magnetic resonance imaging (MRI) scanning with implanted electrodes, increases in spasticity or spasms, infection when using implanted systems, and skin intolerance. They considered theoretical adverse events to include muscle fibrillation, problems caused by faulty equipment, or problems when treating pregnant women or patients who have a pacemaker. # Other comments The Committee noted that most of the evidence related to patients with stroke; that there are a number of different FES devices; and that the technology is evolving. The Committee noted that interpretation of the evidence was difficult because the evidence is based on studies that used different methods of applying the procedure (skin surface or implanted).# Further information NICE has produced a clinical guideline on the diagnosis and management of stroke and transient ischaemic attacks and interventional procedures guidance on selective dorsal rhizotomy for spasticity in cerebral palsy. # Information for patients NICE has produced information on this procedure for patients and carers. It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.# About this guidance NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland. This guidance was developed using the NICE interventional procedure guidance process. It has been incorporated into the NICE pathway on stroke, along with other related guidance and products. We have produced a summary of this guidance for patients and carers. Information about the evidence it is based on is also available. Changes since publication January 2012: minor maintenance. Your responsibility This guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer. Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties. Copyright © National Institute for Health and Clinical Excellence 2009. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE. Contact NICE National Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT www.nice.org.uk nice@nice.org.uk	{'Guidance': 'Current evidence on the safety and efficacy (in terms of improving gait) of functional electrical stimulation (FES) for drop foot of central neurological origin appears adequate to support the use of this procedure provided that normal arrangements are in place for clinical governance, consent and audit.\n\nPatient selection for implantable FES for drop foot of central neurological origin should involve a multidisciplinary team specialising in rehabilitation.\n\nFurther publication on the efficacy of FES would be useful, specifically including patient-reported outcomes, such as quality of life and activities of daily living, and these outcomes should be examined in different ethnic and socioeconomic groups.', 'The procedure': "# Indications and current treatments\n\nDrop foot can be caused by upper or lower motor neurone lesions. Functional electrical stimulation is used to treat the effects of upper motor neurone lesions that can result from conditions such as stroke, cerebral palsy, multiple sclerosis or spinal cord injury but may occur in other conditions. Symptoms and signs of upper motor neurone lesions include muscle weakness in a pyramidal distribution (an imbalance causing arm flexion and leg extension), hypertonicity, exaggerated reflexes, clonus and an extensor plantar response. Functional electrical stimulation is not normally suitable for patients with lower motor neurone lesions.\n\nTreatment options include physiotherapy or an ankle-foot orthosis to align the lower leg and control the motion of the ankle and foot, providing stability and improving gait. Medical therapy includes oral administration of muscle relaxant drugs or botulinum toxin type A injections. Surgery (usually reserved for refractory cases) includes selective tendon release of muscles.\n\n# Outline of the procedure\n\nFunctional electrical stimulation aims to produce muscle contractions that mimic normal voluntary gait movement (lifting the foot and achieving correct placement on the ground) by applying electrical pulses to the common peroneal nerve through skin surface or implanted electrodes.\n\nVarious devices can be used for this procedure. Implanted FES electrodes are usually inserted into the epineurium of the peroneal nerve under general anaesthesia. The electrodes are either percutaneous (passed through the skin and connected to an external pulse generator) or fully implanted (operated by radiofrequency waves). In skin surface FES, electrodes placed over the nerve are connected by leads to a stimulator unit and controlled with a foot switch.\n\nPatients may also use ankle-foot orthosis.\n\nSections 2.3 and 2.4 describe efficacy and safety outcomes which were available in the published literature and which the Committee considered as part of the evidence about this procedure. For more detailed information on the evidence, see the overview.\n\n# Efficacy\n\nA meta-analysis (including three controlled studies) of 71 patients with stroke reported a mean increase of 0.18 metres/second (95% confidence interval [CI] 0.08 to 0.28) in gait speed in 36 patients treated by skin surface FES compared with 35 patients treated by conventional therapy (absolute numbers not given).