Infliximab, adalimumab and golimumab for treating moderately to severely active ulcerative colitis after the failure of conventional therapy

4.30 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.

4.58 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 defaecate, and that these 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, some conventional therapies have toxic side effects that also affected their physical and psychological wellbeing. The Committee appreciated that, because the peak age of onset of ulcerative colitis is 15–30 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 from 1 of the patient experts that they struggled to stop treatment with corticosteroids 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 noted from consultation comments that the use of TNF‑alpha inhibitors in this patient population has become standard practice in Europe. 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 ulcerative colitis.

4.59 The Committee discussed the treatment pathway for active ulcerative colitis (but not acute disease). It heard from the clinical expert that standard practice in the UK is to start on conventional therapy. This may include corticosteroids or 5‑aminosalicylates (for example, mesalazine), with the possibility of then adding on azathioprine. The clinical expert indicated that approximately 8–10% 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 conventional therapy is generally regarded as an ongoing option throughout the treatment pathway for ulcerative colitis so, if response to a conventional therapy was inadequate, patients may have further conventional therapy. Other available options at this stage include TNF‑alpha inhibitors and surgery. The Committee heard that clinicians consider how unwell the patient is when deciding whether or not surgery is appropriate, and that patients who ultimately choose to have surgery may prefer 2–3 years of good quality of life on a TNF‑alpha inhibitor to get them through stressful periods in their life and psychologically prepare for surgery. The Committee concluded that the choice of treatment depends on the specific clinical circumstances of each patient and that no single pathway of care could be defined for adults with moderately to severely active ulcerative colitis or children and young people with severely active ulcerative colitis.

4.60 The Committee discussed whether surgery was an appropriate comparator for TNF‑alpha inhibitors. It heard that in clinical practice, surgery is avoided if possible because, although potentially curative, it does not fully restore the patient's quality of life. This is because, for example, 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‑diarrhoea medication. They may also experience complications such as faecal incontinence and chronic pouchitis, and there is a risk that this surgery may affect fertility in both men and women. As a result, some patients would only have a sub‑total colectomy with a stoma in the first instance to prevent having surgery in the pelvis. However, stomas have a profound psychological and lifestyle impact (for example, on body image and self‑esteem) and need care for the duration of their existence. The Committee heard that, although some of these patients will keep their stoma for life, others may need further surgery to create a pouch and many patients delay this for many years (in some areas of the UK only 30–60% of patients end up having a pouch). The Committee noted from consultation comments that many patients do not wish to have surgery because it is an irreversible step, with potential complications and long‑term consequences on their physical and psychological wellbeing. It heard that, for patients in whom surgery is not an acceptable option, 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 bowel cancer. The Committee concluded that patients and clinicians would rather avoid or delay surgery (unless the patient has acute disease, which is not covered by this appraisal), and that surgery was not an appropriate comparator for TNF‑alpha inhibitors for most patients in whom TNF‑alpha inhibitors would be considered in clinical practice.

4.61 The Committee considered the role of surgery in the management of severely active ulcerative colitis in children and young people. It heard that children and young people are usually more reluctant to have surgery than adults because the younger the patient, the more likely surgery will impact on their life in terms of education and ability to form relationships and start a family. The Committee understood that the rate of surgery is higher among children and young people than adults because young people tend to present with more extensive and severe disease, which is more likely to need surgery. The Committee concluded that the decision to have surgery may be different for children and young people compared with adults and that TNF‑alpha inhibitors are important treatment options that could allow patients to avoid surgery.

4.62 The Committee discussed whether conventional therapy was an appropriate comparator for TNF‑alpha inhibitors. Comments received in response to consultation indicated that TNF‑alpha inhibitors are licensed for use after conventional therapy and that it is at this point in the pathway where TNF‑alpha inhibitors are likely to be used in clinical practice. Because of this, the comments considered that it would be inappropriate to compare TNF‑alpha inhibitors with a treatment that the disease had responded inadequately to, or one that patients cannot tolerate or have medical contraindications for. The Committee heard from patient experts that patients are unlikely to continue on a therapy that did not adequately relieve their symptoms. It was aware that after conventional therapy, if TNF‑alpha inhibitors cannot be offered, treatment options are limited and usually include further conventional therapy or surgery. The Committee understood that, if patients choose not to have further conventional therapy, corticosteroids may be the only remaining option because surgery is generally viewed as the last option when the burden of disease can no longer be coped with. It heard that in 30–40% of patients who have corticosteroids, the disease will not respond to standard doses and the dose will need to be increased, which may consequently increase the potentially irreversible side effects associated with corticosteroids such as osteoporosis, diabetes, hypertension, increased susceptibility to serious infection, adrenal insufficiency and hepatic and ophthalmologic effects. In addition, the long‑term use of corticosteroids in children is of particular concern because of the possible effect on growth. The Committee acknowledged that some patients would rather not have corticosteroids because of the potential long‑term consequences on their health. It considered its earlier discussion about conventional therapy and that this is generally regarded as an ongoing option throughout the treatment pathway for ulcerative colitis (see section 4.59). It appreciated that for some patients in whom conventional therapy had failed, continuing the same type of therapy may be suboptimal. However, there was no evidence on the effectiveness of conventional therapy in these circumstances. The Committee concluded that conventional therapy is an option at the same stage at which TNF‑alpha inhibitors would be considered.

