The Department of Health has asked the National Institute for Health and Care Excellence (NICE) to produce guidance on using infliximab, adalimumab and golimumab in the NHS in England. The Appraisal Committee has considered the evidence submitted and the views of non-manufacturer consultees and commentators, and clinical experts 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 section 9) and the public. This document should be read along with the evidence base (the committee papers).

The Appraisal Committee is interested in receiving comments on the following:

• Has all of the relevant evidence been taken into account?
• Are the summaries of clinical and cost effectiveness reasonable interpretations of the evidence?
• Are the provisional recommendations sound and a suitable basis for guidance to the NHS?
• Are there any aspects of the recommendations that need particular consideration to ensure we avoid unlawful discrimination against any group of people on the grounds of race, gender, disability, religion or belief, sexual orientation, age, gender reassignment, pregnancy and maternity?

Note that this document is not NICE's final guidance on these technologies. The recommendations 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, adalimumab and golimumab in the NHS in England.

For further details, see the Guides to the technology appraisal process.

The key dates for this appraisal are:

Closing date for comments: 15 October 2014

Second Appraisal Committee meeting: 28 October 2014

Details of membership of the Appraisal Committee are given in section 8, and a list of the sources of evidence used in the preparation of this document is given in section 9.

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      Infliximab, adalimumab and golimumab are not recommended within their marketing authorisations for treating adults who have moderately to severely active ulcerative colitis that has responded inadequately to conventional therapy including corticosteroids and mercaptopurine or azathioprine, or who are intolerant to or have medical contraindications for such therapies.[1]

1.2     Infliximab is not recommended within its marketing authorisation for treating children and adolescents aged 6 to 17 years who have severely active ulcerative colitis that has responded inadequately to conventional therapy including corticosteroids and mercaptopurine or azathioprine, or who are intolerant to or have medical contraindications for such therapies.1

1.3     People currently receiving treatment initiated within the NHS that is not recommended for them by NICE in this guidance should be able to continue treatment until they and their NHS clinician consider it appropriate to stop. For children or young people, this decision should be made jointly by the clinician and the child/young person and/or their parents or carers.

2     Clinical need and practice

2.1     Ulcerative colitis is a chronic condition in which inflammation develops in the large intestine. Its exact cause is unknown although hereditary, infectious and immunological factors have been proposed as possible causes. Symptoms vary according to the extent and severity of the disease and may include bloody diarrhoea, abdominal pain, weight loss, fatigue, anaemia and an urgent need to defaecate. Some patients may also have extra-intestinal manifestations involving joints, eyes, skin and liver. Symptoms can flare up then disappear for months or even years, but approximately 50% of patients with ulcerative colitis will relapse at least once a year. Ulcerative colitis can cause complications such as inflamed and damaged bile ducts (primary sclerosing cholangitis), bowel cancer, osteoporosis and toxic megacolon (trapped gases in the colon causing it to swell).

2.2     Ulcerative colitis can develop at any age but the peak incidence is between 15 and 25 years of age with a second, smaller peak between 55 and 65 years. It is estimated that approximately 128,400 people in England have ulcerative colitis. Around 80% of the people affected have mild or moderate disease and 20% have severe disease.

2.3     The modified Truelove and Witts severity index is widely used to classify the severity of ulcerative colitis. It defines mild ulcerative colitis as fewer than 4 bowel movements daily; moderate ulcerative colitis as more than 4 daily bowel movements but the patient is not systemically ill; and severe ulcerative colitis as more than 6 bowel movements daily and the patient is also systemically ill (as shown by tachycardia, fever, anaemia or a raised erythrocyte sedimentation rate). Severe ulcerative colitis, as defined by the Truelove and Witts severity index, is potentially life threatening and normally requires hospitalisation and emergency care. This is aligned with the UK definition of ‘acute severe ulcerative colitis’. Ulcerative colitis (NICE clinical guideline 166) equates ‘subacute ulcerative colitis’ to moderately to severely active ulcerative colitis, which would normally be managed in an outpatient setting and does not require hospitalisation or the consideration of urgent surgical intervention. This appraisal includes moderately to severely active ulcerative colitis but not acute severe ulcerative colitis (that is, severe ulcerative colitis according to the Truelove and Witts severity index). Recommendations for treating acute severe ulcerative colitis can be found in NICE clinical guideline 166 and Infliximab for acute exacerbations of ulcerative colitis (NICE technology appraisal guidance 163).

2.4     Treatment for ulcerative colitis aims to relieve symptoms during a flare-up and then to maintain remission. The management of mildly to moderately active ulcerative colitis involves treatment with oral or topical aminosalicylates (sulfasalazine, mesalazine, balsalazide or olsalazine), or with corticosteroids if aminosalicylates are contraindicated or not tolerated. Oral corticosteroids or drugs that affect the immune response can also be added on if the disease does not respond to aminosalicylates. NICE does not recommend infliximab for treating ‘subacute’ manifestations of moderately to severely active ulcerative colitis in Infliximab for subacute manifestations of ulcerative colitis (NICE technology appraisal guidance 140). NICE was unable to appraise adalimumab for treating moderately to severely active ulcerative colitis in Adalimumab for the treatment of moderate to severe ulcerative colitis (NICE technology appraisal guidance 262) because the company did not make an evidence submission. Colectomy is a treatment option if symptoms are inadequately controlled or the patient has a poor quality of life on conventional therapy.

3     The technologies

3.1     Adalimumab (Humira, AbbVie), golimumab (Simponi, Merck Sharp & Dohme) and infliximab (Remicade, Merck Sharp & Dohme) are monoclonal antibodies that inhibit the pro-inflammatory cytokine, TNF-alpha. All 3 have the same marketing authorisation in the UK for the ‘treatment of moderately to severely active ulcerative colitis in adult patients who have had an inadequate response to conventional therapy including corticosteroids and mercaptopurine or azathioprine, or who are intolerant to or have medical contraindications for such therapies’. Infliximab is also indicated for the ‘treatment of severely active ulcerative colitis, in children and adolescents aged 6 to 17 years, who have had an inadequate response to conventional therapy including corticosteroids and mercaptopurine or azathioprine, or who are intolerant to or have medical contraindications for such therapies’.

Adalimumab

3.2     Adalimumab is administered by subcutaneous injection. The recommended induction dose regimen is 160 mg at week 0 and 80 mg at week 2. After induction treatment, the recommended dose is 40 mg every other week. The summary of product characteristics recommends that therapy should be stopped in patients whose disease failed to respond to adalimumab within 2 to 8 weeks after starting treatment.

3.3     The summary of product characteristics includes the following adverse reactions for adalimumab: infections (such as nasopharyngitis, upper respiratory tract infection and sinusitis), injection site reactions (erythema, itching, haemorrhage, pain or swelling), headache, musculoskeletal pain, hepatitis B reactivation, various malignancies and serious haematological, neurological and autoimmune reactions. For full details of adverse reactions and contraindications, see the summary of product characteristics.

3.4     The price of adalimumab is £352.14 for a pre-filled 40 mg pen or syringe, or a 40 mg/0.8-ml vial (excluding VAT; ‘British National Formulary’ [BNF] edition 67). Assuming the recommended dosage for adalimumab is followed (see section 3.2), the cost of adalimumab induction therapy is £2113; the monthly cost of adalimumab maintenance therapy is £704. Costs may vary in different settings because of negotiated procurement discounts.

Golimumab

3.5     Golimumab is administered by subcutaneous injection. The dose regimen of golimumab depends on the patient’s body weight. For patients with a body weight of less than 80 kg, golimumab is licensed at an initial dose of 200 mg, followed by 100 mg at week 2, and then 50 mg every 4 weeks. For patients with a body weight of 80 kg or more, it is licensed at an initial dose of 200 mg, followed by 100 mg at week 2, then 100 mg every 4 weeks. The summary of product characteristics recommends that continued golimumab therapy should be reconsidered in patients who do not benefit within 12 to 14 weeks after starting treatment (that is, after 4 doses).

3.6     The summary of product characteristics includes the following adverse reactions for golimumab: upper respiratory tract infection and other serious infections (including sepsis, pneumonia, tuberculosis, invasive fungal and opportunistic infections), demyelinating disorders, lymphoma, hepatitis B reactivation, congestive heart failure, autoimmune processes (lupus-like syndrome) and haematologic reactions. For full details of adverse reactions and contraindications, see the summary of product characteristics.

3.7     The price of golimumab is £762.97 for a pre-filled 50 mg pen or syringe and £1525.94 for a 100 mg pre-filled pen (excluding VAT; BNF edition 67). Merck Sharp & Dohme has agreed a patient access scheme with the Department of Health. This will make the 100 mg dose of golimumab available to the NHS at the same cost as the 50 mg dose. The Department of Health considered that this patient access scheme does not constitute an excessive administrative burden on the NHS. Including the patient access scheme and assuming that the recommended dosage for golimumab is followed (see section 3.5), the cost of golimumab induction therapy is £2289; the monthly cost of golimumab maintenance therapy is £763.

Infliximab                         

3.8     Infliximab is administered by intravenous infusion. For both the adult and paediatric populations, the recommended dosage of infliximab is 5 mg/kg at weeks 0, 2 and 6, then at every 8 weeks. The summary of product characteristics recommends that continued infliximab therapy should be carefully reconsidered in adults who do not benefit within the first 14 weeks of treatment. It also states that available data do not support further infliximab therapy in children and adolescents aged 6 to 17 years whose disease does not respond within the first 8 weeks of treatment.

3.9     The summary of product characteristics includes the following adverse reactions for infliximab: upper respiratory tract infection, hepatitis B reactivation, congestive heart failure, serious infections (including sepsis, opportunistic infections and tuberculosis), serum sickness (delayed hypersensitivity reactions), haematologic reactions, systemic lupus erythematosus/lupus-like syndrome, demyelinating disorders, hepatobiliary events, lymphoma, hepatosplenic T-cell lymphoma, and serious infusion reactions. For full details of adverse reactions and contraindications, see the summary of product characteristics.

3.10    The price of infliximab is £419.62 for a 100 mg vial containing powder for reconstitution (excluding VAT; BNF edition 67). Assuming the patient weighs 77 kg and the recommended dosage for infliximab is followed (see section 3.8), the cost of infliximab induction therapy is £5035; the monthly cost of infliximab maintenance therapy is £210. Costs may vary in different settings because of negotiated procurement discounts.

