Guideline:Infliximab for acute exacerbations of ulcerative colitis. Measure Summary

Ulcerative colitis

Note: For subacute manifestations of ulcerative colitis, see the National Guideline Clearinghouse (NGC) summary of the National Institute for Health and Clinical Excellence (NICE) guidance on infliximab.

To evaluate the clinical effectiveness and cost-effectiveness of infliximab for acute exacerbations of ulcerative colitis

Hospitalized patients in the United Kingdom with acute exacerbations of severely active ulcerative colitis in whom ciclosporin is contraindicated or clinically inappropriate, based on a careful assessment of the risks and benefits of treatment in the individual patient

Infliximab within its marketing authorisation

Note from the National Guideline Clearinghouse (NGC): The National Institute for Health and Clinical Excellence (NICE) commissioned an independent academic centre to perform a systematic literature review on the technology considered in this appraisal and prepare an Evidence Review Group (ERG) report. The ERG report for this technology appraisal was prepared by the Department of Public Health and Epidemiology, University of Birmingham (see the "Availability of Companion Documents" field.)

Clinical Effectiveness

Critique of Manufacturer's Approach

This is based on a formal critical appraisal recorded in Appendix 1. Two additional appraisals (Appendices 2 & 3) were conducted on two Cochrane reviews which appeared to have informed the manufacturer review of clinical evidence. The four key studies used in the manufacturer's approach were reappraised and the abstracted data rechecked as documented in Appendices 4-7. Finally the mixed treatment comparison model, for which specific code was provided by the manufacturer, was re-run.

For Appendices 1-7 refer to the ERG report (see the "Availability of Companion Documents" field.)

Description of Manufacturer's Search Strategy and Comment on Whether the Search Strategy Was Appropriate

For infliximab the search strategy of both the submission and the underlying Cochrane review were strong with respect to published data, but possibly slightly limited with respect to unpublished data. For ciclosporin the search strategy was weaker. The terms used to search MEDLINE and EMBASE for the economic evaluation were limited and a syntax error was noted. The ERG verified search strategies and checked for on-going studies. No additional included randomised controlled trials (RCTs) for either infliximab or ciclosporin were identified. The ERG identified one additional on-going trial. This is based in the UK and is comparing infliximab with ciclosporin in steroid-refractory acute severe ulcerative colitis in hospitalised patients.

Statement of the Inclusion/Exclusion Criteria Used in the Study Selection and Comment on Whether They Were Appropriate

The main inclusion/exclusion criteria for the submission were RCTs of infliximab and ciclosporin in patients with acute severe ulcerative colitis in hospitalised patients. This was felt by the ERG to be appropriate as the main evidence base for this single technology appraisal (STA).

In addition, non-randomised interventional studies and observational studies were sought. However, this was only done for infliximab. Given that observational studies tend to present exaggerated estimates of effect, the overall impression created by identifying case-series for infliximab, but not for ciclosporin, may be to over-state the effectiveness of infliximab relative to ciclosporin.

Economic Evaluation

Overview of Manufacturer's Economic Evaluation

The manufacturer identified no published economic evaluations of infliximab in ulcerative colitis, and this finding is supported by the ERG's own literature search. Thus, the report of the cost-effectiveness work focused entirely on the de novo model and economic evaluation undertaken by the manufacturer.

Clinical Effectiveness

• Infliximab: Two randomized controlled trials (RCTs) and a number of case-series were included.
• Ciclosporin: Two randomized controlled trials (RCTs) were included.

Cost-Effectiveness

A manufacturer's model was submitted.

Not applicable

Note from the National Guideline Clearinghouse (NGC): The National Institute for Health and Clinical Excellence (NICE) commissioned an independent academic centre to perform a systematic literature review on the technology considered in this appraisal and prepare an Evidence Review Group (ERG) report. The ERG report for this technology appraisal was prepared by the Department of Public Health and Epidemiology, University of Birmingham (see the "Availability of Companion Documents" field.)