4.63 The Committee heard from the clinical expert that ulcerative colitis shares common genetic factors with Crohn's disease, with the 2 conditions overlapping in some aspects, which sometimes makes them clinically indistinguishable. The Committee heard that, as a result, 10–15% of patients have unclassified (indeterminate) disease. The clinical expert noted that for Crohn's disease, there is positive NICE technology appraisal guidance for using TNF-alpha inhibitors, and these provide symptom control in a significant proportion of patients, particularly in those with Crohn's colitis (where the inflammation is limited to the colon). 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 inhibitors for ulcerative colitis will be similar to that for Crohn's colitis. The Committee concluded that the clinical experience with TNF‑alpha inhibitors for Crohn's disease may provide insight into the potential value of these agents for ulcerative colitis.

4.64 The Committee discussed with the clinical expert the criteria for stopping treatment that are applied with TNF‑alpha inhibitors. It heard that patients normally have induction therapy for 8–14 weeks before response is assessed. If no response is achieved at the end of the induction therapy, treatment will be reconsidered and is likely to be stopped. However, if only a partial response was achieved, clinicians 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 consultation comments suggesting that assessing the disease 1 year after starting TNF‑alpha‑inhibitor therapy and stopping treatment in patients whose disease has gone into remission is likely to be a clinically and cost‑effective treatment strategy, with further treatment only in those whose disease subsequently relapses. The Committee noted the observational evidence cited in the consultation comments to support this strategy, and heard that this evidence suggested that of patients whose disease remitted on an TNF‑alpha inhibitor, two‑thirds to three‑quarters remained in remission when treatment stopped 1 year or later after starting it. Furthermore, in most patients whose disease subsequently relapsed, retreatment with a TNF‑alpha inhibitor was successful. The Committee heard from the clinical expert that there were no RCTs that show what happens to patients with ulcerative colitis when TNF‑alpha‑inhibitor therapy is stopped, but the expert considered the observational evidence to be encouraging and to suggest that continuing therapy is unnecessary when complete remission has been achieved. The Committee understood that for patients who are in deep remission (defined as absence of clinical symptoms and evidence of mucosal healing by colonoscopy or a surrogate marker such as faecal calprotectin, see NICE's diagnostics guidance on faecal calprotectin diagnostic tests for inflammatory diseases of the bowel), the longer the duration of remission the more likely the patient will stay in remission after TNF‑alpha‑inhibitor therapy is stopped. The Committee heard from patient experts that they would not be concerned about stopping treatment when remission can be maintained and they no longer need to be on therapy. The clinical expert stated that for patients whose disease relapses after stopping TNF‑alpha‑inhibitor therapy, measuring drug and drug‑specific antibody levels in the blood can help determine whether or not to re‑treat the patient with a TNF‑alpha inhibitor, although these tests are not yet in routine use in the NHS. The Committee appreciated that it would be difficult to adhere to rigid criteria for stopping treatment in clinical practice. However, having heard the clinical and patient experts' views on this matter, it concluded that stopping TNF‑alpha‑inhibitor therapy after 1 year for patients whose disease goes into remission would be an acceptable treatment strategy for patients and clinicians.