3.11    Biosimilar versions of infliximab (Inflectra, Hospira; Remsima, Celltrion) have a marketing authorisation in the UK for the same indications. The therapeutic indications, dosage and method of administration for Remsima and Inflectra are identical to those for infliximab. Adverse reactions are also similar. Both Inflectra and Remsima did not have an approved list price in the UK at the time of the appraisal.

4    Evidence and interpretation

The Appraisal Committee (section 8) considered evidence from a number of sources (section 9).

     Clinical effectiveness

Adult population

4.1     The Assessment Group’s systematic review identified 9 relevant randomised controlled trials (RCTs) in adults: ULTRA1, ULTRA2 and Suzuki et al. for adalimumab; PURSUIT-SC and PURSUIT-Maintenance for golimumab; and ACT1, ACT2, Probert et al. and UC-SUCCESS for infliximab. All the RCTs were multicentre, double-blind trials that were conducted worldwide (except the study by Suzuki et al. which was conducted in Japan only and the study by Probert et al. which was conducted in the UK and Germany). Apart from UC-SUCCESS which compared infliximab with azathioprine or with infliximab plus azathioprine, all the trials compared adalimumab, golimumab or infliximab with placebo. Most trials included licensed and unlicensed doses of the treatment; only the results for the licensed doses are presented here. Of the 9 trials identified by the Assessment Group, 4 followed up patients in open-label extension studies (ULTRA1, ULTRA2, ACT1 and ACT2). Because no head-to-head evidence was available from RCTs for adalimumab, golimumab or infliximab, the Assessment Group performed a network meta-analysis using the placebo-controlled RCTs for each treatment (that is, an analysis combining direct and indirect evidence for particular pairwise comparisons).

4.2     All the RCTs except the study by Probert et al. used the Mayo score to assess the eligibility of patients. The Mayo score assesses 4 outcomes – stool frequency, rectal bleeding, endoscopic findings and physician’s global assessment – on a scale of 0 to 12, with the score increasing with disease severity. In all these trials patients were eligible if they had a Mayo score of 6 to 12 with disease identified by endoscopic examination, which represents moderate to severe disease. Probert et al. used instead the ulcerative colitis symptom score, but the Assessment Group considered this to be equivalent to the Mayo score. Conventional therapies that patients had to have been treated with before varied across the trials but generally included corticosteroids, aminosalicylates and/or a drug that affects the immune response. Only in ULTRA2 were patients allowed to have had a previous TNF-alpha inhibitor (40% of patients had been treated with one). Patients were excluded from the trials if they had any of the following: ulcerative proctitis (ulcerative colitis that is limited to the rectum), a history of or a risk of having bowel surgery, diseases of the central nervous system, previous serious infection or a deficient immune system, previous cancer, or dysplasia (signs of abnormal growth of cells).

4.3     The average age of patients in the included RCTs ranged from 37 to 42.5 years, 41 to 73% were male and the average duration of disease was 4.9 to 8.5 years. Mayo scores at baseline were consistent across the trials and ranged from 8.1 to 8.9. The Assessment Group noted that none of the trials included patients who had been treated before with corticosteroids and mercaptopurine or azathioprine, even though adalimumab, golimumab and infliximab are licensed for patients whose disease has had an inadequate response to, or who are intolerant to or have medical contraindications for, such therapies. Specifically, UC-SUCCESS included patients if they had not had azathioprine either at all or within the 3 months preceding randomisation; as a result, 90% of the patients enrolled in the trial had not had azathioprine before. In addition, Suzuki et al. included Japanese patients aged 15 years or older; the Assessment Group considered it appropriate to use this trial for the adult population, however, because the average age of patients was over 40 years.

4.4     The primary end point in all the RCTs was clinical response or remission at pre-specified time points. Of the 9 trials in adults, 8 assessed how well the treatment induced clinical response or remission, and 6 assessed how well it maintained it (5 trials assessed both). To assess clinical response or remission, all trials except the study by Probert et al. used the Mayo score, which the Assessment Group considered to be applied consistently in the individual trials. Probert et al. used the ulcerative colitis symptom score. In the trials that used the Mayo score, clinical response was generally defined as:

• a decrease in Mayo score from baseline of at least 3 points and at least 30%, and
• a decrease in the rectal bleeding sub-score from baseline of at least 1 point, or having an absolute rectal bleeding sub-score of 0 or 1.

Similarly, the definition of remission was broadly the same across the RCTs: Mayo score of 2 or less, with no individual sub-score greater than 1.

Adalimumab

4.5     In ULTRA1, 18.5% of patients who were treated with adalimumab 160 mg at week 0 and 80 mg at week 2 (the licensed dose) were in remission at week 8 compared with 9.2% of those who had placebo, a result that was statistically significant (p=0.031). A higher proportion of patients in the adalimumab group had a clinical response (54.6% compared with 44.6%) but the difference was not statistically significant. In ULTRA2, the rate of remission was higher in patients treated with adalimumab than in those treated with placebo both at week 8 (16.5% compared with 9.3%; p=0.019) and at week 52 (17.3% compared with 8.5%; p=0.004). The difference at both time points was statistically significant. Of patients who were in remission at week 8, 8.5% of those having adalimumab and 4.1% of those having placebo remained in remission at week 52 (p=0.047). The open-label extension study ULTRA3 showed that patients generally continued to benefit from adalimumab therapy up to week 60, although 23% did not benefit and stopped treatment.

4.6     The incidence of adverse events was similar with adalimumab or placebo in ULTRA1 (50.2% compared with 48.4%, respectively) and ULTRA2 (82.9% compared with 83.8%). The most frequently reported adverse event in both RCTs was worsening or flare up of ulcerative colitis (ULTRA1: adalimumab 5.8%, placebo 9.4%; ULTRA2: adalimumab 22.6%, placebo 29.2%). The difference in the incidence of adverse events between the adalimumab and the placebo groups was statistically significant only for iron deficiency anaemia, gastroenteritis, and nasopharyngitis, although the incidence was higher with adalimumab for all adverse events. Most adverse events were mild or moderate in severity. In ULTRA2, more patients randomised to placebo stopped treatment because of an adverse event (13.1%) than did patients randomised to adalimumab (8.9%).

4.7     ULTRA1 and ULTRA2 reported health-related quality of life data for adalimumab measured using the Inflammatory Bowel Disease Questionnaire (IBDQ) or Short Form-36 (SF-36) (IBDQ scores range from 32 [poor health] to 224 [perfect health]). In ULTRA1, changes from baseline scores on IBDQ and SF-36 at week 8 were similar in the adalimumab (160 mg at week 0 and 80 mg at week 2) and placebo groups. In ULTRA2, however, changes in IBDQ scores at week 52 were higher in the adalimumab group (27 compared with 19; p<0.05).

4.8     In the study by Suzuki et al., patients were randomised to a licensed or unlicensed dose of adalimumab or to placebo. Results were reported at 8 weeks and 52 weeks, but the 2 adalimumab groups were combined for the analysis at 52 weeks. At week 8, remission rates were similar among treatment groups, but more patients treated with adalimumab 160 mg at week 0 and 80 mg at week 2 (the licensed dose) had a clinical response than did patients treated with placebo (50% compared with 35%; p=0.044). At week 52, more patients having adalimumab maintenance therapy had a clinical response (18% compared with 31%; p=0.021) and remission (7% compared with 23%; p=0.001) than did patients having placebo.

Golimumab

4.9     PURSUIT-SC was an integrated trial that included a double-blind dose-finding study and a dose confirmation study. In the dose confirmation study, rates of clinical response at week 6 were 51.0% among patients who had golimumab 200 mg followed by golimumab 100 mg (the licensed dose), and 30.3% among those who had placebo, a difference that was statistically significant (p<0.0001). The golimumab group was also associated with a statistically significantly higher rate of remission than the placebo group (17.8% compared with 6.4%; p<0.0001). Patients who had golimumab (200 mg then 100 mg) reported experiencing a greater change in IBDQ scores from baseline to week 6 than did patients having placebo (27.0 compared with 14.8, p<0.0001).

4.10    In PURSUIT-Maintenance patients whose disease had responded to golimumab induction therapy in 2 previous golimumab trials (including PURSUIT-SC) were randomised to golimumab 50 mg, golimumab 100 mg or to placebo. Clinical response was maintained through week 54 in 47.0% of patients who had 50 mg golimumab, 49.7% of patients who had 100 mg golimumab and 31.2% of patients who had placebo (p=0.010 and p<0.001 respectively). The proportion of patients who were in remission at both weeks 30 and 54 was higher in the golimumab 100 mg group (27.8%) and the golimumab 50 mg group (23.2%) than in the placebo group (15.6%; p=0.004 and p=0.122 respectively), although the difference between golimumab 50 mg and placebo was not statistically significant. Because PURSUIT-Maintenance included patients whose disease had responded to golimumab induction therapy in 2 earlier trials, the Assessment Group indicated that the results of PURSUIT-Maintenance may be biased.

4.11    In PURSUIT-Maintenance, the number of adverse events was similar in the golimumab 50 mg and 100 mg groups. However, the rate at which patients had serious adverse events or stopped treatment because of an adverse event was higher in the 100 mg group. Among patients having golimumab 50 mg, 8.4% had a serious adverse event and 5.2% stopped treatment because of an adverse event, compared with 14.3% and 9.1% respectively for patients having golimumab 100 mg (most patients who stopped treatment did so because their disease got worse).

Infliximab

4.12    In both the ACT1 and ACT2 trials, clinical response at week 8 occurred in a higher proportion of patients who were treated with infliximab 5 mg/kg (the licensed dose) than in patients treated with placebo (ACT1: 69% compared with 37%, p<0.001; ACT2: 65% compared with 29%, p<0.001). Patients who had infliximab were also more likely to have a clinical response at week 30 than patients who had placebo (p≤0.002 in both studies). In ACT1, clinical response at week 54 was reported for 46% of patients who had infliximab 5 mg/kg compared with 20% of those who had placebo (p<0.001). A statistically significant improvement in quality of life was observed in the infliximab group compared with the placebo group.