Clinical Effectiveness

Description and Critique of Manufacturer's Approach to Validity Assessment

The submission used an early version of the Jadad score to assess validity of the included randomised controlled trials (RCTs), focusing particularly on allocation concealment of the randomisation. This is a well recognised approach and appears to have been reasonably conducted despite the handicap of being conducted by a single reviewer. In contrast there was very little assessment of the validity of the included case-series for infliximab. It is one reason why the results of this component of submission should receive little emphasis in drawing overall conclusions on effectiveness because openness to bias of such study designs does not appear to have been carefully considered.

Describe and Critique the Statistical Approach Used

The summary of the results is weak.

The submission relies on a mixed treatment comparison (MTC) model to provide quantified summary estimates of effect, particularly of colectomy rates to use in the cost-effectiveness model. They claim they have not done meta-analysis, ignoring the fact that the mixed treatment comparison model has achieved the same aim.

The ERG has re-run the MTC model using the code provided by the manufacturer and has obtained the same numerical estimates. However the main concern is the face validity of the results, which bear little relation to actual estimates of effect obtained in the original trials. This is illustrated in tables 1, 2, and 3 of the ERG report (see the "Availability of Companion Documents" field) where the results of the original trials expressed as events rates and odds ratios are tabulated alongside the outputs of the MTC.

A particular example of the mismatch generated by use of the MTC is the 0-3 month colectomy event rates shown in table 1 of the ERG report (see the "Availability of Companion Documents" field). The actual event rates in the trials were 0.27 and 0.21; the event rate predicted by the MTC, and the event used in the economic modelling, was 0.58. The lack of face validity not only undermines the credibility of the model in summarising the available data and making an estimate of the unmeasured effect of infliximab relative to ciclosporin, but also challenges the validity of the effectiveness parameters used in the economic model, which are already challenged by the inclusion of the data by D'Haens et al., a study which measures a different effect.

The ERG re-ran the model without the D'Haens et al. RCT. This resulted in some changes indicated in table 4 of the ERG report (see the "Availability of Companion Documents" field).

The exclusion of D'Haens reduces the estimated colectomy rates for ciclosporin to some extent from 0.58 to 0.48, but these colectomy rates at 0-3 months are still much higher than would be expected in practice, and still far exceed the rate observed in the remaining ciclosporin RCT by Lichtiger et al.  (0.27)

The exclusion of D'Haens et al. from the MTC also means that no rates can be derived for 3-12 months as it is the only study contributing data for ciclosporin over this period.

Refer to Sections 4.1 and 4.2 of the ERG report (see the "Availability of Companion Documents" field) for more information.

Economic Evaluation

Model Validation

Model validation processes were described by the manufacturer and included the following:

• The model structure and content were approved by a panel of UK gastroenterologists and 'external consultants'.
• Predictive validity was assessed through comparison of the patient flows in the model with those observed in the relevant trials. For longer-term outcomes the data was very limited given the short-term nature of the trials.

Critique of Approach Used

Sensitivity Analysis

The univariate sensitivity analysis has very helpfully explored the robustness of results to variation in some of the key parameters. It has highlighted the importance of both the patient weight and the timeframe of the analysis as two important issues that drive the model result. However, the central driver of the model is the colectomy rates (in the short and medium terms) associated with the alternative treatment strategies, and these have not been varied as part of the univariate analyses.

The probabilistic sensitivity analysis (PSA) has been undertaken in a very partial manner, with distributions placed around selected parameters only. The level of uncertainty in the model results is therefore underestimated for this technology.

Refer to Sections 5.1 and 5.2 of the ERG report (see the "Availability of Companion Documents" field) for more information.

Considerations

Technology appraisal recommendations are based on a review of clinical and economic evidence.

Technology Appraisal Process

The National Institute for Health and Clinical Excellence (NICE) invites 'consultee' and 'commentator' organisations to take part in the appraisal process. Consultee organisations include national groups representing patients and carers, the bodies representing health professionals, and the manufacturers of the technology under review. Consultees are invited to submit evidence during the appraisal and to comment on the appraisal documents.