4.65 The Committee further discussed the criteria for stopping TNF‑alpha‑inhibitor therapy in the context of NICE guidance for Crohn's disease. It noted that the guidance recommends that TNF‑alpha inhibitors be given until treatment failure (including the need for surgery), or until 12 months after the start of treatment, whichever is shorter. People should then have their disease reassessed to determine whether ongoing treatment is still clinically appropriate. Continuing treatment is recommended only if there is clear evidence of ongoing active disease. For all patients who are in stable clinical remission after 12 months of treatment, the guidance recommends considering a trial withdrawal from treatment. People who continue treatment should then have their disease reassessed at least every 12 months to determine whether ongoing treatment is still clinically appropriate. People whose disease relapses after treatment is stopped should have the option to start treatment again. 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, and heard that this type of stopping rule could work in patients with ulcerative colitis. It also heard that in most patients with Crohn's disease who stopped TNF‑alpha‑inhibitor therapy and subsequently experienced a disease relapse, the disease responded well to reintroduction of TNF‑alpha‑inhibitor therapy. The Committee would have liked to consider further evidence that shows the treatment outcome in patients with ulcerative colitis who stop TNF‑alpha‑inhibitor therapy after entering into remission, but there was not any. Having heard that ulcerative colitis and Crohn's disease are associated with similar functional changes in the bowel (see section 4.63), the Committee concluded that the criteria for stopping treatment in NICE's technology appraisal guidance for TNF-alpha inhibitors for treating Crohn's disease could also be applied for ulcerative colitis, which would align the treatment strategies for 2 conditions.

4.66 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 6–12) 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. 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 noted consultation comments suggesting that most patients in the trials had moderate disease that was stable. In UK clinical practice, however, TNF‑alpha inhibitors would be reserved for patients with more severe disease and for those whose disease is corticosteroid‑refractory or corticosteroid‑dependent. It heard from the clinical expert that in the trials 85% and 15% of patients had moderate and severe disease respectively, and that in clinical practice patients in whom TNF‑alpha‑inhibitor therapy would be considered are more likely to have severe, rather than moderate, disease. The Committee also noted that the average age of patients in the RCTs ranged from 37 to 42.5 years, whereas in clinical practice patients starting treatment would be younger because the peak incidence of ulcerative colitis is between 15 and 25 years of age. The Committee appreciated that patients included in clinical trials may be fitter and have more stable disease than most people seen in clinical practice. However, it concluded that considering the clinical trial data was useful because these represented the key evidence on the clinical effectiveness of TNF‑alpha inhibitors for ulcerative colitis.

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

4.68 The Committee considered the Assessment Group's network meta‑analysis. It noted that this was based on the clinical trials that included a smaller proportion of patients with severe disease than would be seen in clinical practice (see section 4.66). The Committee heard from the Assessment Group that the trial evidence had been synthesised in the best way possible in the network meta‑analysis. However, the Assessment Group stated that there was not enough evidence to estimate the relative treatment effect for moderate and severe disease separately, which the Committee considered to be a limitation of the analysis. The Committee 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. It also noted that the credible intervals around the point estimates were wide, reflecting imprecise and uncertain estimates. The Committee heard from the clinical expert that, in their experience, all TNF‑alpha inhibitors have the same effectiveness for moderately to severely active ulcerative colitis but patients may choose 1 over the other depending on their preferred method of administration. The Committee agreed that the uncertainty in the results of the network meta‑analysis did not allow a conclusion to be drawn about the relative effectiveness of TNF‑alpha inhibitors, but there was no positive evidence that they were different.

4.69 The Committee discussed the clinical effectiveness of infliximab in children and young people. 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 young people noting that this consisted of 1 open label RCT 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 young people for severely active disease only. It heard from the clinical expert that although 50–60% of patients in the trial 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 shown that infliximab had a favourable effect in children and young people who appeared to have more severe disease than patients in the adult trials. The Committee also heard that children are more likely to have a shorter duration of disease which is associated with better treatment outcomes. Acknowledging the limitations in the RCT for children and young people, the Committee concluded that infliximab was likely to be clinically effective in children and young people but it could not determine the size of the treatment effect from the available evidence.

4.70 The Committee considered the Assessment Group's approach to modelling the effectiveness of TNF‑alpha inhibitors. It noted that the Assessment Group extrapolated the results of its network meta‑analysis to inform the modelling throughout the patients' lifetime. The Committee was aware that the network meta‑analysis was based on the RCTs identified from the systematic review, which provided data over a maximum of 54 weeks. It was also aware that, although the network meta‑analysis was well conducted, it estimated the effectiveness of TNF‑alpha inhibitors for patients with moderate to severe disease and not for those with more severe disease who would start treatment at a younger age than patients in the trials. Furthermore, the wide credible intervals around the point estimates reflected uncertain results, and this uncertainty was propagated across the model by the extrapolation. The Committee concluded that the extrapolation of short‑term trial data over a lifetime time horizon introduced further uncertainty about the health benefits of TNF‑alpha inhibitors estimated by the model.