4.13    In ACT1 and ACT2, similar proportions of patients in the infliximab and placebo groups had an adverse event. However, more adverse events occurred among patients having infliximab in ACT1 than among those having it in ACT2 (87.6% compared with 81.8%). The most common adverse event in ACT1 was worsening of ulcerative colitis (infliximab 19.0%, placebo 33.1%), whereas in ACT2 it was headache (infliximab 15.7%, placebo 14.6%). There were more serious adverse events reported by patients having placebo in both RCTs (ACT1: infliximab 21.5%, placebo 25.6%; ACT2: infliximab 10.7%, placebo 19.5%). Stopping treatment because of an adverse event was more common in the placebo group than in the infliximab group in both studies.

4.14    Probert et al. reported remission rates (ulcerative colitis symptom score less than 2) of 39% in the infliximab group and 30% in the placebo group at week 6, a difference of 9% that was not statistically significant (95% confidence interval [CI] −19 to 34%; p=0.76). At that time, health-related quality of life measured using IBDQ and EQ-5D improved more with infliximab than with placebo (p-value not reported). In UC-SUCCESS, a greater proportion of patients who had infliximab plus azathioprine were in corticosteroid-free remission at week 16 (39.7%) than patients who had infliximab alone (22.1%; p=0.017) or azathioprine alone (23.7%; p=0.813). The greatest changes in IBDQ and SF-36 scores from baseline were for infliximab plus azathioprine (for both IBDQ and SF-36 score changes, p<0.05 compared with azathioprine alone or with infliximab alone).

4.15    Inflectra and Remsima are biosimilar products to infliximab that were developed as a single product, CT-P13. CT-P13 was compared with Remicade (the reference proprietary product) in 2 RCTs:

• PLANET-AS: a trial comparing the pharmacokinetics, efficacy and safety of CT-P13 and Remicade in patients with ankylosing spondylitis (n=250).
• PLANET-RA: a trial comparing the efficacy and safety of CT-P13 and Remicade in patients with rheumatoid arthritis whose disease had an inadequate response to methotrexate (n=606).

The objective of these trials was to demonstrate that CT-P13 was similar to the reference product. The European Public Assessment Reports (EPARs) for Inflectra and Remsima acknowledged that the pharmacokinetics, efficacy, safety, and immunogenicity profiles of CT-P13 were similar to those of Remicade in PLANET-AS and PLANET-RA. Although neither of the trials was for ulcerative colitis, the EPAR states that the totality of the data comparing CT-P13 with Remicade allows for the extrapolation of the evidence generated by PLANET-AS and PLANET-RA to all other indications of Remicade.

Network meta-analysis

4.16    Because no RCTs compared adalimumab, golimumab or infliximab directly with each other, the Assessment Group performed a network meta-analysis using the placebo-controlled RCTs for each intervention. RCTs were eligible for inclusion if they reported data on both clinical response and remission at either an induction (6 to 8 weeks) or maintenance (30 or 52 weeks) time point. Although the study by Probert et al. and UC-SUCCESS provided this, the Assessment Group did not include them because the definitions of clinical response and remission in Probert et al. differed from the other trials and most patients in UC-SUCCESS had not had azathioprine before. ULTRA2 was the only trial to include patients who had been treated before with a TNF-alpha inhibitor and also those who had not. For its base case, the Assessment Group used the data relating only to patients who had not had TNF-alpha inhibitors before. It also excluded the study by Suzuki et al. from the base case because this study was conducted in Japanese patients only. However, the Assessment Group did 3 sensitivity analyses: firstly using data for the overall population in ULTRA2 (patients who had been treated with a TNF-alpha inhibitor before and also those who had not); secondly, including Suzuki et al.; and thirdly, combining these 2 analyses together.

4.17    For the base case and each of the sensitivity analyses, the Assessment Group compared the effects of adalimumab, golimumab, and infliximab with respect to each of the following:

• induction of clinical response or remission at week 8
• maintenance of clinical response or remission at week 32 for patients starting with a clinical response at week 8
• maintenance of clinical response or remission at week 32 for patients starting in remission at week 8
• maintenance of clinical response or remission at week 52 for patients starting with a clinical response at week 32
• maintenance of clinical response or remission at week 52 for patients starting in remission at week 32.

The Assessment Group used between 3 and 5 RCTs to perform the network meta-analysis for each of the above-listed outcomes, noting mild to moderate heterogeneity between individual study results in all the analyses. For each outcome, the Assessment Group reported:

• the effect of each treatment compared with placebo and with the other treatments on the probit scale (where negative values indicate that the intervention is more effective than the comparator) together with credible intervals (CrI)
• the probability of each treatment being ranked the best, second-best, third-best and so on
• the probability of the disease being active, responding and remitting at the end of therapy (week 8 for induction and week 32 or 52 for maintenance) with each treatment.

4.18    In the Assessment Group’s base case, all treatments had a statistically significant favourable effect compared with placebo when assessed for induction therapy. The greatest effect on inducing clinical response or remission was associated with infliximab ( effect relative to placebo −0.92, 95% CrI −1.27 to −0.56), which had a 93% probability of being the best treatment for that outcome. The probability of the disease remaining active, responding or remitting after 8 weeks of infliximab therapy was 29%, 35% and 36% respectively.

4.19    For maintenance therapy, the Assessment Group reported the following results:

• Maintenance of clinical response or remission at week 32 for patients starting with a clinical response at week 8: golimumab 100 mg had the greatest effect compared with placebo, but the effect was not statistically significant (−0.42, 95% CrI −1.06 to 0.21). The probability of golimumab 100 mg being the best treatment for that outcome was 47%. At the end of the maintenance therapy with golimumab 100 mg, the probability of the disease remaining active, responding or remitting was 37%, 29% and 35% respectively.
• Maintenance of clinical response or remission at week 32 for patients starting in remission at week 8: golimumab 50 mg had the greatest effect compared with placebo, but the effect was not statistically significant (−0.36, 95% CrI −1.33 to 0.62). The probability of golimumab 50 mg being the best treatment for that outcome was 47%. At the end of the maintenance therapy with golimumab 50 mg, the probability of the disease remaining active, responding or remitting was 18%, 14% and 69% respectively.
• Maintenance of clinical response or remission at week 52 for patients starting with a clinical response at week 32: infliximab had the greatest effect compared with placebo, but the effect was not statistically significant (−0.42, 95% CrI −1.06 to 0.21). The probability of infliximab being the best treatment for that outcome was 56%. At the end of the maintenance therapy with infliximab, the probability of the disease remaining active, responding or remitting was 25%, 34% and 41% respectively.
• Maintenance of clinical response or remission at week 52 for patients starting in remission at week 32: adalimumab had the greatest effect compared with placebo, which was statistically significant (−1.04, 95% CrI −1.93 to −0.12). The probability of adalimumab being the best treatment for that outcome was 84%. At the end of the maintenance therapy with adalimumab, the probability of the disease remaining active, responding or remitting was 8%, 8% and 83% respectively.

4.20    In all 3 sensitivity analyses, infliximab had the greatest effect on inducing clinical response or remission, as in the base case. For maintenance therapy, the best treatment for each outcome was also the same as in the base case in all sensitivity analyses.

Child and adolescent population

4.21    The Assessment Group identified 1 open-label RCT in children and adolescents, by Hyams et al., which evaluated infliximab as maintenance therapy. Patients initially had 5 mg/kg infliximab induction therapy at weeks 0, 2 and 6. Patients whose disease responded were then randomised to one of 2 infliximab maintenance groups: infliximab 5 mg/kg every 8 weeks (n=22) or infliximab 5 mg/kg every 12 weeks (n=23). Eligible patients were 6 to 17 years old, had moderately to severely active ulcerative colitis defined as a Mayo score of 6 to 12 (with disease identified endoscopically), and had been treated before with at least 1 conventional treatment (aminosalicylates, a drug that affects the immune response or corticosteroids). The primary end point was clinical response assessed at week 8 for induction therapy (before randomisation) and week 54 for maintenance therapy. Remission, a secondary end point, was defined as a Paediatric Ulcerative Colitis Activity Index (PUCAI) score of less than 10 (a PUCAI score of 65 or more reflects severe disease). Infliximab is licensed in children and adolescents for treating severely active ulcerative colitis only, but Hyams et al. included only patients with moderately to severely active disease. Because the Assessment Group did not identify any RCTs comparing infliximab with placebo or with other active treatments in children and adolescents, it included Hyams et al. despite it being for moderately to severely active disease.

4.22    At week 8, 73.3% (44/60) of patients had a clinical response to infliximab and 40.0% (24/60) were in remission. Of those who had a response, a greater proportion of patients who then had infliximab 5mg/kg every 8 weeks were in PUCAI remission at week 54 than patients who had infliximab 5 mg/kg every 12 weeks (38.1% compared with 18.2%; p-values not reported). In addition, 38.5% and 0.0% of patients who had infliximab every 8 weeks or every 12 weeks, respectively, were in PUCAI remission without the use of corticosteroids at week 54. No health-related quality of life data were available from Hyams et al.

4.23    All patients in the study by Hyams et al. reported having at least 1 adverse event. By week 54, more patients having infliximab every 12 weeks had stopped treatment because of an adverse event than patients having infliximab every 8 weeks (6/23 [26.1%] compared with 3/22 [13.6%]). The number of patients who had 1 or more serious adverse event, infections, or reactions at the site of administration was similar in both infliximab groups.

Comments from other consultees

4.24    Patient experts indicated that, because of the symptoms of ulcerative colitis (for example, irregular sleeping patterns, pain and fatigue) and the unpredictable pattern of disease flare-ups, education, employment, personal relationships, and social and family life are affected. In addition, the frequent and urgent need to go to the toilet affects self-esteem and social functioning, and can cause anxiety about loss of bowel control if left untreated. Patient experts also noted that ulcerative colitis presents at an early age when people are beginning their career and long-term relationships. They indicated that 30% of patients continue to experience flare-ups or chronic symptoms despite conventional therapy, so TNF-alpha inhibitors offer hope to these patients and can help them resume their normal lives. However, it was noted that access to TNF-alpha inhibitors is currently limited to patients who are able to secure exceptional funding through their clinical commissioning group. This sometimes leaves the patient without adequate treatment until their disease becomes so severe that they may require emergency surgery.

