The Department of Health and the Welsh Assembly Government have asked the National Institute for Health and Clinical Excellence (NICE or the Institute) to conduct a multiple technology appraisal of infliximab and adalimumab for the treatment of Crohn's disease and provide guidance on their use to the NHS in England and Wales. The Appraisal Committee has had its first meeting to consider both the evidence submitted and the views put forward by non-manufacturer consultees and commentators, and by the clinical specialist and patient expert representatives nominated for this appraisal by non-manufacturer consultees and commentators. The Committee has developed preliminary recommendations on the use of infliximab and adalimumab.

This document has been prepared for consultation with the formal consultees. It summarises the evidence and views that have been considered and sets out the preliminary recommendations developed by the Committee. The Institute is now inviting comments from the formal consultees in the appraisal process (the consultees for this appraisal are listed on the NICE website, www.nice.org.uk. This document should be read in conjunction with the evidence base for this appraisal (the evaluation report) which is available from www.nice.org.uk.

Note that this document does not constitute the Institute's formal guidance on the technologies. The recommendations made in section 1 are preliminary and may change after consultation.

The process the Institute will follow after the consultation period is summarised below. For further details, see the 'Guide to the technology appraisal process' (this document is available on the Institute's website, www.nice.org.uk)

• The Appraisal Committee will meet again to consider the original evidence and this appraisal consultation document in the light of the views of the formal consultees.
• At that meeting, the Committee will also consider comments made on the document by people who are not formal consultees in the appraisal process.
• After considering feedback from the consultation process, the Committee will prepare the final appraisal determination (FAD) and submit it to the Institute.
• Subject to any appeal by consultees, the FAD may be used as the basis for the Institute's guidance on the use of the appraised technology in the
• NHS in England and Wales.

The key dates for this appraisal are:

Closing date for comments: 7 October 2008

Second Appraisal Committee meeting: 22 October 2008

Details of membership of the Appraisal Committee are given in appendix A, and a list of the sources of evidence used in the preparation of this document is given in appendix B.

Note that this document does not constitute the Institute's formal guidance on these technologies. The recommendations made in section 1 are preliminary and may change after consultation.

1 Appraisal Committee's preliminary recommendations

1.1 Infliximab and adalimumab, within their licensed indications, are recommended as treatment options for adults with severe active, non-fistulising Crohn's disease as episodic treatment; that is, they can be re-administered to those people whose disease has responded to the first treatment course but then severe symptoms have recurred.

1.2 For the purposes of this guidance, severe active Crohn's disease is defined as very poor general health with weight loss and sometimes 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.

1.3 The choice of either adalimumab or infliximab in the circumstances described in 1.1 should be determined by the healthcare professional in consultation with patients and carers. The decision should take into account preferences regarding the delivery of the drug and potential adverse effects and contraindications. If all other considerations are equal, the drug with the lowest acquisition and delivery cost should be used.

1.4 Infliximab is recommended as episodic treatment for people with fistulising Crohn's disease who fulfil the criteria in 1.2.

1.5 Infliximab within its licensed indications is recommended for the treatment of children and adolescents with severe Crohn's disease as detailed in section 1.2.

1.6 Infliximab and adalimumab are not recommended for regular maintenance treatment (treatment given continually at regular intervals) to prevent relapse of Crohn's disease.

2 Clinical need and practice

 

2.1 Crohn's disease is a chronic inflammatory condition affecting the gastrointestinal tract (gut). It may 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 low-grade fever.

2.2 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.

2.3 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).

2.4 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.

2.5 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 toxicity.

2.6 Clinical management depends on disease activity, site, behaviour of disease (inflammatory, structuring, fistulising), response to previous medications, side-effect profiles of medications and extra-intestinal manifestations. As Crohn's disease is unpredictable, successful treatment focuses on inducing and maintaining clinical remission.

2.7 Current treatment includes aminosalicylates, corticosteroids, immunosuppressants, TNF α 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, will become corticosteroid resistant. 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.

2.8 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. Maintenance therapy after surgical resection has been found to prolong remission of the disease, although symptoms recur on average in about 35% of patients within 5 years and in about 73% of patients within 20 years.

3 The technologies

3.1 Infliximab (Schering-Plough Ltd) is a tumour necrosis factor alpha (TNF α) inhibitor. 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.

3.2 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.

