The Department of Health and the Welsh Assembly Government have asked the National Institute for Health and Clinical Excellence (NICE) to produce guidance on using infliximab and adalimumab for the treatment of Crohn’s disease in the NHS in England and Wales. The Appraisal Committee has had its second meeting to consider the evidence submitted and the views of non-manufacturer consultees and commentators, and clinical specialists and patient experts.

This document has been prepared for consultation with the consultees. It summarises the evidence and views that have been considered, and sets out the draft recommendations made by the Committee. NICE invites comments from the consultees and commentators for this appraisal (see appendix B) and the public. This document should be read along with the evidence base (the evaluation report), which is available from www.nice.org.uk

Note that this document is not NICE’s final guidance on these technologies. The recommendations made in section 1 may change after consultation.

After consultation:

• The Appraisal Committee will meet again to consider the evidence, this appraisal consultation document and comments from the consultees.
• At that meeting, the Committee will also consider comments made by people who are not consultees.
• After considering these comments, the Committee will prepare the final appraisal determination (FAD).
• Subject to any appeal by consultees, the FAD may be used as the basis for NICE’s guidance on using infliximab and adalimumab in the NHS in England and Wales.
• For further details, see the ‘Guide to the technology appraisal process’ (available at www.nice.org.uk).

The key dates for this appraisal are:

Closing date for comments: 5 October 2009

Third Appraisal Committee meeting: 22 October 2009

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 is not NICE’s final guidance on these technologies. The recommendations in section 1 may change after consultation.

1 Appraisal Committee’s preliminary recommendations

1.1 Adalimumab, within its licensed indications, is recommended as a treatment option for adults with severe active non-fistulising Crohn’s disease as induction treatment followed by maintenance treatment.

1.2 Infliximab, within its licensed indications, is recommended as a treatment option for people with severe active Crohn’s disease as induction treatment followed by maintenance treatment, only in one or more of the following circumstances:

• there is clear evidence of primary intolerance to adalimumab
• the Crohn’s disease is fistulising
• the patient is a child or adolescent

1.3 Maintenance treatment with adalimumab or infliximab (as indicated in 1.1 or 1.2) should continue until treatment failure (which includes the need for surgery), or until 12 months after the start of treatment, whichever is shorter. The person’s disease should then be reassessed. Maintenance treatment should only then be continued if there is clear evidence of ongoing active disease, as determined by clinical symptoms and investigation, including endoscopy if necessary. People whose disease relapses after maintenance treatment is stopped should have the option to resume treatment for a further 12 months. They should then have their disease reassessed to determine whether ongoing treatment is still clinically appropriate.

1.4 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.

1.5 Treatment with infliximab and adalimumab should only be started and reviewed by clinicians with experience of managing Crohn’s disease and with TNF-α inhibitors.

1.6 People already having maintenance treatment with adalimumab or infliximab who do not fulfil the criteria in 1.1 or 1.3 should have the option to continue treatment until they and their clinicians consider it appropriate to stop.

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 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 adverse effects.

2.6 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.

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, 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.

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.

3 The technologies

Infliximab

3.1 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.

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 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 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 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 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 A 100-mg vial of infliximab costs £419.62 (excluding VAT; ‘British national formulary’ (BNF), 57th 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 administration cost for each infusion of £258, the total cost is approximately £3872. 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.

3.9 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.

3.10 Adalimumab costs £357.50 per 40-mg prefilled syringe (excluding VAT; BNF, 57th 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 (seven 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) and longer-term regular dosing regimens given 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 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-α 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.

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 were in line with the indications 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 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).

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 between 11 and 18 years.

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 it 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 et al. 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 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 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 infliximab and adalimumab 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 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 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.

4.2.6 The manufacturer of adalimumab 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.

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 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.

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. 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 4.2.9 to 4.2.14 are based on the updated analysis.

4.2.9 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.

4.2.10 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.

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 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.

4.2.12 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 standard care relapse rate for people 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% to14% 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 sponsors from their clinical trials.

4.2.13 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.

4.2.14 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 the episodic treatment of infliximab, and noted that the inclusion of these costs lowered the ICER.

4.2.15 Consultees also highlighted that a recent publication (Bodger et al. 2009) compared the cost effectiveness of maintenance treatment with adalimumab or infliximab with standard care 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.