4.25    Comments from professional groups indicated that ulcerative colitis is a challenging condition to treat, particularly in patients with disease that does not respond to conventional therapy who, as a result, have a reduced quality of life and often no treatment options but colectomy and the formation of an ileostomy (that is, the diversion of the small intestine through an opening in the abdomen). Comments indicated that often this surgery is needed in young people in whom a stoma (the artificial opening made into the abdomen) may be socially disadvantaging. In addition, young patients, who may not have started a family, often delay or dismiss ileo-anal pouch anastomosis (by which an internal reservoir for stool is surgically created) because this is a surgery in the pelvis that can affect fertility. For these patients, therefore, TNF-alpha-inhibitor therapy is a valuable option because it can avoid surgery when the patient is in education, has not formed permanent relationships or a family, or risks losing employment because of their illness. Comments noted, however, that it is difficult to extrapolate from seemingly uniform clinical trials, with rigid inclusion criteria, to assess the impact of TNF-alpha-inhibitor therapy on patients’ quality of life compared with surgery.

4.26    Professional groups highlighted that the ACT1 and ACT2 trials showed a statistically significant reduction in the rate of colectomy at week 54 in 10% of patients who had infliximab compared with 17% of those who had placebo. It was also noted that long-term follow-up data from ACT1 and ACT2 demonstrated a persistent response to infliximab and low rates of colectomy at up to 4 years after starting treatment. Patient experts also indicated that the risk of colon cancer increases after 8 to 10 years of active disease and that TNF-alpha inhibitors may decrease it. Statements from patients with ulcerative colitis suggested that infliximab is an effective treatment that prevented symptoms from recurring and helped patients maintain a good health state for long periods, although it caused reactions in some patients when first taken. Comments from professional groups stated that, while the clinical evidence base is smaller for adalimumab and golimumab than for infliximab, there are high-quality data with broadly similar results to infliximab for both treatments. Patient experts stated that although TNF-alpha inhibitors are relatively expensive, they reduce the costs of other services, which may offset the high drug costs in the long term.

4.27    Comments from professional groups noted that NICE guidance on TNF-alpha-inhibitor therapy differs for Crohn’s disease and ulcerative colitis, resulting in TNF-alpha inhibitors being widely available for Crohn’s disease but not for ulcerative colitis. The comments indicated that there is growing evidence that Crohn’s disease and ulcerative colitis share common genetic factors, making it difficult to differentiate between them clinically. In addition, both diseases can be associated with chronic active symptoms that do not respond to conventional therapy. The comments summarised that the benefit of TNF-alpha inhibitors for ulcerative colitis will be similar to that for Crohn’s disease, and so guidance for these 2 conditions should also be similar.

4.28    Clinical experts stated that outcomes should explicitly include rates of corticosteroid-free remission. They also advised that treatment goals beyond symptom control and improved quality of life, such as complete mucosal healing and reduced complication rates, are important. Patients who had infliximab stated that the side effects of corticosteroids, notably rounded face and severe acne, lower self-esteem and that TNF-alpha inhibitors can help overcome these problems because they allow the patient to reduce the dose of corticosteroids.

Cost effectiveness

4.29    The Assessment Group’s systematic review of the cost-effectiveness evidence identified 3 published economic evaluations of TNF-alpha inhibitors for ulcerative colitis. However, the Assessment Group did not consider any of these evaluations to provide sufficient evidence on the cost-effectiveness of TNF-alpha inhibitors from a UK perspective. This was mainly because the models did not accurately reflect the natural history of the disease, made questionable assumptions about the relative effectiveness of TNF-alpha inhibitors and used short time horizons.

Company’s model: adalimumab

4.30    The company’s analysis compared the cost-effectiveness of adalimumab plus conventional therapy with conventional therapy alone for moderately to severely active ulcerative colitis that had responded inadequately to conventional therapy. The population in the base case comprised both patients who had been treated before with a TNF-alpha inhibitor other than adalimumab and also those who had not. The company also presented a sensitivity analysis in which it modelled only patients who had not previously had a TNF-alpha inhibitor. The analysis estimated the direct healthcare costs to the NHS and quality-adjusted life years (QALYs) over a 10-year time horizon using a cycle length of 2 weeks.

4.31    The company used a Markov model simulating 8 states: 3 states before surgery (‘remission’, ‘mild’, and ‘moderate-to-severe’), 1 ‘surgery’ state, and 4 states after surgery (‘post-surgery without complication’, ‘transient complication’, ‘chronic complication’, and ‘surgery-related death’). The company derived the probabilities of patients moving between states before surgery primarily from ULTRA2 and the extension study ULTRA3. It derived the transition probabilities for the surgery and post-surgery states based on published literature.

4.32    The company assigned a utility value to each state in the model. ULTRA2 collected health-related quality of life data using the Short Form-36 (SF-36) survey but the company did not transform these data to SF-6D, arguing that this may overestimate the utility value for patients who had severe disease in ULTRA2. Instead, it obtained the utility values for the states before surgery from a study by Swinburn et al. and those for the states after surgery mainly from a study by Tsai et al. The model included costs associated with: the drug, disease state, hospitalisation, surgery, complications after surgery, and surgery-related death. All costs were derived from published literature.

4.33    The base-case ICER for adalimumab plus conventional therapy compared with conventional therapy alone was £34,417 per QALY gained. When the company varied the key parameters in the model 1 at a time, ICERs ranged from £29,437 to £38,073 per QALY gained. The probability of adalimumab plus conventional therapy being cost-effective compared with conventional therapy alone, at a maximum acceptable ICER of £30,000 per QALY gained, was 30%. In the sensitivity analysis relating to patients who had not been treated before with a TNF-alpha inhibitor, the ICER for adalimumab plus conventional therapy was close to the base-case ICER at £35,970 per QALY gained.

4.34    The Assessment Group critiqued the company’s decision problem and stated that the company – having excluded other TNF-alpha inhibitors (golimumab and infliximab) and surgery as comparators – deviated from the final scope. In addition, it stated that the company used a shorter cycle length than the time point for assessing induction in ULTRA2 (6 weeks); did not transform the data collected in ULTRA2 using SF-36 to SF-6D utility values; assumed that surgery improves the utility score by only 0.06 compared with active disease; and inaccurately modelled the rate at which patients had surgery.

Company’s model: golimumab and infliximab

4.35    The company’s model compared adalimumab, golimumab and infliximab with each other and with colectomy for moderate to severe ulcerative colitis that had failed previous treatment. Conventional therapy was not a comparator in the analysis. The company chose a cycle length of 2 months and a 10-year time horizon. The perspective on costs was that of the NHS. Costs and health effects were discounted at an annual rate of 3.5%.

4.36    The company’s model was hybrid in that it used a ‘decision tree’ to model the probabilities of TNF-alpha inhibitors inducing a response or remission, and the probabilities of surviving and of having surgery-related complications after colectomy; then a Markov model (simulating 11 states) to estimate the long-term outcomes of maintenance therapy and colectomy. If patients had responding or remitting disease at the end of induction therapy, they had maintenance therapy. Patients whose disease did not respond to induction therapy, and those in whom previous response was lost during maintenance therapy, had intravenous corticosteroids. They could then continue on corticosteroids or have colectomy. The probabilities of patients moving between states in the induction and maintenance phases were based on network meta-analyses conducted by the manufacturer.

4.37    Costs and utility values were attached to each state. The model incorporated the patient access scheme for golimumab. Utility values were based on PURSUIT-SC in the golimumab model and on ACT1 in the infliximab model. Golimumab and infliximab were assumed to be administered at the licensed dose. For adalimumab, the company used the licensed induction dose regimen of 160 mg at week 0 and 80 mg at week 2, but after induction it assumed that 50% of patients have the licensed initial maintenance dose of 40 mg every other week while the other 50% have 40 mg every week. The company stated that this was because 22.9% of patients in the ULTRA2 trial had 40 mg every week instead of every other week. However, it also stated that, based on clinical advice, up to 80% of patients would have weekly doses in clinical practice. The company assumed that in each treatment group some patients also have background conventional therapy.

4.38    The company presented the cost-effectiveness results as pairwise ICERs (that is, ICERs comparing technologies head-to-head rather than incrementally from the least costly to the most costly). It reported ICERs of £27,994 per QALY gained for golimumab compared with colectomy, and £80,318 saved per QALY lost for golimumab compared with infliximab; compared with adalimumab, golimumab was more effective and less expensive. For infliximab, the ICERs were £38,307 per QALY gained compared with colectomy, £54,564 per QALY gained compared with adalimumab, and £75,998 per QALY gained compared with golimumab.

4.39    The Assessment Group critiqued the models for golimumab and infliximab together because they were submitted by the same company and were identical. It stated that the company’s analysis was generally in line with the NICE reference case, but deviated from the final scope in that conventional therapy was not included as a comparator. Furthermore, it stated that the company – having assumed that patients can only have corticosteroids or colectomy after TNF-alpha-inhibitor therapy fails – modelled a treatment pathway associated with severe disease, not moderate to severe disease for which further medical treatment would still be considered. The Assessment Group also indicated that the company did not describe its network meta-analyses in sufficient detail, did not explain how it estimated the probabilities of moving between states, and did not justify the selection of the data sources for certain parameters. The 2 company models used different sources for the utility values and made different assumptions about resource use, which the Assessment Group did not consider appropriate given that the 2 models addressed identical decision problems. The Assessment Group indicated that in an incremental analysis, infliximab should be compared with golimumab, which results in ICERs of approximately £76,000 to £80,000 per QALY gained.

Assessment Group’s model   

4.40    The Assessment Group developed a de novo economic model to assess the cost-effectiveness of adalimumab, golimumab and infliximab (at their licensed doses) compared with each other and with conventional therapy or surgery for moderate to severe ulcerative colitis that had failed at least 1 previous therapy. Conventional therapy comprised corticosteroids, aminosalicylates and drugs that affect the immune response. The Assessment Group used a lifetime time horizon which it divided into 2 phases, induction and maintenance. The cycle length for the induction phase was 8 weeks and for the maintenance phase it was 26 weeks. The perspective of the analysis was that of the NHS and personal social services, and costs and health effects were discounted at an annual rate of 3.5%. The model was fully probabilistic (that is, produced results by varying the input parameters simultaneously with values from a probability distribution).

4.41    The Assessment Group’s model was a state-transition Markov cohort model simulating 8 states:

• on biological therapy (adalimumab, golimumab or infliximab) – active disease (that is, no response or remission)
• on biological therapy – response
• on biological therapy – remission
• on conventional therapy – active disease
• on conventional therapy – response
• on conventional therapy – remission
• post-surgery (with or without complications)
• dead.