3.3 For severe, active Crohn's disease, infliximab is given as a 5 mg/kg intravenous infusion over a 2-hour period followed by an additional 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 can either be given as maintenance treatment (another 5-mg/kg infusion at 6 weeks after the initial dose, followed by infusions every 8 weeks) or as 're-administration' treatment (an infusion of 5 mg/kg if signs and symptoms of the disease recur). In adults, dose escalation is an option in those whose disease has stopped responding.

3.4 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 3 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 in those whose disease has stopped responding.

3.5 For children and adolescents, 5 mg/kg is given as an intravenous infusion followed by additional 5 mg/kg doses at 2 and 6 weeks after the first dose, then every 8 weeks thereafter.

3.6 The net price for a 100 mg vial of infliximab is £419.62 (excluding VAT; 'British National Formulary' (BNF), 55th 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 £1,678, corresponding to four 100-mg vials needed for a dose of 365 mg. For a course of two infusions, with an assumed administration cost for each infusion of £258, the total cost is approximately £3,872. The total cost of regular maintenance treatment for 1 year is approximately £12,584. Costs may vary in different settings because of negotiated procurement discounts.
Adalimumab.

3.7 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. The SPC states that there is no evidence about treating children with Crohn's disease with adalimumab.

3.8 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 active infections. For full details of side effects and contraindications, see the SPC.

3.9 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.

3.10 Adalimumab costs £357.50 per 40-mg prefilled syringe or prefilled pen (excluding VAT; BNF, 55th edition). Normal induction treatment costs approximately £1073 and maintenance for 1 year costs £9295. Costs may vary in different settings because of negotiated procurement discounts.

4 Evidence and interpretation

The Appraisal Committee (appendix A) considered evidence from a number of sources (appendix B).

4.1 Clinical effectiveness

4.1.1 Eleven randomised controlled trials (RCTs) that included licensed doses of infliximab and adalimumab met the criteria for inclusion in the assessment report (eight for infliximab and four for adalimumab). These trials covered short treatment regimens given with the aim of inducing remission in people with active Crohn's disease (induction regimens) as well as longer-term regular dosing regimens used with the aim of preventing 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 adolescents.

4.1.2 The outcomes reported in the clinical trials were mainly based on the Crohn's Disease Activity Index (CDAI), which has eight variables related to the disease weighted according to their ability to predict disease activity. The total score ranges from 0 to 600. 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), an instrument similar to the CDAI but with less emphasis on subjectively reported symptoms and more emphasis on laboratory parameters of intestinal inflammation, 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.

4.1.3 Two placebo-controlled trials of induction regimens were identified for each of infliximab and adalimumab. Another study investigated infliximab induction treatment in children and adolescents 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 (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 α inhibitor; the second (GAIN, n = 325) included people who had previously been treated with infliximab, but had either not responded to the treatment and/or had not tolerated it. The Assessment Group were unable to carry out an indirect comparison or meta-analysis because of considerable heterogeneity between the trials.

4.1.4 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% CI 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.

4.1.5 The study of infliximab induction therapy 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 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.

4.1.6 The studies of adalimumab as induction therapy 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 are in line with the recommendations in 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 in the CLASSIC I study and 2.96 in the GAIN study), '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). In CLASSIC I, only the result for 'response 70' (RR 1.61 95% CI 1.13 to 2.29) was statistically significant; 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).

4.1.7 Four studies of maintenance therapy 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 not responded for most analyses. The second 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.

4.1.8 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).
4.1.9 Two studies (CHARM, n = 778) and (CLASSIC II, n = 55) examined adalimumab maintenance at a dose of 40 mg every other week or every week, in people who 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 56 in CHARM and at weeks 26 and 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 [95% CI 1.94 to 4.84] for the every other week schedule, and 3.52 [95% CI 2.24 to 5.53] 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.

4.1.10 The Assessment Group identified an additional study that investigated maintenance treatment in fistulising disease (n = 282). All participants received an induction course of three doses of infliximab 5 mg/kg and subsequently 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 due to 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.

4.1.11 The Assessment Group identified two trials that analysed infliximab in children and adolescents: one 12-week trial of induction therapy (n = 21) and one 54-week trial of maintenance therapy (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 combined treatment arms.

4.1.12 In addition to the evidence 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 their 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 participant's experience of biological treatment was 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 11-18.

