Ulcerative colitis (acute exacerbations) - infliximab: appraisal consultation document
NATIONAL INSTITUTE FOR HEALTH AND CLINICAL EXCELLENCE
Appraisal consultation document
Infliximab for acute exacerbations of ulcerative colitis
The Department of Health has asked the National Institute for Health and Clinical Excellence (NICE or the Institute) to conduct a single technology appraisal (STA) of infliximab for acute exacerbations of ulcerative colitis and provide guidance on its use to the NHS in England. The Appraisal Committee has had its first meeting to consider both the evidence submitted by the manufacturer and the views put forward by non-manufacturer consultees and commentators, and by the clinical specialist and patient expert representatives nominated for this appraisal by non-manufacturer consultees and commentators. The Committee has developed preliminary recommendations on the use of infliximab for acute ulcerative colitis.
This document has been prepared for consultation with the formal consultees. It summarises the evidence and views that have been considered and sets out the preliminary recommendations developed by the Committee. The Institute is now inviting comments from the formal consultees in the appraisal process (the consultees for this appraisal are listed on the NICE website, www.nice.org.uk). This document should be read in conjunction with the evidence base for this appraisal (the evaluation report) which is available from www.nice.org.uk
Note that this document does not constitute the Institute's formal guidance on this technology. The recommendations made in section 1 are preliminary and may change after consultation .
The process the Institute will follow after the consultation period is summarised below. For further details, see the ‘Guide to the single technology appraisal process' (this document is available on the Institute's website, www.nice.org.uk).
The Appraisal Committee will meet again to consider the original evidence and this appraisal consultation document in the light of the views of the formal consultees.
At that meeting, the Committee will also consider comments made on the document by people who are not formal consultees in the appraisal process.
After considering feedback from the consultation process, the Committee will prepare the final appraisal determination (FAD) and submit it to the Institute.
Subject to any appeal by consultees, the FAD may be used as the basis for the Institute's guidance on the use of the appraised technology in the NHS in England.
The key dates for this appraisal are:
Closing date for comments: 3 September 2008
Second Appraisal Committee meeting: 18 September 2008
Details of membership of the Appraisal Committee are given in appendix A, and a list of the sources of evidence used in the preparation of this document is given in appendix B.
|Note that this document does not constitute the Institute's formal guidance on this technology. The recommendations made in section 1 are preliminary and may change after consultation.|
|1||Appraisal Committee's preliminary recommendations|
|This preliminary guidance relates only to the use of infliximab within its marketing authorisation for the treatment of acute exacerbations of severely active ulcerative colitis and relates to an induction course of three doses of infliximab.|
|1.1||Infliximab is recommended as an option for the treatment of acute exacerbations of severely active ulcerative colitis only in patients in whom ciclosporin is contraindicated.|
|1.2||In people who do not meet the criterion described in 1.1, infliximab should only be used for the treatment of acute exacerbations of severely active ulcerative colitis in the context of clinical trials.|
|2.1||Infliximab (Remicade, Schering-Plough Ltd) is a tumour necrosis factor alpha (TNF-α) inhibitor and has a UK marketing authorisation for the treatment of moderately to severely active ulcerative colitis. Infliximab is indicated for intravenous use in adults whose ulcerative colitis has responded inadequately to conventional therapy (including corticosteroids and 6-mercaptopurine or azathioprine), or who are intolerant of or have medical contraindications to such therapies. The recommended dose of infliximab for the treatment of ulcerative colitis is 5 mg/kg body weight infused intravenously over a 2-hour period followed by additional 5mg/kg infusions at 2 and 6 weeks after the first infusion, then every 8 weeks. The summary of product characteristics (SPC) states that continued therapy should be carefully reconsidered in patients who show no evidence of therapeutic benefit within this time period.|