Surgery was incorporated as an event rather than a state (that is, patients had colectomy then moved to the post-surgery state if they survived or to the death state if not). The probability of patients moving between states was based on the Assessment Group’s network meta-analysis. The model used the same definitions of clinical response and remission as the RCTs identified from the systematic review (see section 4.4).

4.42    The Assessment Group assumed that patients enter the model at the age of 40 years and have an average body weight of 77 kg, in line with the patient characteristics in the RCTs. In the model, all patients started in the induction phase and had biological or conventional therapy, or had surgery (early colectomy). Patients who had TNF-alpha-inhibitor therapy were assumed to also have conventional background therapy. If the TNF-alpha inhibitor led to a clinical response or remission, the patient continued on the same treatment in the maintenance phase; if not, they stopped that treatment and had conventional therapy. Patients who continued TNF-alpha-inhibitor therapy in the maintenance phase had it for as long as response or remission was maintained; if response was lost, they moved to conventional therapy. Patients who started on conventional therapy and those who started on a TNF-alpha inhibitor but then moved to conventional therapy continued conventional therapy in the maintenance phase whether or not their disease responded or remitted, but they could have colectomy if their disease remained active. Therefore, colectomy was included in the analysis both as a comparator (early colectomy) and as an intervention further down the treatment pathway after biological or conventional therapy. All patients who had colectomy remained in the post-surgery state until they died.

4.43    To derive the rate at which patients have colectomy, the Assessment Group used a study by Solberg et al. estimating that every 6 months 0.51% of patients have colectomy. Based on another study by Arai et al., it assumed that 47.3% and 5% of those patients will develop transient or chronic complications respectively. In patients who survived surgery, all transient complications were assumed to occur and resolve during the first cycle after surgery, whereas chronic complications continued until the patient died.

4.44    The model included 2 types of mortality: mortality during colectomy and mortality from causes other than ulcerative colitis and colectomy. The Assessment Group assumed that 3% of patients who had colectomy died during surgery, an estimate it obtained from the UK Inflammatory Bowel Disease audit. All patients in the model had a probability of dying from other causes, which the Assessment Group modelled based on data from the Office for National Statistics.

4.45    In the model, the patient’s health-related quality of life depended on the outcome of drug therapy (whether the disease remained active, responded or remitted), whether the patient had colectomy, and if so, whether they developed complications afterwards. It did not depend on whether the patient had biological or conventional therapy. The Assessment Group stated that the studies by Woehl et al. and Swinburn et al. were the most useful to source utility values in the model because they were UK-based, included reasonably large number of patients (n=180 and n=230 respectively) and reported EQ-5D utility values for most states in the model:

• Woehl et al.: patients in the study may or may not have had surgery. Among patients who did not have surgery, utility values were reported to be 0.87 (standard deviation [SD] 0.15) for remitting disease, 0.76 (SD 0.18) for mild disease, and 0.41 (SD 0.34) for moderate to severe disease. These categories of disease severity were based on the Simple Colitis Activity Index. The Assessment Group assumed that the utility value for moderate to severe disease that responded to treatment was equal to the value for mildly active disease in Woehl et al. (0.76). In patients who had surgery, the utility value was 0.71, which the Assessment Group adjusted to account for the effect of chronic complications after colectomy on the patient’s quality of life, estimating a utility value of 0.70 in the post-surgery state.
• Swinburn et al.: of the 230 patients included in the study, 30 had previously had surgery. EQ-5D utility values were collected through an online survey across different categories of disease severity measured using the IBDQ. The utility value for patients who had surgery was 0.59 (95% CI 0.55 to 0.63). For patients who did not have surgery, utility values were 0.91 (95% CI 0.87 to 0.95) for remitting disease (n=78); 0.80 (95% CI 0.70 to 0.85) for mild disease (n=47); 0.68 (95% CI 0.58 to 0.78) for moderate disease (n=31); and 0.45 (95% CI 0.35 to 0.55) for severe disease (n=44). Because the model included patients who had ‘moderate to severe disease’ (rather than moderate or severe disease), the Assessment Group averaged the utility values for ‘moderate’ and ‘severe’ disease in Swinburn et al. to derive a value for moderately to severely active disease that did not respond to treatment. It also assumed that the utility value for moderate to severe disease that responded to treatment was equal to the value for mildly active disease in Swinburn et al. (0.80). The Assessment Group noted that Swinburn et al. reported that utility values were, on average, lower in patients who had surgery than in those who did not (p=0.016).

The Assessment Group chose to use values from Woehl et al. in its base case and from Swinburn et al. in a sensitivity analysis (see section 4.50). This was because the utility value after surgery in Woehl et al. (0.71) was more consistent with those reported in other studies than that from Swinburn et al (0.59).

4.46    The Assessment Group modelled the cost of adalimumab, golimumab and infliximab assuming that each treatment would be administered at its licensed dosage. However, it assumed that a fixed proportion of patients (27%) have adalimumab 40 mg as maintenance therapy every week instead of every 2 weeks (the licensed regimen) based on data reported in the company’s submission for adalimumab. The summary of product characteristics for golimumab recommends that therapy should be reconsidered in patients who do not benefit within 12 to 14 weeks after starting treatment (that is, after 4 doses). However, only the first 2 doses of golimumab were costed in the induction phase. This was because PURSUIT-SC, from which the data for golimumab were obtained, evaluated golimumab after 2 doses (at week 6). Only infliximab incurred administration costs in the model (adalimumab and golimumab are administered subcutaneously and so are not associated with administration costs). The model incorporated the patient access scheme for golimumab. For conventional therapy, the Assessment Group assumed that in both the induction and maintenance phases, 100% of patients have corticosteroids and aminosalicylates, 80% have mercaptopurine, and 20% have azathioprine. Costs associated with consultant visits, endoscopy, hospitalisation, blood tests and surgery (including surgery-related complications) were also included in the model.

4.47    The Assessment Group presented results for patients in whom colectomy is a potential option, and separately for those in whom it is not. In addition, it performed one-way sensitivity analyses, varying parameters in the model 1 at a time. The parameters varied included the dataset used to estimate clinical effectiveness, the time horizon, utility values, health state costs, and assumptions around hospitalisations, surgery and chronic complications after surgery.

For patients in whom colectomy is an option

4.48    The Assessment Group’s probabilistic base-case results estimated that colectomy provides 14.72 QALYs at a cost of £41,921. Adalimumab, golimumab, infliximab and conventional therapy were dominated by colectomy; that is, they provided fewer QALYs at a higher cost than colectomy.

4.49    The probability of colectomy being the most cost-effective treatment at maximum acceptable ICERs of £20,000 and £30,000 per QALY gained was 97% and 96% respectively. Adalimumab, golimumab and infliximab had a 0% probability of being cost-effective compared with colectomy at these maximum acceptable ICERs.

4.50    In all one-way sensitivity analyses but 1, adalimumab, golimumab and infliximab were dominated by colectomy. This result changed only when the Assessment Group incorporated utility values (except post-surgical complications) from Swinburn et al. In this analysis, colectomy became the least effective option. In the incremental analysis, golimumab and conventional therapy were dominated and excluded from the analysis. Among the remaining alternatives, colectomy was the cheapest, followed by adalimumab then infliximab. The ICER for adalimumab compared with colectomy was £80,315 per QALY gained and that for infliximab compared with adalimumab was £179,374 per QALY gained.

For patients in whom colectomy is not an option

4.51    When medical options only were compared with each other, infliximab was dominated by adalimumab (although the difference in QALYs was small), and golimumab was extendedly dominated by adalimumab and conventional therapy (that is, a QALY was attained at a higher cost with golimumab than with adalimumab because the ICER for golimumab compared with conventional therapy [£97,149 per QALY gained] was higher than that for adalimumab compared with conventional therapy). The incremental ICER for adalimumab compared with conventional therapy was £50,624 per QALY gained.

4.52    At a maximum acceptable ICER of £20,000 per QALY gained, adalimumab had a 0% probability of being cost-effective compared with conventional therapy. Its probability of being cost-effective compared with conventional therapy at a maximum acceptable ICER of £30,000 per QALY gained was approximately 5%.

4.53    Because the difference in effectiveness between adalimumab and infliximab was small (0.01 QALY), the results were sensitive to the dataset used to estimate clinical effectiveness for TNF-alpha inhibitors. In all the sensitivity analyses in which alternative datasets were used, golimumab was extendedly dominated and excluded from the analyses. When the Assessment Group used data from ULTRA2 for the overall population or included data from Suzuki et al., infliximab provided more QALYs than adalimumab but the ICER for infliximab compared with adalimumab was greater than £250,000 per QALY gained in both analyses. For adalimumab compared with conventional therapy, the ICER was £54,309 per QALY gained in the first analysis and £56,656 per QALY gained in the second (compared with a base-case ICER of £50,624 per QALY gained). When the Assessment Group included data from ULTRA2 for the overall population and data from Suzuki et al. in the same analysis, infliximab was dominated by adalimumab; the ICER for adalimumab compared with conventional therapy was £56,014 per QALY gained. The Assessment Group also presented pairwise analyses comparing adalimumab, golimumab and infliximab head-to-head with conventional therapy using direct evidence from the respective RCTs. Compared with conventional therapy, the ICER for adalimumab was £70,075 per QALY gained, for golimumab it was £90,720 per QALY gained, and for infliximab it was £96,682 per QALY gained.

For children and adolescents

4.54    The Assessment Group presented a scenario analysis comparing infliximab with conventional therapy or colectomy in children and adolescents (golimumab and adalimumab are not licensed for this population). However, it advised that this analysis should be treated as exploratory because there were no RCTs comparing infliximab with placebo or with other active treatments in children and adolescents, so the data on the efficacy of infliximab were those provided by trials conducted in adults. This analysis differed from the base case in adults only in that the starting age of patients in the model was set to 15 years (the median age in the study by Hyams et al.).

4.55    In children and adolescents in whom colectomy is a potential option, colectomy provided 17.55 QALYs at a cost of £47,871. Infliximab provided fewer QALYs (13.01) at a higher cost (£106,759), and so was dominated by colectomy. There was a 0% probability of infliximab being cost-effective compared with colectomy or conventional therapy at a maximum acceptable ICER of £20,000 per QALY gained.