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 also took into account the effective use of NHS resources.

4.3.2 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) had a major effect on impairment of growth in children and adolescents, 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 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 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.

4.3.4 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.

4.3.5 The Committee discussed the different modes of treatment with TNF-α inhibitors in severe Crohn’s disease, namely induction, episodic and maintenance therapy. 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 not 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, although it was accepted that this was more of an issue with infliximab than adalimumab.
• Although early clinical trials of the TNF-α inhibitors in moderate to severe Crohn’s disease had used episodic therapy, the evidence from clinical practice now strongly favoured maintenance therapy.

4.3.6 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 collective body of evidence was sufficient to inform the Committee’s decision on the cost-effective use of TNF-α inhibitor therapy.

4.3.7 The Committee agreed that, despite the limitations of the available evidence, the transition probabilities from remission to relapse (relapse rate) could be considerably higher in those people for whom TNF-α inhibitor therapy is indicated than the transition probabilities used in the Assessment Group 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, and 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 a higher relapse rate than that used in the Assessment Group model.

4.3.8 The Committee noted that for episodic treatment (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 the analyses presented. However, in light of testimony from the clinical specialists (see section 4.3.5), the Committee considered that episodic treatment with infliximab and adalimumab should not be considered as the preferred option for the treatment of severe Crohn’s disease, and that its recommendations should be based on consideration of the clinical and cost effectiveness of maintenance therapy relative to standard care alone.

4.3.9 The Committee considered the use of infliximab and adalimumab as maintenance therapies. It acknowledged that, despite the limitations associated with the clinical trial data as noted by the Assessment Group and the DSU, there was sufficient evidence to conclude that the interventions were more clinically effective than standard care.

4.3.10 The Committee considered the cost effectiveness of maintenance treatment with infliximab and adalimumab compared with standard care. The Committee noted that both infliximab and adalimumab were suggested to be cost effective when used continuously for limited periods in people who respond to induction therapy. However, it also noted that changes to assumptions regarding the time horizon of the economic analysis affected the ICERs for both agents. The Committee concluded that there was a great deal of uncertainty about the clinical and cost effectiveness of both agents over periods longer than 1 or 2 years.

4.3.11 The Committee heard from the clinical specialists that they were concerned about the longer-term effectiveness and safety of TNF-α inhibitors. It also heard that there was recent evidence suggesting that it may be reasonable to try withdrawing treatment in those who demonstrated a complete response, although it noted that there may still be a significant risk of relapse. The clinical specialists also noted that Crohn’s disease usually fluctuated between periods of high and low activity. The Committee was persuaded that a trial of withdrawing treatment after 12 months, if the disease had become inactive (as indicated by a combination of clinical symptoms and investigations, including endoscopy if necessary), would be a reasonable course of action.

4.3.12 The Committee considered that maintenance treatment with adalimumab compared with standard care was more cost effective than for infliximab. This was because the Committee was persuaded that both agents could not be distinguished in terms of clinical effectiveness for non-fistulising disease and therefore could only be differentiated by their cost. The Committee considered that the cost-effectiveness estimates across the evidence available supported the use of maintenance therapy with adalimumab as long as the effect of the treatment was monitored on an ongoing basis. The Committee concluded that adalimumab should be recommended for maintenance therapy for 12 months after induction, with the option to continue treatment if an adequate response is demonstrated and there is evidence that active disease is still present.

4.3.13 The Committee noted that people with severe Crohn’s disease who had clear evidence of primary intolerance to adalimumab should have the option of induction treatment with infliximab, and subsequent maintenance treatment for up to 12 months before reassessment. Maintenance therapy should only be continued if there is clear evidence of ongoing active disease, as determined by clinical symptoms and investigation, including endoscopy if necessary. People whose disease relapses after maintenance treatment is stopped should have the option to have treatment with infliximab for a further 12 months.

4.3.14 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 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 TNF-α inhibitors were potentially cost effective in this situation.

4.3.15 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. The Committee concluded that maintenance treatment of fistulising disease with infliximab could be cost effective if the definition of severe disease (see 1.5 and 4.3.14) was met.

4.3.16 The Committee discussed the use of infliximab for the treatment of children and adolescents. The Committee noted 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 potential lifelong effects on quality of life and avoidance of potential toxicity from alternative therapies. Given these factors the Committee concluded that infliximab could be cost effective for the treatment of children and adolescents with severe Crohn’s disease.