4.71 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 that, as a result of this assumption, no patient in the model had a TNF‑alpha inhibitor for longer than 3 years. The Committee heard from the clinical expert that, of patients who start on a TNF‑alpha inhibitor, one‑third to one‑half are expected to continue therapy in the long term. It also noted that the patient experts who attended the meeting had been on a TNF‑alpha inhibitor for longer than 3 years. The Committee recognised that some patients might have TNF‑alpha‑inhibitor therapy for prolonged periods and that these patients were not represented in the model. Without further evidence on the cost effectiveness of continuing or stopping TNF‑alpha‑inhibitor therapy in different clinical circumstances, the Committee concluded that the criteria in NICE's technology appraisal guidance for TNF-alpha inhibitors for treating Crohn's disease could also be applied in this appraisal (see section 4.65). However, it appreciated that it would be difficult to model any such criteria given the lack of efficacy data for TNF‑alpha inhibitors (including response and relapse rates) beyond the durations of the trials.

4.72 The Committee discussed the most appropriate sources of utility values for ulcerative colitis, noting that the results of the Assessment Group's model were highly sensitive to the utility values used, specifically to the difference between the values for patients having medical treatment and those having surgery. The Committee noted that the Assessment Group considered the utility studies by Woehl et al. and Swinburn et al. to be the most useful for this population. The Assessment Group indicated that it had chosen the study by Woehl et al. for its base case because this study used a preference‑based measure of health‑related quality of life and provided utility data for most states in the model. In addition, it stated 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 heard from the clinical expert that, although the study by Woehl et al. included 180 patients, only 19 had ileostomies and 10 had pouches; this introduced uncertainty in the utility value after surgery estimated by this study. The Committee considered that if the utility after surgery is similar to the utility for mild disease, patients may be indifferent between having surgery or medical treatment. However, it heard from patient experts that surgery is likely to be considered as a last line of treatment when all other options had failed. The Committee was aware that both studies by Woehl et al. and Swinburn et al. were available in abstract form only and provided little detail on the patient characteristics at baseline, which made the interpretation of the findings difficult. The Committee concluded that, although there was considerable uncertainty around the validity of the utility values reported in the studies by Woehl et al. and Swinburn et al., these studies represented the most relevant evidence on the quality of life of patients with ulcerative colitis.

4.73 The Committee discussed the data on health‑related quality of life used in the economic analysis. It noted the consultation comments suggesting that the utility value for patients who had surgery was overestimated in Woehl et al. The Committee was aware that, in the model, the benefit of surgery was maintained until the patient dies, whereas for patients having TNF‑alpha inhibitors the utility values varied over time as patients transitioned between the different states. Therefore, it was particularly important to capture the difference in utility between the 2 states accurately. The Committee heard from the clinical expert that several studies illustrated the poor quality of life of patients after surgery, resulting from post‑surgical complications including reduced fertility and faecal incontinence (see section 4.60). Furthermore, the responses to consultation received from patients, either through patient groups or the NICE website, suggested that quality of life after surgery is worse than that reported by Woehl et al. The Committee was aware that patients with more severe disease (who, in clinical practice, are more likely to have TNF‑alpha inhibitors) are likely to experience a greater change in their quality of life from treatment. This, in turn, would generate more QALY gains and improve the cost effectiveness of the treatment. The Committee concluded that the study by Woehl et al. is likely to have overestimated the utility value for patients who had surgery.

4.74 The Committee discussed whether the changes in health‑related quality of life had been adequately captured in the economic analysis. It heard from patient experts that the emotional distress that patients experience when preparing for surgery is difficult to take into account in the QALY calculation, and so is the fact that some patients will want to avoid surgery. The Committee was aware that surgery is an irreversible step, with potential long‑term complications and negative consequences on the patient's wellbeing, which can all affect the patient's ability to live a normal life in various ways (see section 4.60). Because of this, the Committee agreed that it would be difficult to capture all aspects of the patient's quality of life after surgery in the descriptive system of the EQ‑5D, particularly the emotional aspects and the long‑term effects such as reduced fertility. The Committee concluded that these are important issues affecting the quality of life of patients with ulcerative colitis which should be taken into account, particularly for young people who may not cope well with the consequences of surgery and in whom the impact of surgery may be different. However, on this occasion, the Committee was not satisfied that they had been adequately captured in the economic analysis.