4.56    When colectomy was not a potential option, infliximab provided an additional 0.34 QALYs at an additional cost of £23,268 to conventional therapy, resulting in an ICER of £68,364 per QALY gained for infliximab compared with conventional therapy. There was a 0% probability of infliximab being cost-effectiveness compared with conventional therapy at a maximum acceptable ICER of £20,000 per QALY gained.

Limitations in the Assessment Group’s model

4.57    The Assessment Group listed the following as the main limitations in its model:

• There was considerable uncertainty associated with the extrapolation of short-term trial data (maximum 54 weeks) to a lifetime horizon.
• The model assumed that conventional therapy would not be given sequentially but that in any cycle, fixed proportions of patients would have corticosteroids, 5-aminosalicylates and drugs that affect the immune response.
• Evidence on the complications of colectomy was not identified through a systematic review.

Consideration of the evidence

The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of infliximab, adalimumab and golimumab, having considered evidence on the nature of ulcerative colitis and the value placed on the benefits of infliximab, adalimumab and golimumab by people with the condition, those who represent them, and clinical experts. It also took into account the effective use of NHS resources.

4.58    The Committee discussed with the clinical expert the treatment pathway for moderately to severely active ulcerative colitis. It heard that in UK clinical practice, standard practice for patients with moderately to severely active ulcerative colitis (but not acute disease) would be to start on conventional therapy. This may include corticosteroids and/or 5-aminosalicylates (for example, mesalazine), with the possibility of then adding on azathioprine. The clinical expert indicated that approximately 8 to10% of patients cannot tolerate azathioprine. At this point in the pathway, treatment becomes individualised and may include long-term corticosteroids or ciclosporin. Alternatively, a patient with ulcerative proctitis (where the inflammation is limited to the rectum) may use topical enemas. The Committee understood that if response to conventional therapy was inadequate, patients may have TNF-alpha-inhibitor treatment. After subsequent relapses, patients could have an alternative TNF-alpha inhibitor, conventional therapy or colectomy.

4.59    The Committee discussed the role of surgery in the management of ulcerative colitis and whether it was an appropriate comparator for TNF-alpha inhibitors. It understood that in clinical practice, colectomy would be avoided if possible, and that most patients who ultimately elect to have surgery would prefer 2 to 3 years of good quality of life on a TNF-alpha inhibitor to get them through particularly stressful periods in their life, and to allow them to come to terms with their disease and psychologically prepare for surgery. The Committee heard that there are patients for whom surgery is not an acceptable option. For these patients, if a TNF-alpha inhibitor cannot be offered, engagement with the patient may be lost and the patient becomes at risk of further complications including faecal incontinence, bowel cancer and being unable to work or socialise. The Committee understood that surgery itself, although potentially curative, does not fully restore the patient’s quality of life because for example, creating pouches could affect fertility in men and fecundity in women. As a result, some patients would only have a sub-total colectomy with a stoma in the first place to prevent having surgery in the pelvis, but stomas can affect social life and require continuous care. Although some of these patients will keep their stoma for life, others may then have to have further surgery to create a pouch and many young people delay this for many years (in some areas of the UK only 30 to 60% of patients end up having pouches). Patients in whom pouches are created will still need to wake up at night to go to the toilet and be on life-long anti-diarrhoeal medication. The Committee was also aware that surgery is associated with complications, including chronic pouchitis. The Committee concluded that conventional therapy was an ongoing option throughout the treatment pathway for moderately to severely active ulcerative colitis because most patients are unlikely to consider surgery until later (unless the patient has acute disease, which is not covered by this appraisal).

4.60    The Committee discussed with patient experts the nature of the condition and their experience with treatment. It heard that symptoms of ulcerative colitis include bloody diarrhoea, abdominal pain, weight loss, fatigue, irregular sleeping patterns, anaemia, and urgent need to defecate, which can profoundly affect the patient’s quality of life and disrupt their education, employment and family and social life. The Committee heard from patient experts that besides the symptoms of their disease which had a negative impact on their quality of life, the side effects of some conventional therapies also affected their emotional and physical wellbeing. The Committee appreciated that, as the peak age of onset of ulcerative colitis is 15 to 30 years, the side effects of using corticosteroids for prolonged periods, as well as having ulcerative colitis, can severely damage the patient’s confidence and self-esteem at a critical point in life when there may be other stressful events happening such as exams, university, forming relationships and beginning a family. The Committee heard how one of the patient experts who had needed long-term corticosteroid use could not stop it because when the dose was decreased, the symptoms of ulcerative colitis returned. The Committee also heard from the patient expert that they had tried azathioprine but this affected their white blood cell count so they had to stop using that too. Patient experts stated that with TNF-alpha inhibitors, the symptoms of ulcerative colitis had stopped, they felt ‘normal’ again, were able to work and lead a normal life and their quality of life improved. The Committee concluded that patients and clinicians considered TNF-alpha inhibitors to be a valuable option that could offer long-term remission to some patients with moderately to severely active ulcerative colitis.

4.61    The Committee heard from the clinical expert that ulcerative colitis shares common genetic factors with Crohn’s disease and that the 2 conditions overlap, which sometimes makes them clinically indistinguishable. The clinical expert noted that for Crohn’s disease, TNF-alpha inhibitors are available and provide symptom control in a significant proportion of patients, particularly in those with Crohn’s colitis. For ulcerative colitis, however, the expert indicated that TNF-alpha inhibitors are available only for patients with severe disease, and in whom ciclosporin is contraindicated or ineffective. The Committee noted that, in the clinical expert’s opinion, the benefit of TNF-alpha-inhibitor therapy for moderately to severely active ulcerative colitis will be similar to that for Crohn’s disease for which there is positive NICE guidance for using TNF-alpha inhibitors (NICE technology appraisal guidance 187).

4.62    The Committee discussed with the clinical expert the criteria for stopping treatment that are applied with TNF-alpha inhibitors. It understood that patients normally have induction therapy for 8 to 14 weeks before the response to treatment is assessed. If a response is not achieved by the end of the induction therapy, treatment is likely to be stopped. However, if only a slight response was achieved, patients and their clinician may or may not choose to stop treatment because there are no rigid criteria for stopping treatment in these circumstances. The Committee also heard that the difference between response and remission is clinically important because remission is typically associated with better long-term outcomes than response. The Committee noted that patient experts had not considered stopping infliximab while in remission because of the benefit they gained from treatment. The clinical expert indicated that, of patients who start TNF-alpha-inhibitor therapy, one-third to one-half are expected to continue treatment in the long term. The Committee noted that NICE guidance for Crohn’s disease recommends that clinicians reassess patients at 12 months and then annually to make sure the patient’s disease is still in remission; if not, then treatment is stopped. The Committee discussed with the clinical expert whether TNF-alpha inhibitors could be used in clinical practice for ulcerative colitis in the same way as they are for Crohn’s disease. It heard that this type of stopping rule could work in patients with ulcerative colitis but the clinical expert was not aware of any evidence from randomised controlled trials (RCTs) that shows what happens to patients with ulcerative colitis when treatment with a TNF-alpha inhibitor is stopped. The Committee also heard that when patients with Crohn’s disease stop TNF-alpha-inhibitor treatment, a small proportion would be expected to remain in total remission, but in 50% of patients their symptoms will worsen and they will need to change treatment.

4.63    The Committee discussed whether the RCTs identified by the Assessment Group were generalisable to UK clinical practice. It heard from the clinical expert that the inclusion criterion for disease severity used in the RCTs (Mayo score of 6 to12) represents patients who would be considered to have moderately to severely active disease in clinical practice in the NHS. However, the clinical expert pointed out that the trials typically excluded patients with ulcerative proctitis. They explained that this is a chronic condition with symptoms that do not respond to treatment but that it is not acute, so patients are not admitted to hospital even though their condition may be significantly disabling. In the clinical expert’s opinion, it is important to consider clinical effectiveness in these patients because their disease seems to respond to TNF-alpha-inhibitor treatment and they are not usually suitable for colectomy because of how the disease is distributed in their bowel. The Committee concluded that the RCTs were otherwise representative of patients in clinical practice.

4.64    The Committee discussed the RCTs for adalimumab, golimumab and infliximab. It noted that the proportion of patients whose disease responded or remitted in the RCTs meant that patients were still benefiting from medical treatment, and that the trials included patient populations in whom surgery was unlikely to be considered an acceptable option at that point in the treatment pathway. The Committee noted that some patients responded to placebo but that the TNF-alpha inhibitors were associated with a statistically significant favourable effect compared with placebo in most RCTs. The Committee therefore concluded that the TNF-alpha inhibitors were clinically effective in the RCTs.

4.65    The Committee considered the Assessment Group’s network meta-analysis. It noted that, although all TNF-alpha inhibitors had a statistically significant favourable effect compared with placebo for induction therapy, the difference for maintenance therapy was not statistically significant except for adalimumab for 1 maintenance outcome. The Committee heard from the clinical expert that for some outcomes, the results of the network meta-analysis were inconsistent with what was observed in the RCTs. The Committee agreed that the network meta-analysis did not allow a conclusion to be drawn about the relative effectiveness of TNF-alpha inhibitors.

4.66    The Committee discussed the clinical effectiveness of infliximab in children and adolescents. It heard from the clinical expert that there was no biologically plausible reason for the effect of infliximab to differ according to the age of patients. The Committee considered the RCT evidence in children and adolescents noting that this consisted of 1 open label RCT, by Hyams et al., that compared 2 infliximab regimens. The Committee was aware that the trial included patients with moderately to severely active ulcerative colitis, although infliximab is licensed in children and adolescents for severely active disease only. It heard from the clinical expert that although 50 to 60% of patients in the study by Hyams et al. had been treated before with azathioprine, compared with 40% in the adult trials, the efficacy of infliximab was broadly similar in the 2 populations. The clinical expert considered this to have showed that infliximab had a favourable effect in children and adolescents who appeared to have more severe disease than patients in the adult trials. Acknowledging the limitations in the study by Hyams et al., the Committee concluded that infliximab was likely to be a clinically effective treatment in children and adolescents, but it could not determine an estimate of the size of the effectiveness from the available evidence.