|2.2||The most common adverse events reported during infliximab therapy, for all indications, include viral infections, serum sickness-like reaction, headache, vertigo, dizziness, flushing, lower and upper respiratory tract infections, abdominal pain, diarrhoea, nausea, dyspepsia, increased transaminases, urticaria, rash, pruritus, hyperhidrosis, dry skin, infusion-related reactions, chest pain, fatigue and fever. Infliximab is contraindicated in people with moderate or severe heart failure and active infections. Before starting treatment, people must be screened for both active and inactive tuberculosis. The SPC lists a number of uncommon but serious adverse events related to infliximab's immunomodulatory activity. For full details of side effects and contraindications, see the SPC.|
|2.3||Infliximab (vial with powder for reconstitution) is available at a net price of £419.62 for a 100-mg vial (excluding VAT; ‘British national formulary' [BNF] edition 55). The drug cost varies from patient to patient because the dose is adjusted to each patient's body weight. For example, for a person weighing 73 kg the cost per infusion (if no vial sharing is assumed) would be £1678.48, corresponding to four vials of 100 mg for a dose of 365 mg. Therefore, for a ‘course' of infliximab, assuming three doses, the drug cost is £5035.44. Costs may vary in different settings because of negotiated procurement discounts.|
|3||The manufacturer's submission|
|The Appraisal Committee (appendix A) considered evidence submitted by the manufacturer of infliximab and a review of this submission by the Evidence Review Group (ERG; appendix B).|
|3.1||The manufacturer developed a systematic review of the literature on the use of infliximab and comparator drugs in the target population. Two randomised controlled trials (RCTs) comparing infliximab with placebo were included in the review. For the comparator drug, ciclosporin, two RCTs were included. Searches carried out by the ERG identified no additional RCTs for either infliximab or ciclosporin. The ERG noted that the total number of participants in the studies was small.|
|3.2||The primary outcome in both the review of clinical effectiveness and the economic evaluation was the avoidance of colectomy. In the larger of the two infliximab studies (n = 45) 67% and 29% of patients treated with placebo and infliximab, respectively, had a colectomy within the first 3 months. Within 12 months, 71% and 42% of patients treated with placebo and infliximab, respectively, underwent colectomy. In the smaller infliximab study (n = 11), all three participants treated with placebo underwent colectomy whereas none of the three patients treated with infliximab did so within the first 3 months. Both studies included people with severe acute ulcerative colitis that had not responded to intravenous corticosteroids. The larger study also included people with moderately severe ulcerative colitis. Infliximab was given as a single infusion at a dose of approximately 5 mg/kg in the larger study. In the smaller study, patients were randomly assigned to single doses of 5 mg/kg, 10 mg/kg or 20 mg/kg. Neither study used a multiple-dose regimen as specified in the SPC for infliximab.|
|3.3||The two studies investigating ciclosporin differed from each other in the populations included and in the comparator. In one study, ciclosporin was compared with placebo in people with acute severe ulcerative colitis that had not responded to corticosteroids. In this respect it was similar to the infliximab studies. In this study (n = 20) 44% of people treated with placebo and 27% of those treated with ciclosporin underwent colectomy within the first 3 months. The second study, by D'Haens and coworkers, was different in that it compared ciclosporin with intravenous corticosteroid treatment in people (n = 30) who had not already received treatment with intravenous corticosteroids. In this study, 20% of people treated with corticosteroids and 21% of those treated with ciclosporin underwent colectomy within the first 3 months, and 40% of the corticosteroid-treated group and 36% of the ciclosporin-treated group underwent colectomy within 12 months.|
|3.4||To compare the effectiveness of infliximab with ciclosporin in the absence of a study comparing them directly, a mixed-treatment comparison (MTC) model was used to synthesise the relative treatment effects in respect of colectomy outcomes observed within the trials. The objective was to develop probabilities of colectomy that could be used in an economic evaluation comparing infliximab with ciclosporin. The probabilities of a patient undergoing colectomy were estimated to be 0.67, 0.23 and 0.58 for placebo, infliximab and ciclosporin, respectively, for the first 3 months. The respective probabilities for 3–12 months were 0.14, 0.27 and 0.18 for placebo, infliximab and ciclosporin. The ERG pointed out that it is likely that the model does not appropriately estimate the true effects of the different treatment options, particularly with respect to the effectiveness of ciclosporin. The estimate of colectomy rate in the MTC was nearly twice that actually observed in the RCTs of ciclosporin. In the ERG's view it was not appropriate to include the study by D'Haens and coworkers in this analysis because neither the population nor the comparator treatment was in line with the other infliximab and ciclosporin RCTs. In a further analysis undertaken by the ERG the exclusion of this study reduced the estimated 3-month colectomy probability for ciclosporin from 0.58 to 0.48. According to the ERG, however, these probabilities were still much higher than would be expected in practice.|