4.2 Cost effectiveness

4.2.1 The Assessment Group reviewed the cost-effectiveness data submitted by the manufacturers of infliximab and adalimumab. In addition they conducted a literature search for any published cost-effectiveness studies.

4.2.2 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 made use of an epidemiological model constructed by Silverstein and coworkers 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 made use of 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.

4.2.3 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 adolescents. 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 therapy 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 result for severe active Crohn's disease for maintenance treatment compared with standard care was an ICER of £25,903 per QALY gained. For ICD treatment, infliximab dominated standard care (was more effective and less expensive). 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 to 70 kg from 60kg it caused the ICERs to increase over £30,000 per QALY gained in all adult analyses.

4.2.4 Abbott produced two economic models, one comparing the cost effectiveness of adalimumab as a maintenance therapy against standard care, and the other comparing adalimumab and infliximab as maintenance therapies. 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 the 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.

4.2.5 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 discontinue 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.

4.2.6 The manufacturer of adalimumab argued that they 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.

4.2.7 The Assessment Group carried out analyses for courses of induction treatment given when required (also known as episodic treatment) 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 an episodic use of the intervention. The Assessment Group constructed a four-stage Markov model based on the model by Silverstein and coworkers, but included only four health states (out of an original seven): remission, relapse, surgery and postsurgery remission. The transition probabilities to model natural history were derived from the Silverstein data set. The treatments were then assumed to have an equivalent affect on the probability of remaining in remission or relapse for moderate and for 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.

4.2.8 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. In addition, the Assessment Group adopted an additional 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 below are based on the updated analysis.

4.2.9 The Assessment Group only presented ICERs for adalimumab and infliximab 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 adalimumab and infliximab dominated standard care (that is, they were associated with greater health gain at lower cost than standard care). For maintenance treatment in severe disease, the ICER for adalimumab relative to standard care was £7,478 per QALY gained. However, since standard care is dominated by induction treatment, it is appropriate to draw the comparison with induction treatment rather than 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.

4.2.10 Following comments from consultees on the assumptions about relapse rates based on the model by Silverstein and coworkers, 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. In this scenario standard care was dominated by adalimumab and the ICER for adalimumab maintenance treatment compared with induction treatment was £37,007 per QALY gained.

4.2.11 The Assessment Group presented a threshold analysis for the use of infliximab in children and adolescents. The Assessment Group extrapolated the utilities, effectiveness and non-drug costs from the adult analyses to children. Only the drug costs associated with infliximab due to the lower body weight were altered. The Assessment Group carried out analyses at body weights of 60-40 kg and 40-20 kg. 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.

4.3 Consideration of the evidence

4.3.1 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 was also mindful of the need to take account of the effective use of NHS resources.

4.3.2 The Committee heard from clinical specialists and patient experts about the side effects of current standard care (particularly in relation to the use of corticosteroids) and the effects of Crohn's disease on everyday activities. 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) specifically had a major effect on impairment of growth in children and adolescents, especially during puberty. The Committee heard from the patient experts of 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 was considered of paramount importance to people with Crohn's disease.

4.3.3 The Committee considered the definition of severe Crohn's disease. It heard from clinical specialists and patient experts 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 an appropriate definition of severe Crohn's disease, 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 since some people with severe disease may not meet this criterion because 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.

4.3.4 The Committee noted that both infliximab and adalimumab are 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 considered that it was reasonable to generalise the results from the trials to the patient population under consideration. The Committee was mindful of the limitations of the trial data, but considered that the analyses presented provided the most reasonable estimate of treatment effectiveness.

4.3.5 The Committee discussed the cost-effectiveness analyses presented by the manufacturers and the Assessment Group. It noted that the assumptions of constant utilities in the health states and of instantaneous transitions did not accurately represent the course of the condition, especially the variation in health-related quality of life. The Committee noted the paucity of evidence in Crohn's disease and the difficulties this created. The Assessment Group model assumed that all patients received three doses of infliximab before being assessed for response. The Committee noted that the licence for infliximab specifies that response is assessed after only two doses. The Committee was mindful that the removal of a third dose of infliximab would reduce the cost of infliximab induction regimens. It considered that despite these limitations, the structure of the models presented were adequate for the purposes of decision-making.