Commentator organisations include manufacturers of the products with which the technology is being compared, the National Health Service (NHS) Quality Improvement Scotland and research groups working in the area. They can comment on the evidence and other documents but are not asked to submit evidence themselves.

NICE then commissions an independent academic centre to review published evidence on the technology and prepare an 'assessment report'. Consultees and commentators are invited to comment on the report. The assessment report and the comments on it are then drawn together in a document called the evaluation report.

An independent Appraisal Committee then considers the evaluation report. It holds a meeting where it hears direct, spoken evidence from nominated clinical experts, patients and carers. The Committee uses all the evidence to make its first recommendations, in a document called the 'appraisal consultation document' (ACD). NICE sends all the consultees and commentators a copy of this document and posts it on the NICE website. Further comments are invited from everyone taking part.

When the Committee meets again it considers any comments submitted on the ACD; then it prepares its final recommendations in a document called the 'final appraisal determination' (FAD). This is submitted to NICE for approval.

Consultees have a chance to appeal against the final recommendations in the FAD. If there are no appeals, the final recommendations become the basis of the guidance that NICE issues.

Who is on the Appraisal Committee?

NICE technology appraisal recommendations are prepared by an independent committee. This includes health professionals working in the NHS and people who are familiar with the issues affecting patients and carers. Although the Appraisal Committee seeks the views of organisations representing health professionals, patients, carers, manufacturers and government, its advice is independent of any vested interests.

Not applicable

The Evidence Review Group (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.

The base-case cost-effectiveness estimates presented in the manufacturer's submission were 11,589 pounds sterling per additional quality-adjusted life year (QALY) gained for infliximab compared with standard care; 18,425 pounds sterling per additional QALY gained for infliximab compared with ciclosporin; and 13,407 pounds sterling per additional QALY gained for infliximab compared with surgery. These incremental cost-effectiveness ratios (ICERs) after minor   corrections by the ERG rose to 12,307 pounds sterling, 19,922 pounds sterling and 14,427 pounds sterling, respectively. When the ERG excluded the study by D'Haens and coworkers (which the ERG considered was included in the analysis inappropriately), the ICER for infliximab versus ciclosporin increased considerably from 19,922 pounds sterling to 48,367 pounds sterling per QALY gained.

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 pounds sterling 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 the effectiveness of ciclosporin for the first 3 months, the ICER rose to 48,400 pounds sterling per QALY gained. The Committee observed that in this analysis, the estimate of the colectomy rate during months 4–12 following ciclosporin treatment had been taken from the study that had been excluded. The Committee was aware that there was no alternative estimate of this parameter and therefore considered the effect that varying this parameter had on the estimate of effectiveness. They noted sensitivity analyses presented by the manufacturer showing that when a high value of the colectomy rate was assumed (0.48), the ICER for infliximab versus ciclosporin was reduced (9300 pounds sterling per QALY) and conversely when a low value was assumed (0.143) the ICER increased (52,000 pounds sterling per QALY). The Committee considered that it was extremely unlikely that the colectomy rate during months 4–12 would be as high as 0.48, recalling their earlier discussions with the clinical experts that suggested that those patients who did not respond to ciclosporin would be likely to have a colectomy within the first few weeks following presentation. The Committee agreed that the lower estimates of colectomy rate during months 4–12 were more likely, and that the ERG reanalysis giving an ICER of 48,400 pounds sterling per QALY represented the best available reflection of the cost effectiveness of infliximab relative to ciclosporin.

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 was 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 pounds sterling to approximately 33,000 pounds sterling 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 pounds sterling 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.