|3.5||Neither of the infliximab RCTs reported any deaths and the frequency of adverse events appeared to be comparable between the infliximab and placebo groups. In these studies, two patients treated with infliximab had serious adverse events that required prolonged hospitalisation, and one had long-lasting bleeding. In the ciclosporin studies, no deaths were reported. Adverse events reported in the ciclosporin groups included paresthesias, grand mal seizure and headaches.|
A decision analytical model was used to simulate the progression of hypothetical cohorts of patients. The structure of this model was informed by the infliximab (first infusion was 5 mg/kg including concomitant intravenous corticosteroids) and ciclosporin (4 mg/kg daily, intravenously) RCTs, information on current UK clinical practice, and expert opinion. People with severe active ulcerative colitis hospitalised for an acute exacerbation of the disease were considered in the economic evaluation. These patients were tracked as they received one of the four treatment strategies:
The time horizon used in the base case was 1 year. The course of the disease was represented by post-hospitalisation outcomes including medical remission, surgical remission and surgical complications. Treatment outcomes were characterised in the model as short-term (0–3 months) and medium-term (4–12 months). In the first 3 months, treatment with infliximab, ciclosporin or standard care caused the ulcerative colitis to either respond to treatment and go into remission, or the treatment failed and patients underwent colectomy. For the rest of the base-case analysis (4–12 months), patients whose disease went into initial remission either stayed in remission or the response was lost and they underwent surgery. An extrapolated analysis up to 10 years was also conducted to address the long-term treatment effect. Overall, the ERG considered that the structure of the manufacturer's economic model appropriately addressed the acute phase of the disease. However, the model did not take into account the costs and disutilities associated with adverse events. The ERG noted this was especially important because trials of infliximab in patients with ulcerative colitis described ‘serious adverse events'. Mortality was also not included in the model.
|3.7||The parameter estimates used in the model were obtained from clinical studies of infliximab and ciclosporin and other sources. Although the baseline risk of disease progression was estimated using the placebo arm from the larger infliximab study, this was inconsistently stated in the manufacturer's submission. The primary source for the base-case utilities was an unpublished study based on the Health Outcomes Data Repository (HODaR), which was conducted using the EQ-5D instrument in patients with ulcerative colitis in south Wales. These were supplemented with utilities from another study in which utilities were estimated using the time trade-off method. Estimates of healthcare resource use and concomitant medication use were based on the opinions of a panel of UK gastroenterologists. The costs of all drugs were calculated based on the average doses used in the clinical trials and on pack sizes listed in the BNF. Drug administration costs were obtained from the NHS reference costs.|
|3.8||Univariate sensitivity analyses were performed considering variations in treatment effect, patient weight, utility estimates, infliximab administration cost, hospitalisation period and infliximab infusion doses. Probabilistic sensitivity analyses were conducted to assess the uncertainty of the cost-effectiveness estimates by assigning distributions around the primary outcome (colectomy), secondary outcome (post-surgery complications), utility estimates and unit costs. The ERG considered that the sensitivity analyses were appropriate, although they noted that the colectomy rates associated with the alternative treatment arms were not varied as part of the univariate analyses. The incremental cost-effectiveness ratios (ICERs) were shown by the ERG to be most sensitive to these colectomy rates. Also, the probabilistic sensitivity analysis placed distributions around selected parameters only.|