4.3.6 The Committee noted that for episodic treatment (referred to as induction in the Assessment Group's altered analysis; defined as patients having the opportunity to undergo another course of treatment if their disease initially responded to treatment but then relapsed) of severe Crohn's disease, both infliximab and adalimumab were more effective and less costly than standard care in all the analyses presented. It heard evidence from clinical specialists that episodic treatment was not favoured by clinicians because of concerns about the development of antibodies to the drug and the potential for loss of effect. However, in the light of the results of the cost-effectiveness analyses, the Committee considered that episodic treatment with infliximab and adalimumab should be recommended as an option for the treatment of severe Crohn's disease.

4.3.7 The Committee noted that there was no cost-effectiveness analyses that compared infliximab and adalimumab. Therefore, it could not distinguish between the two drugs on cost-effectiveness grounds. The Committee concluded that the least expensive treatment option should be chosen, taking into account dose and administration cost.

4.3.8 The Committee considered the use of infliximab and adalimumab as maintenance therapies. It acknowledged the difficulties associated with the clinical trial data as noted by the Assessment Group, particularly with respect to crossover to open-label treatment within the clinical trials. The Committee considered, however, that there was sufficient evidence to conclude that the interventions were more effective than standard care.

4.3.9 The Committee noted that standard care was dominated by episodic treatment (that is, episodic treatment was both less costly and more effective than standard care). Consequently, in assessing cost effectiveness, maintenance treatment should be compared with episodic treatment (the next best option) rather than standard care. In the base case the incremental ICERs for infliximab and adalimumab maintenance treatment compared with episodic treatment were approximately £5,030,000 and £4,980,000 per QALY gained, respectively.

4.3.10 The Committee noted that the cost effectiveness of different treatment strategies depended on the number of relapses a person is assumed to have over the course of the natural history of the disease, and therefore the number of relapses that would be prevented by maintenance treatment. It noted that the Assessment Group model assumed a very low yearly relapse rate and that the patient and clinical specialists had commented that in severe disease, a much higher relapse rate would be expected. The Committee considered the Assessment Group's sensitivity analyses when the relapse rate was increased to 3.9 per year (probability of relapse 0.3 per cycle). At this high relapse rate infliximab episodic treatment is no longer cost effective in comparison with standard care. Therefore, in this scenario infliximab maintenance should be compared with standard care. Under this assumption the ICER for infliximab maintenance treatment compared with standard care was £43,700 per QALY gained. For adalimumab, standard care remained dominated, and the ICER for adalimumab maintenance therapy compared with episodic treatment was approximately £37,000 per QALY gained. The Committee considered that the cost-effectiveness estimates based on this high relapse rate did not support the use of maintenance therapy. The Committee concluded that it could not recommend maintenance therapy with either drug.

4.3.11 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 α 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 would constitute severe symptoms and concluded that TNF α inhibitors were potentially cost effective in this situation.

4.3.12 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 and had not considered episodic treatment in the analysis. Given the analyses for non-fistulising disease, the Committee inferred that the ICER for the episodic treatment for fistulising disease was likely to be lower than that for maintenance therapy. It therefore concluded that episodic treatment of fistulising disease with infliximab could be cost-effective if the definition of severe disease (given in 1.2) was met.

4.3.13 The Committee discussed the use of infliximab for the treatment of children and adolescents. The Committee considered that it was unfortunate that the trials were not placebo controlled. However, it acknowledged the difficulties of conducting clinical trials in children and adolescents 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 adolescents and noted the Assessment Group's concerns over the data and analysis. It considered the lower weight of children and adolescents and the consequent lower infliximab drug costs. In addition, the Committee noted children and adolescents could potentially benefit more from treatment than adults, especially with regard to the effects of Crohn's disease on growth, peer interactions and schooling, and thus potential lifelong effects on quality of life. Given these factors the Committee concluded that infliximab would be cost effective for the treatment of children and adolescents with severe Crohn's disease.

5 Implementation

5.1 The Healthcare Commission assesses the performance of NHS organisations in meeting core and developmental standards set by the Department of Health in 'Standards for better health' issued in July 2004. The Secretary of State has directed that the NHS provides funding and resources for medicines and treatments that have been recommended by NICE technology appraisals normally within 3 months from the date that NICE publishes the guidance. Core standard C5 states that healthcare organisations should ensure they conform to NICE technology appraisals.