The Committee heard from the clinical specialists that some patients requiring treatment for acute ulcerative colitis would have other conditions that may mean that ciclosporin was contraindicated or inappropriate. The Committee was persuaded that there could be situations in which clinicians and patients judged that the potential risks from using ciclosporin in acute ulcerative colitis outweighed the likely clinical benefits. The Committee noted that in those situations, the ICER for infliximab relative to standard care from the manufacturer's submission was 11,600 pounds sterling per QALY gained and the ICER relative to immediate surgery was 13,400 pounds sterling per QALY gained. Even after the ERG corrections to the model, these ICERs were similar: 12,300 pounds sterling and 14,400 pounds sterling per QALY gained, respectively. The Committee concluded that infliximab would be a cost-effective use of National Health Service (NHS) resources if ciclosporin is contraindicated or clinically inappropriate based on an assessment of the risks and benefits.

Refer to Sections 3 and 4 of the original guideline document for details of the economic analyses provided by the manufacturer, the ERG comments, and the Appraisal Committee considerations.

Consultee organizations from the following groups were invited to comment on the draft scope, Assessment Report and the Appraisal Consultation Document (ACD) and were provided with the opportunity to appeal against the Final Appraisal Determination.

• Manufacturer/sponsors
• Professional/specialist and patient/carer groups
• Commentator organisations (without the right of appeal)

In addition, individuals selected from clinical expert and patient advocate nominations from the professional/specialist and patient/carer groups were also invited to comment on the ACD.

This guidance relates only to the use of infliximab within its marketing authorisation, for the treatment of acute exacerbations of severely active ulcerative colitis. It relates to an induction course of three doses of infliximab.

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 or clinically inappropriate, based on a careful assessment of the risks and benefits of treatment in the individual patient.

In people who do not meet the above-mentioned criterion, infliximab should only be used for the treatment of acute exacerbations of severely active ulcerative colitis in clinical trials.

None provided

The type of evidence supporting the recommendations is not specifically stated.

Appropriate use of infliximab for acute exacerbation of ulcerative colitis

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. Before starting treatment, people must be screened for both active and inactive tuberculosis. The Summary of Product Characteristics (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.

Infliximab is contraindicated in people with moderate or severe heart failure and active infections.

For full details of side effects and contraindications, see the Summary of Product Characteristics (SPC).

Not applicable: The guideline was not adapted from another source.

National Institute for Health and Clinical Excellence (NICE)

Appraisal Committee

Committee Members: Professor A E Ades, Professor of Public Health Science, Department of Community Based Medicine, University of Bristol; Dr Amanda Adler, Consultant Physician, Cambridge University Hospitals Trust; Ms Anne Allison, Nurse Clinical Adviser, Healthcare Commission; Dr Tom Aslan, General Practitioner, The Hampstead Group Practice, London; Professor David Barnett (Chair), Professor of Clinical Pharmacology, Leicester Royal Infirmary; Dr Matt Bradley, Head of HTA and Business Environment, Sanofi-Aventis; Mrs Elizabeth Brain, Lay Member; Mr David Chandler, Lay Member; Dr Karl Claxton, Professor of Health Economics, Department of Economics & Related Research, the University of York; Dr Simon Dixon, Reader in Health Economics, University of Sheffield; Mrs Fiona Duncan, Clinical Nurse Specialist, Anaesthetic Department, Blackpool Victoria Hospital, Blackpool; Dr Paul Ewings, Statistician, Taunton & Somerset NHS Trust, Taunton; Mr John Goulston, Chief Executive, Barking, Havering and Redbridge Hospitals NHS Trust; Ms Eleanor Grey, Lay Member; Dr Richard Harling, Director of Public Health, Worcestershire PCT and Worcestershire County Council; Professor Philip Home (Vice Chair), Professor of Diabetes Medicine, Newcastle University; Dr Vincent Kirkbride, Consultant Neonatologist, Regional Neonatal Intensive Care Unit, Sheffield; Dr Simon Maxwell, Senior Lecturer in Clinical Pharmacology and Honorary Consultant Physician, Queens Medical Research Institute, University of Edinburgh; Dr Alec Miners, Lecturer in Health Economics, London School of Hygiene and Tropical Medicine; Dr Rubin Minhas, General Practitioner; Dr Ann Richardson, Lay Member; Mrs Angela Schofield, Chairman, Bournemouth and Poole Teaching PCT; Mr Mike Spencer, General Manager, Facilities and Clinical Support Services, Cardiff and Vale NHS Trust; Mr Cliff Snelling, Lay Member; Dr Simon Thomas, Consultant Physician and Reader in Therapeutics, Newcastle Hospitals NHS Foundation Trust and Newcastle University; Mr David Thomson, Lay Member; Mr William Turner, Consultant Urologist, Addenbrooke's Hospital; Dr Norman Vetter, Reader, Department of Primary Care and Public Health, School of Medicine, University of Cardiff