|3.9||The base-case cost-effectiveness estimates presented in the manufacturer's submission were £11,589 per additional quality-adjusted life year (QALY) gained for infliximab compared with standard care, £18,425 per additional QALY gained for infliximab compared with ciclosporin, and £13,407 per additional QALY gained for infliximab compared with surgery. These ICERs after minor corrections by the ERG rose to £12,307, £19,922 and £14,427, respectively. When the ERG excluded the study by D'Haens and coworkers (which the ERG considered was included in the analysis inappropriately; see 3.3 and 3.4), the ICER for infliximab versus ciclosporin increased considerably from £19,922 to £48,367 per QALY gained.|
|3.10||Full details of all the evidence are in the manufacturer's submission and the ERG report, which are available from www.nice.org.uk/TAxxx|
|4||Consideration of the evidence|
|4.1||The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of infliximab, having considered evidence on the nature of acute exacerbations of ulcerative colitis and the value placed on the benefits of infliximab by people with the condition, those who represent them, and clinical specialists. It was also mindful of the need to take account of the effective use of NHS resources.|
|4.2||The Committee understood that the symptoms of ulcerative colitis may fluctuate in severity and often the disease can remain inactive for some time. In patients who present with severe exacerbations, hospital admission is often necessary. The Committee also noted that the acute onset of severe ulcerative colitis requiring hospital admission has been defined by the British Society of Gastroenterology.|
|4.3||The Committee heard from the clinical specialists that if acute severe ulcerative colitis does not respond to treatment with intravenous corticosteroids within 72 hours, patients are very likely to require urgent colectomy. In these circumstances, infliximab or ciclosporin may be used in an attempt to avoid the need for surgery. The Committee also understood that although these strategies may reduce the need for urgent colectomy, the likelihood of colectomy as an elective procedure may still remain in the long term. The Committee further understood from the patient experts that it is important psychologically for patients to delay colectomy in order to have time to consider and come to terms with the implications of major surgery and the possibility of the provision of a stoma.|
|4.4||The clinical specialists told the Committee that a single dose of infliximab is often used in clinical practice to treat acute severe ulcerative colitis in order to delay or avoid urgent colectomy after failure of intravenous corticosteroids. The Committee appreciated that this approach clearly differs from the regimen specified in the SPC for infliximab, which involves at least three doses for induction of infliximab treatment for patients with ulcerative colitis.|
|4.5||The clinical specialists described to the Committee the current management of acute colitis using ciclosporin. They expressed the view that there was widespread concern among clinicians treating acute ulcerative colitis about the adverse effects of ciclosporin in this indication, particularly the risk of serious infections and the associated risk of mortality. The clinical specialists also indicated that ciclosporin is not used routinely in all centres because of these concerns. However, the Committee noted that the evidence on the relative safety of infliximab in this setting was not adequately researched given the small sizes of the available studies. The Committee was mindful of the results of the indirect comparison presented in the manufacturer's submission. Specifically, the Committee discussed whether the estimated colectomy rates following the use of ciclosporin were in line with those observed in clinical practice. The Committee was aware that these rates with ciclosporin might have been overestimated in the manufacturer's submission, resulting in underestimation of the clinical benefit of ciclosporin and overestimation of the clinical effect of infliximab. The Committee also appreciated that comparative colectomy rates for infliximab and ciclosporin were important in the cost-effectiveness analysis. The Committee concluded that, while noting the concerns of the clinical specialists, ciclosporin was the most appropriate comparator for infliximab in this setting. The Committee also considered the views of patients about the potential adverse effects associated with drug treatments for acute severe ulcerative colitis, and their need to receive full information about these options.|