5 Implementation

5.1 The Secretary of State and the Welsh Assembly Minister for Health and Social Services have issued directions to the NHS on implementing NICE technology appraisal guidance. When a NICE technology appraisal recommends use of a drug or treatment, or other technology, the NHS must provide funding and resources for it within 3 months of the guidance being published. If the Department of Health issues a variation to the 3-month funding direction, details will be available on the NICE website. The NHS is not required to fund treatments that are not recommended by NICE.

5.2 NICE has developed tools to help organisations put this guidance into practice (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 that support this locally.
• A costing statement explaining the resource impact of this guidance.
• Audit support for monitoring local practice.

6 Proposed recommendations for further research

6.1 Randomised controlled trials should be carried out that compare infliximab and adalimumab.

6.2 Trials should be carried out of maintenance treatment using infliximab and adalimumab designed to allow a true, unbiased comparison with standard care.

6.3 Trials of adalimumab maintenance therapy should be carried out 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, particularly 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 suitable for 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

• Guidance on the use of infliximab for Crohn’s disease. NICE technology appraisal guidance 40 (2002). Available from www.nice.org.uk/TA40

8 Proposed date for review of guidance

NICE proposes that the guidance on this technology is 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.

David Barnett
Chair, Appraisal Committee
September 2009

Appendix A: Appraisal Committee members and NICE project team

A Appraisal Committee members

The Appraisal Committee is one of NICE’s standing advisory committees. 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

Dr Matt Bradley
Value Demonstration Director, AstraZeneca

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

Dr Fiona Duncan
Clinical Nurse Specialist, Anaesthetic Department, Blackpool Victoria Hospital, Blackpool

Dr Simon Dixon
Reader in Health Economics, University of Sheffield

Mr Christopher Earl
Surgical Care Practitioner, Renal Transplant Unit, Manchester Royal Infirmary

Dr Paul Ewings
Statistician, Taunton & Somerset NHS Trust, Taunton

Professor John Geddes
Professor of Epidemiological Psychiatry, University of Oxford

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 Ian Lewin
Consultant Endocrinologist, North Devon District Hospital

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 James Moon
Consultant Cardiologist and Senior Lecturer, University College London Hospital (UCLH) and UCL

Dr David Newsham
Lecturer (Orthoptics), University of Liverpool

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

Professor Iain Squire
Consultant Physician, University Hospitals of Leicester

Dr Simon Thomas
Consultant Physician and Reader in Therapeutics, Newcastle Hospitals NHS Foundation Trust and Newcastle University

Mr David Thomson
Lay Member

Dr William Turner
Consultant Urologist, Addenbrooke’s Hospital, Cambridge University Hospitals NHS Trust

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

B 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

Fiona Rinaldi (from June 2009)
Technical Lead

Janet Robertson
Technical Adviser

Bhash Naidoo (from August 2009)
Technical Adviser

Eloise Saile
Project Manager

Bijal Joshi (from September 2008)
Project Manager

Appendix B: Sources of evidence considered by the Committee

A 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 α) inhibitors (adalimumab, and infliximab [review]) for Crohn’s disease: a systematic review and economic evaluation, July 2008

B The Decision Support Unit (DSU) reports for this appraisal were prepared by The School of Health and Related Research, University of Sheffield:

• Wailoo, A et al., Use of tumour necrosis factor alpha (TNF α) inhibitors (adalimumab and infliximab) for Crohn's disease: Report by the Decision Support Unit, January, 2009.
• Wailoo, A et al., Use of tumour necrosis factor alpha (TNF α) inhibitors (adalimumab and infliximab) for Crohn's disease: Report by the Decision Support Unit, June, 2009.

C The following organisations accepted the invitation to participate in this appraisal as consultees and commentators. 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 Manufacturers/sponsors:

• 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

D 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 by attending the initial Committee discussions 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
• Professor Chris Hawkey, President of BSG, nominated by British Society of Gastroenterology – clinical specialist (from August 2009)
• Professor Jon Rhodes, Professor of Medicine and Honorary Consultant Gastroenterologist, nominated by Royal College of Physicians – clinical specialist (from August 2009)