5.2 'Healthcare standards for Wales' was issued by the Welsh Assembly Government in May 2005 and provides a framework both for self-assessment by healthcare organisations and for external review and investigation by Healthcare Inspectorate Wales. Standard 12a requires healthcare organisations to ensure that patients and service users are provided with effective treatment and care that conforms to NICE technology appraisal guidance. The Assembly Minister for Health and Social Services issued a Direction in October 2003 that requires local health boards and NHS trusts to make funding available to enable the implementation of NICE technology appraisal guidance, normally within 3 months.

5.3 NICE has developed tools to help organisations implement this guidance (listed below). These are available on our website (www.nice.org.uk/TAXXX). [NICE to amend list as needed at time of publication]

• Slides highlighting key messages for local discussion.
• Costing report and costing template to estimate the savings and costs associated with implementation.
• Implementation advice on how to put the guidance into practice and national initiatives which support this locally.
• Audit support for monitoring local practice.

6 Proposed recommendations for further research

6.1 Randomised controlled trials that compare infliximab and adalimumab.

6.2 Trials of maintenance treatment in adalimumab and infliximab designed to allow a true, unbiased comparison with standard care.

6.3 Trials of adalimumab maintenance therapy exploring less-frequent dosing regimens.

6.4 Data should be collected on the effect of TNF α inhibitors on the natural history of Crohn's disease; in particular, the effect on relapse rates.

6.5 Health-related quality of life information should be collected in people with Crohn's disease.

6.6 Clinically meaningful instruments should be developed to help identify patients for suitable treatment with infliximab and adalimumab.

6.7 A register should be set up to monitor people who receive TNF α inhibitors for the treatment of Crohn's disease.

7 Related NICE guidance

Published

Guidance on the use of infliximab for Crohn's disease'. NICE technology appraisal guidance 40 (2002). Available from www.nice.org.uk/TA040

8 Proposed date for review of guidance

8.1 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.

8.2 It is proposed that the guidance on this technology is considered for review in September 2011. The Institute would particularly welcome comment on this proposed date.

Philip Home
Vice Chair, Appraisal Committee
September 2008

Appendix A: Appraisal Committee members and NICE project team

A Appraisal Committee members

The Appraisal Committee is a standing advisory committee of the Institute. Its members are appointed for a 3-year term. A list of the Committee members who took part in the discussions for this appraisal appears below. The Appraisal Committee meets three times a month except in December, when there are no meetings. The Committee membership is split into three branches, each with a chair and vice chair. Each branch considers its own list of technologies and ongoing topics are not moved between the branches.
Committee members are asked to declare any interests in the technology to be appraised. If it is considered there is a conflict of interest, the member is excluded from participating further in that appraisal.
The minutes of each Appraisal Committee meeting, which include the names of the members who attended and their declarations of interests, are posted on the NICE website.

• Dr Jane Adam
  Radiologist, St George's Hospital, London
• Professor A E Ades
  Professor of Public Health Science, Department of Community Based Medicine, University of Bristol
• Dr Amanda Adler
  Consultant Physician, Cambridge University Hospitals Trust
• Dr Tom Aslan
  General Practitioner, The Hampstead Group Practice, London
• Professor David Barnett (Chair)
  Professor of Clinical Pharmacology, Leicester Royal Infirmary
• Mrs Elizabeth Brain
  Lay Member
• Dr Robin Carlisle
  Deputy Director of Public Health, Rotherham PCT
• Dr Karl Claxton
  Professor of Health Economics, Department of Economics & Related Research, the University of York
• Mrs Fiona Duncan
  Clinical Nurse Specialist, Anaesthetic Department, Blackpool Victoria Hospital, Blackpool
• Dr Paul Ewings
  Statistician, Taunton & Somerset NHS Trust, Taunton
• Mr John Goulston
  Chief Executive, Barking, Havering and Redbridge Hospitals NHS Trust
• Dr Richard Harling
  Director of Public Health, Worcestershire PCT and Worcestershire County Council.
• Professor Philip Home (Vice Chair)
  Professor of Diabetes Medicine, Newcastle University
• Dr Terry John
  General Practitioner, The Firs, London
• Dr Simon Maxwell
  Senior Lecturer in Clinical Pharmacology and Honorary Consultant Physician, Queens Medical Research Institute, University of Edinburgh
• Dr Alec Miners
  Lecturer in Health Economics, London School of Hygiene and Tropical Medicine
• Dr Ann Richardson
  Lay Member
• Mrs Angela Schofield
  Chairman, Bournemouth and Poole Teaching PCT
• Mr Mike Spencer
  General Manager, Facilities and Clinical Support Services, Cardiff and Vale NHS Trust
• Dr William Turner
  Consultant Urologist, Addensbrooke's Hospital, Cambridge University Hospitals NHS Trust.
• Dr Simon Thomas
  Consultant Physician and Reader in Therapeutics, Newcastle Hospitals NHS Foundation Trust and Newcastle University
• Mr David Thomson
  Lay Member
• Dr Norman Vetter
  Reader, Department of Primary Care and Public Health, School of Medicine, University of Cardiff
• Dr Paul Watson
  Director of Commissioning, East of England Strategic Health Authority