|4.6||The clinical specialists advised the Committee that, of those people with acute severe ulcerative colitis, approximately half would, with medical management (infliximab or ciclosporin), avoid colectomy in the short term (that is, during the course of the initial hospital admission) and approximately one quarter would avoid it in the long term. The Committee also discussed how appropriate it was to include the comparison of ciclosporin with corticosteroids in newly treated acute ulcerative colitis in the manufacturer's submission in the synthesis of relative treatment effects; both the population (people in whom a course of corticosteroids had not yet been tried) and the comparator (intravenous corticosteroids) studied in this trial differed from those in the other clinical trials included in the synthesis. The Committee agreed with the ERG that the inclusion of the comparison of ciclosporin with corticosteroids was inappropriate in this case. Because of the lack of any direct comparison between infliximab and ciclosporin, the Committee considered that the comparative effectiveness of ciclosporin and infliximab in acute ulcerative colitis was subject to considerable uncertainty and that it could not estimate the true clinical effectiveness of infliximab relative to ciclosporin based on the evidence available. The Committee concluded that there was insufficient evidence to assume a clinical benefit of infliximab over ciclosporin and was persuaded by the clinical specialists that the colectomy rates with the two drugs were likely to be similar.|
|4.7||The Committee considered the economic analysis presented by the manufacturer and noted that the manufacturer's base-case analysis suggested that the ICER for infliximab relative to ciclosporin was £18,400 per QALY gained. However, the Committee also noted that when the ERG made corrections to the model and excluded the study they considered inappropriate from the analysis of relative effectiveness, the ICER rose to £48,400 per QALY gained. The Committee agreed that the ERG reanalysis represented a more accurate reflection of the cost effectiveness of infliximab relative to ciclosporin.|
|4.8||The Committee appreciated that the cost effectiveness of infliximab would be sensitive to the number of doses given. It noted that the economic analysis presented by the manufacturer assumed that all patients received the full induction course of three doses even if they underwent urgent colectomy. The Committee believed that the average course would be fewer than three doses because those who underwent colectomy would not receive further infliximab, and some people would discontinue treatment for other reasons. The Committee noted that if the average number of doses of infliximab were reduced from three to two and a half, while keeping the initial colectomy rates used in the model constant, then the ICER for the comparison with ciclosporin would fall from over £48,000 to approximately £33,000 per QALY gained; if the number of doses was assumed to be two then the ICER for infliximab compared with ciclosporin was approximately £20,000 per QALY gained. However, the Committee considered that on the evidence available to it the actual average number of doses used in clinical practice was uncertain.|
|4.9||The Committee also noted that there was considerable uncertainty around the ICERs, in that the univariate sensitivity analyses for the comparison of infliximab with ciclosporin resulted in ICERs ranging from £1400 to £64,500. The former occurred when all responders were assumed to continue in remission with no colectomy after the first year, and the latter when all patients were assumed to undergo colectomy within the first cycle of the economic model (0–3 months) after the first year. In addition, the Committee noted that the failure to include adverse events and mortality in the manufacturer's economic analyses increased the uncertainty around the cost-effectiveness estimates. Because the available evidence did not show infliximab to be more clinically and cost effective than ciclosporin, the Committee felt unable to recommend it as a treatment option in people for whom ciclosporin is suitable. The Committee stated that further research is needed in order to establish a more accurate representation of the relative clinical and cost effectiveness of infliximab and ciclosporin. The Committee therefore concluded that using infliximab in research would reduce this uncertainty.|
|4.10||The Committee heard from the clinical specialists that some patients requiring treatment for acute ulcerative colitis would have concurrent conditions that may mean that ciclosporin was contraindicated. These conditions include abnormal renal function, uncontrolled hypertension and uncontrolled infections. The Committee noted that for these patients the comparison of infliximab with ciclosporin was not relevant. The Committee noted that the ICER for infliximab relative to standard care from the manufacturer's submission was £11,600 per QALY gained and the ICER relative to surgery was £13,400 per QALY gained. Even after the ERG corrections to the model, these ICERs were similar; £12,300 and £14,400 per QALY gained for infliximab compared with standard care or immediate surgery, respectively. The Committee concluded that infliximab would be a cost-effective use of NHS resources in the circumstances in which ciclosporin is contraindicated.|