4.67    The Committee considered the Assessment Group’s model in which it was assumed that patients whose disease responds or remits on TNF-alpha-inhibitor therapy continue treatment until that benefit is lost. It noted comments suggesting that treatment might be stopped if the patient is not satisfied with the response or if complete remission is required as a minimum to continue treatment. The Committee would have liked to consider further the stopping rules for patients with ulcerative colitis who had a TNF-alpha inhibitor then entered into remission, but there was no robust evidence in this regard. Furthermore, it noted that the cost effectiveness of continuing treatment when only a partial response was achieved compared with a full response remained unknown. However, it agreed that in clinical practice patients who experience some degree of response would be most likely to continue treatment (see section 4.62). Without any other evidence, the Committee concluded that the Assessment Group’s approach to modeling the stopping rules was appropriate for the purpose of its decision-making in this appraisal.

4.68    The Committee considered how health-related quality of life was captured in the Assessment Group’s model. It noted that the results were highly sensitive to the utility values used, specifically to the difference between the utility values for patients having medical treatment and those having surgery. The Committee heard from the clinical expert that the study from which utility values were obtained (Woehl et al.) was published in abstract form only, and although it included 180 patients, only 19 had ileostomies and 10 had ileo-anal pouches. The Committee heard from the Assessment Group that, based on expert opinion, the utility value after surgery should be similar to the utility value for mild disease, which was the case in Woehl et al. (post-surgery: 0.71; mild disease: 0.76) but not in Swinburn et al. (post-surgery: 0.59; mild disease: 0.80). The Committee concluded that the utility values from Woehl et al. could be considered appropriate.

4.69    The Committee noted comments suggesting that the Assessment Group’s model underestimated the cost of conventional therapy because most patients in clinical practice have higher doses of mesalazine than those applied in the model. The comments also noted that the model used the cheapest preparation of mesalazine but it should have used the range of preparations available based on the market share of each preparation. The Committee noted the Assessment Group’s response that the doses applied in the model were based on expert opinion and that it used the cheapest preparation of mesalazine because there was limited evidence on the relative effectiveness of the different products. The Committee acknowledged that higher doses and more expensive preparations of mesalazine might be used in clinical practice, but concluded that, given the magnitude of the ICERs produced by the model, increasing the cost for conventional therapy was unlikely to change the overall conclusion about the cost effectiveness of TNF-alpha inhibitors.

4.70    The Committee heard from the clinical expert that the Assessment Group used a study by Solberg et al. to estimate the rate at which patients have surgery. The clinical expert stated that this study was likely to have underestimated this rate because it included newly diagnosed patients and patients with any degree of disease severity. They thought that the rate in clinical practice would be much higher than that used in the model because 10 to 15% of patients are likely to have had surgery in their first year after diagnosis and up to 40% are likely to have had it at 10 years. The Committee noted that comments on the assessment report highlighted a study by Hillson et al. which reported a 1-year rate of surgery of 18.2% among patients with severe disease. In response to this issue, the Assessment Group indicated that the study by Solberg et al. appeared to be the most relevant to the population in the scope, but agreed that the rate of surgery in the model was highly uncertain. The Committee concluded that the actual rate of surgery may be higher in clinical practice.

4.71    The Committee discussed the comment on the assessment report suggesting that the cost of surgery was underestimated in the Assessment Group’s model. The comment indicated that most patients in the UK will first have colectomy with an ileostomy. Subsequently, many patients may have a second and third procedure to create an ileo-anal pouch (and possibly require fertility treatment afterwards), a scenario which the Assessment Group did not model. Furthermore, it was pointed out that the cost of maintaining the ileostomy in the medium to long term and that of caring for the stoma were not included in the model. The Committee noted that when the Assessment Group doubled the cost of surgery in a sensitivity analysis, this did not change the relative cost effectiveness of TNF-alpha inhibitors. The Committee concluded that the cost of surgery was not a key driver of cost-effectiveness in the model.

4.72    The Committee discussed the cost-effectiveness results in adults from the Assessment Group’s and the companies’ models. It agreed that infliximab, adalimumab and golimumab should be compared with conventional therapy and that surgery was not a relevant comparator for most patients with moderately to severely active disease. The Committee was aware that the company’s models for infliximab and golimumab did not include conventional therapy as a comparator. In the company’s model for adalimumab, the base-case ICER for adalimumab compared with conventional therapy was £34,400 per QALY gained, which the Committee agreed was above the normally acceptable maximum ICER that would represent cost-effective interventions. The Committee noted that when the Assessment Group compared medical options only, infliximab was dominated by adalimumab, and golimumab was extendedly dominated by adalimumab and conventional therapy. The base-case ICER for adalimumab compared with conventional therapy was £50,600 per QALY gained. Because the difference in QALYs between infliximab and adalimumab was small, the Committee considered the sensitivity analyses in which alternative datasets were used to estimate clinical effectiveness (see section 4.53). It noted that in all 3 sensitivity analyses, golimumab was extendedly dominated and excluded from the analyses. In 2 of the analyses, infliximab provided more QALYs than adalimumab, but the ICER for infliximab compared with adalimumab was greater than £250,000 per QALY gained and the ICER for adalimumab compared with conventional therapy was greater than £50,000 per QALY gained. The Committee agreed that using different estimates of clinical effectiveness did not have a material effect on the results. The Committee concluded that the ICERs for adalimumab, infliximab and golimumab did not represent a cost-effective use of NHS resources in adults with moderately to severely active ulcerative colitis that has responded inadequately to conventional therapy.

4.73    The Committee discussed the cost-effectiveness of infliximab in children and adolescents. It noted that the Assessment Group presented a scenario analysis in this population which differed from the analysis in adults only in that the starting age of patients in the model was set to 15 years. In the analysis that compared infliximab with conventional therapy only (that is, when colectomy is not an option), the ICER was £68,400 per QALY gained. The Committee was aware that the company’s submission for infliximab did not include a separate analysis in children and adolescents. Given the ICER estimated by the Assessment Group, the Committee concluded that infliximab could not be considered a cost effective use of NHS resources for treating children and adolescents with severely active ulcerative colitis that has responded inadequately to conventional therapy.

4.74    The Committee discussed whether using biosimilar versions of infliximab could improve the cost effectiveness of TNF-alpha inhibitors. Because there was no approved list price in the UK for biosimilars, the Committee was not presented with any evidence on the cost effectiveness of biosimilars. The Committee was therefore unable to make any recommendations on the use of biosimilars.

4.75    On the basis of the considerations in 4.72 and 4.73 the Committee concluded that infliximab, adalimumab and golimumab could not be recommended for treating adults with moderately to severely active ulcerative colitis that has responded inadequately to conventional therapy. It also concluded that infliximab could not be recommended for treating children and adolescents aged 6 to 17 years with severely active ulcerative colitis that has responded inadequately to conventional therapy.