C NICE project team

Each technology appraisal is assigned to a team consisting of one or more health technology analysts (who act as technical leads for the appraisal), a technical adviser and a project manager.

Prashanth Kandaswamy
Technical Lead

Janet Robertson
Technical Adviser

Eloise Saile
Project Manager

Appendix B: Sources of evidence considered by the Committee

The assessment report for this appraisal was prepared by the West Midlands Health Technology Assessment Collaboration:

• Dretzke, J et al. Use of tumour necrosis factor alpha (TNF ) inhibitors adalimumab and infliximab for Crohn's disease. July 2008.

A The following organisations accepted the invitation to participate in this appraisal. They were invited to comment on the draft scope, assessment report and the appraisal consultation document (ACD). Organisations listed in I and II were also invited to make written submissions and have the opportunity to appeal against the final appraisal determination.

I Manufacturer/sponsor:

• Abbott Laboratories Ltd (adalimumab)
• Schering-Plough (infliximab)

II Professional/specialist and patient/carer groups:

• National Association for Colitis and Crohn's Disease (NACC)
• Association of Coloproctology of Great Britain and Ireland
• British Society of Gastroenterology
• Royal College of Nursing
• Royal College of Physicians

III Other consultees

• Hammersmith and Fulham PCT
• Department of Health
• Welsh Assembly Government

IV Commentator organisations (did not provide written evidence and without the right of appeal):

• British National Formulary
• Department of Health, Social Services and Public Safety for Northern Ireland
• NHS Quality Improvement Scotland
• Dr Falk Pharma UK Ltd (mesalazine, budesonide)
• Ferring Pharmaceuticals Ltd (mesalazine) (Not participating)
• Forest Laboratories UK Ltd (prednisolone) (Not participating)
• IVAX Pharmaceuticals UK Ltd (mesalazine) (Not participating)
• Mayne Pharma plc (methotrexate) (Not participating)
• Novartis Pharmaceuticals Ltd (ciclosporin)
• Pfizer Ltd (sulfasalazine)
• Procter and Gamble Pharmaceuticals (UK) Ltd (mesalazine)
• Sandoz Ltd (mesalazine, metronidazole) (Not participating)
• Sanofi-Aventis Ltd (sodium cromoglicate, metronidazole)
• UCB Pharma Ltd (olsalazine sodium, prednisolone)
• Winthrop Pharmaceuticals UK Ltd (metronidazole)
• National Coordinating Centre for Health Technology Assessment
• West Midlands Health Technology Assessment Collaboration.

B The following individuals were selected from clinical specialist and patient advocate nominations from the non-manufacturer/sponsor consultees and commentators. They participated in the Appraisal Committee discussions and provided evidence to inform the Appraisal Committee's deliberations. They gave their expert personal view on infliximab and adalimumab for the treatment of Crohn's disease (review of technology appraisal guidance 40) by attending the initial Committee discussion and/or providing written evidence to the Committee. They are invited to comment on the ACD.

• Mr Charlie Croft, nominated by the National Association for Colitis and Crohn's Disease - patient expert
• Ms Elaine Steven, nominated by the National Association for Colitis and Crohn's Disease - patient expert
• Professor Subrata Ghosh, Consultant in General Medicine, Imperial College School of Medicine, nominated by the British Society of Gastroenterology - clinical specialist
• Professor Sally Mitton, Consultant Paediatric Gastroenterologist, British Society for Paediatric Gastroenterology, Hepatology and Nutrition, nominated by the National Association for Colitis and Crohn's Disease - clinical specialist.