|5.1||The Healthcare Commission assesses the performance of NHS organisations in meeting core and developmental standards set by the Department of Health in ‘Standards for better health' issued in July 2004. The Secretary of State has directed that the NHS provides funding and resources for medicines and treatments that have been recommended by NICE technology appraisals normally within 3 months from the date that NICE publishes the guidance. Core standard C5 states that healthcare organisations should ensure they conform to NICE technology appraisals.|
|5.2||Standard 12a requires healthcare organisations to ensure that patients and service users are provided with effective treatment and care that conforms to NICE technology appraisal guidance. The Assembly Minister for Health and Social Services issued a Direction in October 2003 that requires local health boards and NHS trusts to make funding available to enable the implementation of NICE technology appraisal guidance, normally within 3 months.|
NICE has developed tools to help organisations implement this guidance (listed below). These are available on our website (www.nice.org.uk/TAXXX). [NICE to amend list as needed at time of publication]
|6||Proposed recommendations for further research|
|6.1||The Committee recommended that a direct comparison should be conducted between infliximab and ciclosporin exploring the clinical effectiveness of the two therapies in the treatment of acute exacerbations of severely active ulcerative colitis.|
The Committee noted that there are two ongoing studies relevant to this guidance:
|7||Related NICE guidance|
|Infliximab for subacute manifestations of ulcerative colitis. NICE technology appraisal guidance 140 (2008). Available from www.nice.org.uk/TA140|
|8||Proposed date for review of guidance|
|8.1||The review date for a technology appraisal refers to the month and year in which the Guidance Executive will consider whether the technology should be reviewed. This decision will be taken in the light of information gathered by the Institute, and in consultation with consultees and commentators.|
|8.2||It is proposed that the guidance on this technology is considered for review in July 2011.|
Chair, Appraisal Committee
|Appendix A. Appraisal Committee members and NICE project team|
|A||Appraisal Committee members|
The Appraisal Committee is a standing advisory committee of the Institute. Its members are appointed for a 3-year term. A list of the Committee members who took part in the discussions for this appraisal appears below. The Appraisal Committee meets three times a month except in December, when there are no meetings. The Committee membership is split into three branches, each with a chair and vice chair. Each branch considers its own list of technologies, and ongoing topics are not moved between the branches.
Committee members are asked to declare any interests in the technology to be appraised. If it is considered there is a conflict of interest, the member is excluded from participating further in that appraisal.
The minutes of each Appraisal Committee meeting, which include the names of the members who attended and their declarations of interests, are posted on the NICE website.
Professor A E Ades
Dr Amanda Adler
Ms Anne Allison
Dr Tom Aslan
Professor David Barnett (Chair)
Dr Matt Bradley
Mrs Elizabeth Brain
Mrs Fiona Duncan
Mr John Goulston
Professor Philip Home (Vice Chair)
Dr Vincent Kirkbride
Dr Alec Miners
Dr Rubin Minhas
Dr Ann Richardson
Mrs Angela Schofield
Mr Mike Spencer
Dr Simon Thomas
Mr David Thomson
Ms Eleanor Grey
|B||NICE project team|
Each technology appraisal is assigned to a team consisting of one or more health technology analysts (who act as technical leads for the appraisal), a technical adviser and a project manager.
|Appendix B. Sources of evidence considered by the Committee|
The Evidence Review Group (ERG) report for this appraisal was prepared by Department of Public Health and Epidemiology University of Birmingham.
|B||The following organisations accepted the invitation to participate in this appraisal. They were invited to comment on the draft scope, the ERG report and the appraisal consultation document (ACD). Organisations listed in I were also invited to make written submissions. Organisations listed in II and III had the opportunity to give their expert views. Organisations listed in I, II and III have the opportunity to appeal against the final appraisal determination.|
Professional/specialist and patient/carer groups:
Commentator organisations (did not provide written evidence and without the right of appeal)
The following individuals were selected from clinical specialist and patient advocate nominations from the non-manufacturer/sponsor consultees and commentators. They gave their expert personal view on infliximab for the treatment of acute exacerbations of ulcerative colitis by providing oral evidence to the Committee. They are invited to comment on the ACD.
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