Summary of Appraisal Committee’s key conclusions

TAXXX	Appraisal title: Infliximab, adalimumab and golimumab for treating moderately to severely active ulcerative colitis after the failure of conventional therapy (including a review of TA140 and TA262)		Section
Key conclusion
Infliximab, adalimumab and golimumab are not recommended within their marketing authorisations for treating adults who have moderately to severely active ulcerative colitis that has responded inadequately to conventional therapy including corticosteroids and mercaptopurine or azathioprine, or who are intolerant to or have medical contraindications for such therapies. Infliximab is not recommended within its marketing authorisation for treating children and adolescents aged 6 to 17 years who have severely active ulcerative colitis that has responded inadequately to conventional therapy including corticosteroids and mercaptopurine or azathioprine, or who are intolerant to or have medical contraindications for such therapies. The Committee did not consider the ICERs for adalimumab, infliximab and golimumab to represent a cost-effective use of NHS resources in adults with moderately to severely active ulcerative colitis that has responded inadequately to conventional therapy. Nor did it consider the ICER for infliximab in children and adolescents with severely active ulcerative colitis to represent a cost-effective use of NHS resources.			1.1, 1.2, 4.72, 4.73
Current practice
Clinical need of patients, including the availability of alternative treatments		The Committee heard that not only do the symptoms of ulcerative colitis have a negative impact on the patient’s quality of life, but also some conventional therapies have side effects that affect emotional and physical wellbeing. The Committee appreciated that, as the peak age of onset of ulcerative colitis is 15 to 30 years, the side effects of using corticosteroids for prolonged periods can severely damage the patient’s confidence and self-esteem. The Committee understood that most patients who ultimately elect to have surgery would prefer 2 to 3 years of good quality of life on a TNF-alpha inhibitor to get them through particularly stressful periods in their life, and to allow them to come to terms with their disease and psychologically prepare for surgery. The Committee heard that there are patients for whom surgery is not an acceptable option. For these patients, if a TNF-alpha inhibitor cannot be offered, engagement with the patient may be lost and the patient becomes at risk of further complications. The Committee concluded that patients and clinicians considered TNF-alpha inhibitors to be a valuable option that could offer long-term remission to some patients with moderately to severely active ulcerative colitis.	4.59, 4.60
The technology
Proposed benefits of the technology How innovative is the technology in its potential to make a significant and substantial impact on health-related benefits?		The Committee heard from patient experts that with TNF-alpha inhibitors, the symptoms of their ulcerative colitis had stopped, they felt ‘normal’ again, were able to work and lead a normal life and their quality of life improved.	4.60
What is the position of the treatment in the pathway of care for the condition?		The Committee understood that if response to conventional therapy was inadequate, patients may have TNF-alpha-inhibitor treatment. After subsequent relapses, patients could have an alternative TNF-alpha inhibitor, conventional therapy or colectomy. However, the Committee agreed that most patients are unlikely to consider surgery until later.	4.58, 4.59
Adverse reactions		No specific Committee considerations on adverse reactions.
Evidence for clinical effectiveness
Availability, nature and quality of evidence		The Committee considered the Assessment Group’s network meta-analysis and heard from the clinical expert that for some outcomes, the results of the analysis were inconsistent with what was observed in the randomised controlled trials (RCTs). The Committee noted that the RCT evidence in children and adolescents consisted of 1 open label RCT, by Hyams et al., that compared 2 infliximab regimens. The Committee was aware that this trial included patients with moderately to severely active ulcerative colitis, although infliximab is licensed in children and adolescents for severely active disease only.	4.65, 4.66
Relevance to general clinical practice in the NHS		The Committee heard from the clinical expert that the inclusion criterion for disease severity used in the RCTs (Mayo score of 6 to 12) represents patients who would be considered to have moderately to severely active disease in clinical practice in the NHS. However, the clinical expert pointed out that the trials typically excluded patients with ulcerative proctitis who are not usually suitable for surgery and whose disease seems to respond to TNF-alpha-inhibitor treatment. The Committee concluded that the RCTs were otherwise representative of patients in clinical practice.	4.63
Uncertainties generated by the evidence		The Committee discussed the criteria for stopping treatment that are applied with TNF-alpha inhibitors and heard that there are no rigid criteria for stopping treatment when only a slight response is achieved. The Committee noted that there was no evidence from RCTs that shows what happens to patients with ulcerative colitis when treatment with a TNF-alpha inhibitor is stopped.	4.62
Are there any clinically relevant subgroups for which there is evidence of differential effectiveness?		There are no clinically relevant subgroups for which there is evidence of differential effectiveness.
Estimate of the size of the clinical effectiveness including strength of supporting evidence		The Committee agreed that the network meta-analysis did not allow a conclusion to be drawn about the relative effectiveness of TNF-alpha inhibitors. The Committee concluded that infliximab was likely to be a clinically effective treatment in children and adolescents, but it could not determine an estimate of the size of the effectiveness from the available evidence.	4.65, 4.66
Evidence for cost effectiveness
Availability and nature of evidence		The Committee was aware that the company’s models for infliximab and golimumab did not include conventional therapy as a comparator. The Committee noted that the Assessment Group presented a scenario analysis for children and adolescents which differed from the analysis in adults only in that the starting age of patients in the model was set to 15 years. The Committee was aware that the company’s submission for infliximab did not include a separate analysis in children and adolescents.	4.72, 4.73
Uncertainties around and plausibility of assumptions and inputs in the economic model		The Committee considered the Assessment Group’s model in which it was assumed that patients whose disease responds or remits on TNF-alpha-inhibitor therapy continue treatment until that benefit is lost. The Committee would have liked to consider further the stopping rules for patients with ulcerative colitis who had a TNF-alpha inhibitor then had only a partial response or entered into remission, but there was no robust evidence in this regard. The Committee heard from the clinical expert that the study by Solberg et al. used by the Assessment Group was likely to have underestimated the rate at which patients have surgery because it included newly diagnosed patients and patients with any degree of disease severity. The Committee concluded that the actual rate of surgery may be higher in clinical practice. The Committee noted comments suggesting that the cost of surgery was underestimated in the Assessment Group’s model because after the first surgery, many patients may have a second and third procedure to create an ileo-anal pouch, a scenario which the Assessment Group did not model. The Committee noted that when the Assessment Group doubled the cost of surgery in a sensitivity analysis, this did not change the relative cost effectiveness of TNF-alpha inhibitors. The Committee concluded that the cost of surgery was not a key driver of cost-effectiveness in the model.	4.67, 4.70, 4.71
Incorporation of health-related quality-of-life benefits and utility values Have any potential significant and substantial health-related benefits been identified that were not included in the economic model, and how have they been considered?		The Committee heard from the clinical expert that the study from which utility values were obtained (Woehl et al.) was published in abstract form only, and included relatively few patients who had surgery. The Committee heard from the Assessment Group that, based on expert opinion, the utility value after surgery should be similar to the utility value for mild disease, which was the case in Woehl et al. but not in Swinburn et al. The Committee concluded that the utility values from Woehl et al. could be considered appropriate.	4.68
Are there specific groups of people for whom the technology is particularly cost effective?		There are no specific groups of people for whom the technology is particularly cost effective.
What are the key drivers of cost effectiveness?		The Committee noted that the results were highly sensitive to the utility values used, specifically to the difference between the utility values for patients having medical treatment and those having surgery.	4.68
Most likely cost-effectiveness estimate (given as an ICER)		In the company’s model for adalimumab, the base-case ICER for adalimumab compared with conventional therapy was £34,400 per QALY gained. The Committee noted that when the Assessment Group compared medical options only, infliximab was dominated by adalimumab, and golimumab was extendedly dominated by adalimumab and conventional therapy; the base-case ICER for adalimumab compared with conventional therapy was £50,600 per QALY gained. In the Assessment Group’s scenario analysis that compared infliximab with conventional therapy only in children and adolescents, the ICER was £68,400 per QALY gained.	4.72, 4.73
Additional factors taken into account
Patient access schemes (PPRS)		Merck Sharp & Dohme has agreed a patient access scheme with the Department of Health. This will make the 100 mg dose of golimumab available to the NHS at the same cost as the 50 mg dose. The Department of Health considered that this patient access scheme does not constitute an excessive administrative burden on the NHS.	3.7
End-of-life considerations		Not applicable.
Equalities considerations and social value judgements		The Committee heard that the impact of surgery on fertility may disadvantage those who are yet to have a family. Given that the Committee agreed that conventional therapy is the main comparator for TNF-alpha inhibitors in this appraisal, this was not considered further.

 

5     Implementation

5.1     NICE has developed tools [link to www.nice.org.uk/guidance/TAXXX] to help organisations put this guidance into practice (listed below). [NICE to amend list as needed at time of publication]

• Slides highlighting key messages for local discussion.
• Costing template and report to estimate the national and local 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     Related NICE guidance

Details are correct at the time of consultation and will be removed when the final guidance is published. Further information is available on the NICE website.

Published

• Ulcerative colitis. NICE clinical guideline 166 (2013).
• Adalimumab for the treatment of moderate to severe ulcerative colitis. Terminated NICE technology appraisal guidance 262 (2012).
• Infliximab for the treatment of acute exacerbations of ulcerative colitis. NICE technology appraisal guidance 163 (2008).
• Infliximab for subacute manifestations of ulcerative colitis. NICE technology appraisal guidance 140 (2008).

Under development

• Vedolizumab for treating moderately to severely active ulcerative colitis. NICE technology appraisal. April 2015.

 

7     Proposed date for review of guidance

7.1     NICE proposes that the guidance on this technology is considered for review by the Guidance Executive 3 years after publication of the guidance. 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.

    Iain Squire
   Chair, Appraisal Committee
   September 2014

8     Appraisal Committee members, guideline representatives and NICE project team

Appraisal Committee members

The Appraisal Committees are standing advisory committees of NICE. 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. There are 4 Appraisal Committees, each with a chair and vice chair. Each Appraisal Committee meets once a month, except in December when there are no meetings. Each Committee considers its own list of technologies, and ongoing topics are not moved between Committees.

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 (Chair)
Department of Diagnostic Radiology, St George’s Hospital, London

Professor Iain Squire (Vice-Chair)
Consultant Physician, University Hospitals of Leicester

Dr Graham Ash
Consultant in General Adult Psychiatry, Lancashire Care NHS Foundation Trust

Dr Gerardine Bryant
GP, Swadlincote, Derbyshire

Matthew Campbell-Hill
Lay member

Dr Peter Heywood
Consultant Neurologist, Frenchay Hospital, Bristol

Dr Sharon Saint Lamont
Head of Clinical Quality, NHS England (North)

Mr Cliff Snelling
Lay member

Dr Ian Lewin
Honorary Consultant Physician and Endocrinologist, North Devon District Hospital

Dr Louise Longworth
Reader in Health Economics, HERG, Brunel University

Dr Alec Miners
Senior lecturer in Health Economics, London School of Hygiene and Tropical Medicine

Pamela Rees
Lay Member

Dr Ann Richardson
Lay Member

Ellen Rule
Director of Transformation and Service Redesign, Gloucestershire CCG

Stephen Sharp
Senior Statistician, University of Cambridge MRC Epidemiology Unit

Dr Peter Sims
GP, Devon

Dr John Watkins
Clinical Senior Lecturer, Cardiff University; Consultant in Public Health Medicine, National Public Health Service Wales

Professor Olivia Wu
Professor of Health Technology Assessment, University of Glasgow

NICE project team

Each technology appraisal is assigned to a team consisting of 1 or more health technology analysts (who act as technical leads for the appraisal), a technical adviser and a project manager.

Ahmed Elsada
Technical Lead

Joanna Richardson
Technical Adviser

Bijal Joshi
Project Manager

 

9     Sources of evidence considered by the Committee

A.     The assessment report for this appraisal was prepared by ScHARR, The University of Sheffield:

• Archer R, Tappenden P, Ren S, et al. Infliximab, adalimumab and golimumab for treating moderately to severely active ulcerative colitis after the failure of conventional therapy (including a review of TA140 and TA262): Clinical effectiveness systematic review and economic model, June 2014

B.     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, II and III were also invited to make written submissions and have the opportunity to appeal against the final appraisal determination.

   I.    Manufacturers/sponsors:

        AbbVie (adalimumab)

        Celltrion Healthcare (infliximab)

        Merck Sharp and Dohme (golimumab, infliximab)

   II.   Professional/specialist and patient/carer groups:

        British Society of Gastroenterology

        British Society of Paediatric Gastroenterology, Hepatology and Nutrition

        Crohn’s and Colitis UK

        Royal College of Nursing

        Royal College of Physicians

        United Kingdom Clinical Pharmacy Association

   III.   Other consultees:

        Department of Health

        NHS England

        Welsh Government

   IV.   Commentator organisations (without the right of appeal):

        Department of Health and Social Services and Public Safety, Northern Ireland (DHSSPSNI)

        Healthcare Improvement Scotland

        National Institute for Health Research Technology Assessment Programme

        Pfizer (sulfasalazine)

        School of Health & Related Research University Sheffield, (ScHARR)

C.     The following individuals were selected from clinical specialist and patient expert nominations from the 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, adalimumab and golimumab for treating moderately to severely active ulcerative colitis after the failure of conventional therapy (including a review of TA140 and TA262) by attending the initial Committee discussion and/or providing written evidence to the Committee. They are invited to comment on the ACD.

• Dr A Barney Hawthorne, Consultant Gastroenterologist, nominated by organisation representing British Society of Gastroenterology – clinical specialist
• Ms Julie Duncan, Clinical nurse specialist – IBD & IBD Network National Committee Chair, nominated by organisation representing Royal College of Nursing – clinical specialist
• Mr Mark Byrne, nominated by organisation representing Crohn’s and Colitis UK – patient expert
• Mr Joseph Fitzgerald, nominated by organisation representing Crohn’s and Colitis UK – patient expert

D. Representatives from the following manufacturers/sponsors attended Committee meetings. They contributed only when asked by the Committee chair to clarify specific issues and comment on factual accuracy.

• AbbVie (adalimumab)
• Celltrion Healthcare (infliximab)
• Merck Sharp and Dohme (golimum