\n\nA case series including 111 patients with stroke treated by skin surface FES reported a mean increase in walking speed of 27% (p < 0.01) and a reduction in effort of 31% (p < 0.01), assessed with stimulation at 18 weeks. Corresponding improvements in speed and effort without stimulation were 14% (p < 0.01) and 19% (p < 0.01) respectively.\n\nA randomised controlled trial (RCT) of 29 patients with stroke reported a 23% improvement in walking speed (during daily activity) in the 14 patients treated by implanted FES (assessed with stimulation), compared with 3% in the 15 patients who had conventional therapy (follow-up: 26 weeks; p = 0.010).\n\nA second RCT of 29 patients with stroke, of whom 14 were treated by implanted FES over 12 weeks, reported subjective achievement of functional milestones (such as 'prepared dinner', 'walked outside') in 53 instances in the FES group and 11 instances in the conventional therapy group (assessed by bimonthly questionnaires; follow-up not stated).\n\nThe Specialist Advisers considered key efficacy outcomes to include improved gait, reduction in effort when walking, reduction in pain and discomfort, reduction in falls, return to work and other quality of life outcomes.\n\n# Safety\n\nIn an RCT of 29 patients with stroke, 14 of whom received implanted electrodes (percutaneous), there were four reports of skin erythema. In a case series of 17 patients who all received implanted electrodes (percutaneous), 14 cases of skin erythema were reported in 6 patients (1 of the 6 required electrode removal). A case series of 15 patients who received implanted electrodes (radiofrequency) reported wound infection in 2 patients. The second RCT of 29 stroke patients (14 of whom had implanted electrodes [radiofrequency]) reported one instance of device malfunction after 10 weeks.\n\nThe Specialist Advisers noted anecdotal adverse events included an increase in seizure incidence among patients with epilepsy, autonomic dysreflexia in patients with spinal cord injuries, problems with computed tomography (CT) or magnetic resonance imaging (MRI) scanning with implanted electrodes, increases in spasticity or spasms, infection when using implanted systems, and skin intolerance. They considered theoretical adverse events to include muscle fibrillation, problems caused by faulty equipment, or problems when treating pregnant women or patients who have a pacemaker.\n\n# Other comments\n\nThe Committee noted that most of the evidence related to patients with stroke; that there are a number of different FES devices; and that the technology is evolving.\n\nThe Committee noted that interpretation of the evidence was difficult because the evidence is based on studies that used different methods of applying the procedure (skin surface or implanted).", 'Further information': 'NICE has produced a clinical guideline on the diagnosis and management of stroke and transient ischaemic attacks and interventional procedures guidance on selective dorsal rhizotomy for spasticity in cerebral palsy.\n\n# Information for patients\n\nNICE has produced information on this procedure for patients and carers. It explains the nature of the procedure and the guidance issued by NICE, and has been written with patient consent in mind.', 'About this guidance': 'NICE interventional procedure guidance makes recommendations on the safety and efficacy of the procedure. It does not cover whether or not the NHS should fund a procedure. Funding decisions are taken by local NHS bodies after considering the clinical effectiveness of the procedure and whether it represents value for money for the NHS. It is for healthcare professionals and people using the NHS in England, Wales, Scotland and Northern Ireland, and is endorsed by Healthcare Improvement Scotland for implementation by NHSScotland.\n\nThis guidance was developed using the NICE interventional procedure guidance process.\n\nIt has been incorporated into the NICE pathway on stroke, along with other related guidance and products.\n\nWe have produced a summary of this guidance for patients and carers. Information about the evidence it is based on is also available.\n\nChanges since publication\n\nJanuary 2012: minor maintenance.\n\nYour responsibility\n\nThis guidance represents the views of NICE and was arrived at after careful consideration of the available evidence. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not, however, override the individual responsibility of healthcare professionals to make appropriate decisions in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.\n\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.\n\nCopyright\n\n© National Institute for Health and Clinical Excellence 2009. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.\n\nContact NICE\n\nNational Institute for Health and Clinical ExcellenceLevel 1A, City Tower, Piccadilly Plaza, Manchester M1 4BT\n\nwww.nice.org.uk\n \n nice@nice.org.uk\n 0845 033 7780'}	https://www.nice.org.uk/guidance/ipg278

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