4.75 The Committee noted comments suggesting that the use of corticosteroids was assumed to be same in the model whether the patient was having TNF‑alpha‑inhibitor or conventional therapy, although in clinical practice, one of the aims of TNF‑alpha‑inhibitor therapy is to avoid using corticosteroids. The Committee noted that, although corticosteroids themselves are cheap, they are associated with multiple consequences that can be costly (see section 4.62), and these costs were not included in the model. The Committee concluded that the model should include higher rates of corticosteroid use among patients having conventional therapy than among those having TNF‑alpha inhibitors, together with the cost of treating the side effects of corticosteroids. The Committee was also aware that a utility decrement would be associated with the side effects of corticosteroids, which would favour treatment with TNF‑alpha inhibitors.

4.76 The Committee discussed the rate at which patients have surgery in the model, noting that the Assessment Group used a study by Solberg et al. to estimate this rate at 1.02% per year. The Committee heard from the clinical expert that this study was likely to have underestimated the rate of surgery because it included newly diagnosed patients and patients with any degree of disease severity. They thought that in clinical practice, 10–15% 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 Assessment Group indicated that no study was ideal or reflected the more severe population that would receive TNF‑alpha inhibitors in clinical practice, but that it had chosen the study by Solberg et al. because this study did not specifically relate to patients who had experienced a flare‑up of ulcerative colitis. However, the Assessment Group agreed that the appropriate rate of surgery to include in the model was highly uncertain. The Committee noted that the rate of surgery in the trials for TNF‑alpha inhibitors ranged from 0.7% to 5.8% in the individual trial groups at 1 year, but heard from the clinical expert that these rates are lower than those observed in clinical practice where patients are likely to have more severe disease. The Committee noted that when the Assessment Group increased the rate of surgery, the ICERs for the medical options remained high because surgery was included in the model as a possible downstream intervention after all medical options and occurred at similar rates for patients who had a TNF‑alpha inhibitor and for those who had conventional therapy. The Committee heard, however, that after TNF‑alpha‑inhibitor therapy, surgery rates are expected to be lower because TNF‑alpha inhibitors are given with the intention to avoid surgery, and that observational studies showed that the growing use of TNF‑alpha inhibitors reduced the need for surgery. The Committee concluded that the actual rate of surgery is likely to be higher in clinical practice and that different rates of surgery should be applied for patients who have a TNF‑alpha inhibitor and those who have conventional therapy. The Committee, however, acknowledged the scarcity of the evidence on the appropriate rates of surgery for each of these cohorts.

4.77 The Committee considered the consultation comments suggesting that the cost of surgery was underestimated in the Assessment Group's model. The comments indicated that the Assessment Group assumed that patients have only 1 procedure, whereas on average they will have 2 or more procedures. The Committee understood that most patients in the UK will first have a colectomy with an ileostomy, and while some patients will keep their ileostomy in the medium to long term, others will have a second and third procedure to create an ileo‑anal pouch. The Committee noted that maintaining the ileostomy in the medium to long term and caring for the stoma are associated with costs that were not included in the original model. Alternatively, the patient may have a colectomy with ileal pouch‑anal anastomosis, which may require up to 3 procedures; first to remove the colon and create an ileostomy, then to remove the rectum and form the ileum into a pouch, then to close the ileostomy and reattach the small intestine to the pouch. The Committee also heard from patient experts that at some point after surgery the stoma may need to be revised or the pouch may need to be redone, but the expert could not estimate the proportion of patients who undergo such procedures. The Committee concluded that the cost of surgery was underestimated in the model; however, it agreed that there were insufficient data to model the number of procedures required for the patient, and the frequency of, and costs associated with, each of these procedures.

4.78 The Committee discussed the cost‑effectiveness estimates from the Assessment Group's and the companies' models. It agreed that, for most patients with ulcerative colitis, surgery was not a relevant comparator for TNF‑alpha inhibitors. The Committee noted 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. This was revised to £23,000 per QALY gained in response to consultation on the assessment report; a revision not critiqued by the Assessment Group. 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. For children and young people, the Assessment Group estimated an ICER of £68,400 per QALY gained for infliximab compared with conventional therapy. The Committee took note of the range of ICERs presented in this appraisal and agreed that there was a high degree of uncertainty associated with the following aspects in the models:

4.79 The Committee discussed whether further analyses were warranted to address its concerns about the modelling. It noted that there was no explicit treatment pathway for ulcerative colitis because treatment tends to be individualised based on, among other factors, the patient's preferences and tolerability to treatments, as well as the duration and severity of the disease and how the inflammation is distributed in the colon. The choice of treatment also takes into account the patient's age and personal circumstances, and weighs the benefit of treatment against the potential long‑term consequences on the patient's health and wellbeing. Because of this, the Committee agreed that it would be challenging to make accurate assumptions about the pathway of care for ulcerative colitis and to model the proportion of patients who would follow each possible pathway. In addition, there was limited evidence to inform the uncertain parameters in the model and it would be difficult to source robust data for these parameters. The Committee also noted that there was inherent uncertainty arising from extrapolating the efficacy of TNF‑alpha inhibitors from trials with maximum follow‑up of just over 1 year (56 weeks) over a lifetime time horizon, and that the trials themselves did not totally represent patients in clinical practice (see section 4.66). Therefore, the Committee took the view that the existing evidence would not allow the long‑term benefits of TNF‑alpha inhibitors to be estimated in such a way that could usefully inform the clinical and cost effectiveness of these agents in practice. Although the Committee would have liked to have seen robustly modelled ICERs for TNF‑alpha inhibitors, in its judgement revising the model was, on the whole, unlikely to estimate cost effectiveness with significantly more certainty than currently available to the Committee, and further analyses to explore the cost effectiveness of TNF‑alpha inhibitors were unlikely to represent an efficient use of resources. The Committee concluded that further analyses were not warranted given the existing evidence.

4.80 The Committee discussed whether or not it could recommend the use of TNF‑alpha inhibitors for ulcerative colitis. It noted that the uncertainty around the costs and QALYs for TNF‑alpha inhibitors, in addition to the potential uncaptured QALY benefits (see section 4.74), meant that the costs are likely to be overestimated and the QALYs underestimated, which when taken together, would improve the cost effectiveness of TNF‑alpha inhibitors. In addition, applying the criteria for continuing and stopping TNF‑alpha inhibitors (see section 4.71) would further improve the cost effectiveness of treatment. The Committee was aware that, aside from the TNF‑alpha inhibitors, there have been relatively few advances in the management of ulcerative colitis and the available treatment options remain limited. It acknowledged that TNF‑alpha inhibitors represent a significant change in the management of ulcerative colitis by adding to the options available to clinicians to treat the condition, and that this was not adequately captured in the QALY calculation. The Committee noted from the clinical expert at the meeting and the professional groups that responded to consultation that often there are only subtle clinical differences between ulcerative colitis and Crohn's colitis and that, for this reason, clinicians would like the treatment strategy for the 2 conditions to be aligned. The Committee concluded that the costs were likely to have been overestimated and the QALYs underestimated. As a consequence, it was likely that TNF‑alpha inhibitors could be considered a cost‑effective use of NHS resources for treating active ulcerative colitis in patients whose disease has responded inadequately to conventional therapy, or who cannot tolerate, or have medical contraindications for, such therapy, particularly if the same criteria for stopping treatment as in NICE's technology appraisal guidance on TNF-alpha inhibitors for treating Crohn's disease were applied.

4.81 The Committee was aware that biosimilar versions of infliximab are licensed for the same indications as the reference product, although they are not yet available in the UK. It discussed whether the guidance on infliximab should also apply to the biosimilars. The Commitee noted that the European Medicines Agency was content that the pharmacokinetics, efficacy, safety, and immunogenicity profiles of the biosimilars were similar to those of the reference product. The Committee concluded that its recommendations for infliximab could apply both to the reference product and to its biosimilars.

4.82 On the basis of the considerations in sections  4.79 and 4.80, the Committee concluded that infliximab, adalimumab and golimumab could be recommended for treating moderately to severely active ulcerative colitis in adults whose disease has responded inadequately to conventional therapy, or who cannot tolerate, or have medical contraindications for, such therapy. For golimumab, this is only if the company provides the 100 mg dose of golimumab at the same cost as the 50 mg dose, as agreed in the patient access scheme. The choice of treatment between infliximab, adalimumab or golimumab should be made on an individual basis after discussion between the responsible clinician and the patient about the advantages and disadvantages of the treatments available, taking into consideration therapeutic need and whether or not the patient is likely to adhere to treatment. If more than 1 treatment is suitable, the least expensive should be chosen (taking into account administration costs, dosage and price per dose).

4.83 The Committee also concluded that infliximab could be recommended for treating severely active ulcerative colitis in children and young people aged 6–17 years whose disease has responded inadequately to conventional therapy, or who cannot tolerate, or have medical contraindications for, such therapy.