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.

This is the current release of the guideline.

Electronic copies: Available in Portable Document Format (PDF) format from the National Institute for Health and Clinical Excellence (NICE) Web site .

The following are available:

• Infliximab for acute exacerbations of ulcerative colitis. Quick reference guide. London (UK): National Institute for Health and Clinical Excellence (NICE); 2008 Dec. 2 p. (Technology appraisal 163). Available in Portable Document Format (PDF) from the National Institute for Health and Clinical Excellence (NICE) Web site .
• Infliximab for acute exacerbations of ulcerative colitis. Costing statement. London (UK): National Institute for Health and Clinical Excellence (NICE); 2008 Dec. 2 p. (Technology appraisal 163). Available in Portable Document Format (PDF) from the NICE Web site .
• Infliximab for acute exacerbations of ulcerative colitis. Audit support. London (UK): National Institute for Health and Clinical Excellence (NICE); 2008. 5 p. (Technology appraisal 163). Available in Portable Document Format (PDF) from the NICE Web site .
• Infliximab for the treatment of acute exacerbations of ulcerative colitis. Evidence review group report. London (UK): National Institute for Health and Clinical Excellence (NICE); 2008 Jun. 120 p. (Technology appraisal 163). Available in Portable Document Format (PDF) from the NICE Web site .

The following is available:

• Infliximab for acute ulcerative colitis. Understanding NICE guidance - Information for people who use NHS services. London (UK): National Institute for Health and Clinical Excellence (NICE); 2008 Dec. 4 p. (Technology appraisal 163). Available in Portable Document Format (PDF) from the National Institute for Health and Clinical Excellence (NICE) Web site .

Please note: This patient information is intended to provide health professionals with information to share with their patients to help them better understand their health and their diagnosed disorders. By providing access to this patient information, it is not the intention of NGC to provide specific medical advice for particular patients. Rather we urge patients and their representatives to review this material and then to consult with a licensed health professional for evaluation of treatment options suitable for them as well as for diagnosis and answers to their personal medical questions. This patient information has been derived and prepared from a guideline for health care professionals included on NGC by the authors or publishers of that original guideline. The patient information is not reviewed by NGC to establish whether or not it accurately reflects the original guideline's content.

This NGC summary was completed by ECRI Institute on August 18, 2008. This summary was updated by ECRI Institute on October 12, 2011 following the U.S. Food and Drug Administration (FDA) advisory on Tumor Necrosis Factor-alpha (TNFα) Blockers.

The National Institute for Health and Clinical Excellence (NICE) has granted the National Guideline Clearinghouse (NGC) permission to include summaries of their Technology Appraisal guidance with the intention of disseminating and facilitating the implementation of that guidance. NICE has not verified this content to confirm that it accurately reflects the original NICE guidance and therefore no guarantees are given by NICE in this regard. All NICE technology appraisal guidance is prepared in relation to the National Health Service in England and Wales. NICE has not been involved in the development or adaptation of NICE guidance for use in any other country. The full versions of all NICE guidance can be found at www.nice.org.uk .

This NGC summary is based on the original guideline, which is subject to the guideline developer's copyright restrictions.